app203836 novellus fungicide - epa

SCIENCE MEMO

APP203836 – NOVELLUS FUNGICIDE

MAY 2020

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Science memo for application to import or manufacture NOVELLUS FUNGICIDE for release (APP203836)

MAY 2020

Standard terms and abbreviations

Abbreviation Definition

ai active ingredient

ADE Acceptable Daily Exposure

ADI Acceptable Daily Intake

AOEL Acceptable Operator Exposure Level

BBCH Biologische Bundesanstalt, Bundessortenamt und CHemische Industrie

BCF BioConcentration Factor

Bw body weight

CAS # Chemical Abstract Service Registry Number

cm centimetres

CoA Certificate of Analysis

CRfD Chronic Reference Dose

CS Capsule Suspension

DDD Daily Dietary Dose

DT50 Dissipation Time (days) for 50% of the initial residue to be lost

dw dry weight

EbC50 EC50 with respect to a reduction of biomass

EC European Commission

EC25 Effective Concentration at which an observable adverse effect is caused in 25 %

of the test organisms

EC50 Effective Concentration at which an observable adverse effect is caused in 50 %

of the test organisms

EEC Estimated Environmental Concentration

EEL Environmental Exposure Limit

EFSA European Food Safety Authority

ErC50 EC50 with respect to a reduction of growth rate (r)

ER50 Effective Residue concentration to 50% of test organisms

FAO Food and Agriculture Organization

g grams

GAP Good Agricultural Practice

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GENEEC Generic Estimated Environmental Concentration

ha hectare

HQ Hazard Quotient

Kd partition (distribution) coefficient

Koc organic carbon adsorption coefficient

Kow octanol water partition coefficient

Kg Kilogram

L litres

Lb pounds

LC50 Lethal Concentration that causes 50% mortality

LD50 Lethal Dose that causes 50% mortality

LOAEC Lowest Observable Adverse Effect Concentration

LOAEL Lowest Observable Adverse Effect Level

LOC Level Of Concern

LOD Limit Of Detection

LOEC Lowest Observable Effect Concentration

LOEL Lowest Observable Effect Level

LR50 Lethal Rate that causes 50% mortality

M Molar

m3 cubic metre

MAF Multiple Application Factor

μm micrometre (micron)

mg milligram

μg microgram

mol mole(s)

MSDS Material Safety Data Sheet

NAEL No Adverse Effect Level

ng nanogram

NOAEC No Observed Adverse Effect Concentration

NOAEL No Observed Adverse Effect Level

NOEC No Observed Effect Concentration

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NOEL No Observed Effect Level

OECD Organisation for Economic Cooperation and Development

PDE Potential Daily Exposure

PEC Predicted Environmental Concentration

PHI Pre-Harvest Interval

pKa Acid dissociation constant (base 10 logarithmic scale)

PNEC Predicted No Effect Concentration

POW Partition coefficient between n-octanol and water

ppb parts per billion (10-9)

PPE Personal Protective Equipment

ppm parts per million (10-6)

REI Restricted Entry Interval

RPE Respiratory Protective Equipment

RQ Risk Quotient

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Executive Summary

The applicant EDEN Research PLC has submitted an application on 8 April 2019 to import or manufacture

NOVELLUS FUNGICIDE for release. It was given Application Number APP203836 and was formally

received on 2 July 2019 as a Category B application.

All three active ingredients are essential oils commonly found in plants. Eugenol is naturally occurring in the

environment, being found in many plant extracts (in particular, cloves and clove oil, where it constitutes up to

80% dry matter). Geraniol is a plant oil, which is found naturally in the environment in a variety of fruits,

vegetables, herbs and spices. Geraniol is one of the main components found in citronella oil and is a

naturally occurring terpene substance synthesized by a wide range of plants. Thymol is a plant oil, which is

found naturally in the environment in a variety of fruits, vegetables and herbs. All three active ingredients

have been approved in the European Union as fungicides. 3EAY (=Novellus Fungicide) was the

representative formulation for the assessment of eugenol (EC 2011a), geraniol (EC 2011b) and thymol (EC

2011c) with the same use pattern being considered (fungicide for the control of Botrytis cinerea on grapes)

Mammalian toxicity studies with NOVELLUS FUNGICIDE indicate that the substance is not classified for

acute toxicity (oral, dermal or inhalation). The substance is not irritating to the skin but is an irritant to the

eyes (6.4A), and is not a contact sensitiser. Data available on the formulation and on the active ingredients

indicate that the substance can be classified as 9.1D.

It is considered that there is potential for significant exposure to people and the environment during the use

phase of the lifecycle of NOVELLUS FUNGICIDE. As such, quantitative risk assessments have been

undertaken to understand the likely exposures to the substance under the use conditions proposed by the

applicant, using the endpoint data available and the standard risk assessment methodologies used by the

EPA

It is considered that the risks to human health from the proposed use of NOVELLUS FUNGICIDE are

acceptable even without the use of appropriate Personal Protective Equipment (PPE). There is no need for

an application of a re-entry interval control or a need for a buffer zone to protect bystanders

It is considered that the risks to the environment from the proposed use of NOVELLUS FUNGICIDE are

acceptable with the proposed controls

A set of controls have been proposed for NOVELLUS FUNGICIDE, and are detailed under section 6.

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Table of Contents

APP203836 – NOVELLUS FUNGICIDE ................................................................................................. 1

Standard terms and abbreviations ...................................................................................................... 2

Executive Summary .............................................................................................................................. 5

Table of Contents .................................................................................................................................. 6

1. Introduction/Background ........................................................................................................... 9

2. Hazardous properties ............................................................................................................... 11

Hazard classification of NOVELLUS FUNGICIDE ...................................................................... 11

3. Risk assessment context ......................................................................................................... 11

4. Human health risk assessment................................................................................................ 12

5. Environmental risk assessment .............................................................................................. 12

6. Proposed controls ..................................................................................................................... 14

Application rate ............................................................................................................................ 14

Application method ...................................................................................................................... 14

Impurities ..................................................................................................................................... 14

Appendix A: Identity of the active ingredient, use pattern and mode of action ........................... 15

Regulatory status ........................................................................................................................ 15

Impurities and or restrictions on purity or composition ................................................................ 15

Use pattern and mode of action .................................................................................................. 16

Use pattern ........................................................................................................................ 16

Mode of action ................................................................................................................... 16

Table 3: List of intended uses for NOVELLUS FUNGICIDE............................................. 17

Appendix B: Physico-chemical properties of NOVELLUS FUNGICIDE ......................................... 18

Appendix C: Mammalian toxicology .................................................................................................. 19

Executive summaries and list of endpoints for NOVELLUS FUNGICIDE .................................. 19

Appendix D: Environmental fate ........................................................................................................ 20

Executive summaries and list of endpoints ................................................................................. 20

Residues relevant to the environment ......................................................................................... 20

Degradation and fate of eugenol, geraniol and thymol in aquatic environments ........................ 20

Degradation and fate of eugenol, geraniol and thymol in soil ..................................................... 21

Fate and behaviour of eugenol, geraniol and thymol in air ......................................................... 26

General conclusion about environmental fate ............................................................................. 26

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Appendix E: Ecotoxicity ..................................................................................................................... 29

Executive summaries and list of endpoints ................................................................................. 29

Aquatic toxicity ............................................................................................................................ 29

Uncertainties and data gaps ............................................................................................. 33

General conclusion about aquatic toxicity......................................................................... 33

Soil toxicity................................................................................................................................... 34


General conclusion about soil toxicity ............................................................................... 36


General conclusion about ecotoxicity to terrestrial vertebrates ........................................ 37

Ecotoxicity to bees and other terrestrial invertebrates ................................................................ 37


General conclusion about ecotoxicity to bees and terrestrial invertebrate toxicity 39

Appendix F: Hazard classification of NOVELLUS FUNGICIDE ....................................................... 40

Appendix G: Human health risk assessment ................................................................................... 43

Qualitative risk assessment ......................................................................................................... 43

Quantitative risk assessment ...................................................................................................... 43

Input values for the human health risk assessment .......................................................... 43

Operator exposure assessment ........................................................................................ 45

Re-entry worker exposure assessment ............................................................................ 46

Quantitative bystander risk assessment ........................................................................... 46

Conclusions of the human health risk assessment ........................................................... 47

Appendix H: Environmental risk assessment .................................................................................. 48

Applicant’s environmental risks assessment ............................................................................... 48

Evaluation of toxicity of the mixture ............................................................................................. 48

Aquatic risk assessment .............................................................................................................. 48

Calculation of expected environmental concentrations .................................................... 48

Output from the GENEEC2 model .................................................................................... 50

Eugenol ............................................................................................................................. 50

Geraniol ............................................................................................................................. 50

Thymol............................................................................................................................... 51

Calculated risk quotients ................................................................................................... 51

Conclusions of the aquatic risk assessment ..................................................................... 53

Groundwater risk assessment ..................................................................................................... 53

Conclusions of the groundwater risk assessment ............................................................ 54

Sediment risk assessment .......................................................................................................... 54

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Terrestrial risk assessment ......................................................................................................... 54

Soil macro-organisms ....................................................................................................... 54

Soil micro-organisms ......................................................................................................... 56

Conclusions of the soil organism risk assessment ........................................................... 56

Non-target plant risk assessment ................................................................................................ 56

Conclusion for non-target plant risk assessment .............................................................. 57

Bird risk assessment ................................................................................................................... 57

Screening assessment ...................................................................................................... 57

Secondary poisoning ......................................................................................................... 58

Conclusions for bird risk assessment ............................................................................... 58

Pollinator risk assessment ........................................................................................................... 58

Conclusions of the pollinator risk assessment .................................................................. 59

Non-target arthropod risk assessment ........................................................................................ 60

Conclusion for non-target arthropod risk assessments .................................................... 61

Conclusions of the ecological risk assessment ........................................................................... 61

Appendix I: Study summaries ............................................................................................................ 63

Toxicity study summaries ............................................................................................................ 63

Mammalian toxicology - Robust study summaries for NOVELLUS FUNGICIDE ............. 64

Environmental fate studies .......................................................................................................... 73

Appendix J: References ...................................................................................................................... 89

Appendix K: Confidential Composition ............................................................................................ 90

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1. Introduction/Background

1.1. This application is to import or manufacture NOVELLUS FUNGICIDE for release.

1.2. NOVELLUS FUNGICIDE is a capsule suspension (CS) containing the active ingredients eugenol at

33 g/L, geraniol at 66 g/L and thymol at 66 g/L, plus other components.

1.3. NOVELLUS FUNGICIDE is intended to be used as a fungicide on grapes for the control of grey

mould/bunch rot (Botrytis cinerea) at the maximum use rate of 0.13 kg eugenol/ha, 0.26 kg geraniol/ha

and 0.26 kg thymol/ha.

1.4. All three active ingredients are essential oils commonly found in plants. Eugenol is naturally occurring

in the environment, being found in many plant extracts (in particular, cloves and clove oil, where it

constitutes up to 80% dry matter). Geraniol is a plant oil, which is found naturally in the environment in

a variety of fruits, vegetables, herbs and spices. Geraniol is one of the main components found in

citronella oil and is a naturally occurring terpene substance synthesized by a wide range of plants.

Thymol is a plant oil, which is found naturally in the environment in a variety of fruits, vegetables and

herbs. All three active ingredients have been approved in the European Union as fungicides. 3EAY

(=Novellus Fungicide) was the representative formulation for the assessment of eugenol (EC 2011a),

geraniol (EC 2011b) and thymol (EC 2011c) with the same use pattern being considered (fungicide for

the control of Botrytis cinerea on grapes)

1.5. More details about the use pattern of NOVELLUS FUNGICIDE and the regulatory status of eugenol,

geraniol and thymol can be found in Appendix A.

1.6. It is considered that there is potential for significant exposure to people and the environment during

the use phase of the lifecycle of NOVELLUS FUNGICIDE. As such, quantitative risk assessments

have been undertaken to understand the likely exposures to the substance under the use conditions

proposed by the applicant, using the endpoint data available and the standard risk assessment

methodologies used by the EPA . Full context related to the risk assessment of NOVELLUS

FUNGICIDE is given in section 3.

1.7. Physical and Chemical properties of NOVELLUS FUNGICIDE can be found in Appendix B.

1.8. Mammalian toxicological properties NOVELLUS FUNGICIDE have been reported in Appendix C.

1.9. Environmental Fate properties of the three active ingredients have been reported in Appendix D.

1.10. Ecotoxicological properties of NOVELLUS FUNGICIDE and the active ingredients have been reported

in Appendix E.

1.11. Hazard properties and classification determination of NOVELLUS FUNGICIDE derived from their

properties can be found under 2.Hazardous properties and Appendix F.

1.12. Mammalian toxicological data have subsequently been used to generate human health risk

assessment and this is detailed in Appendix G.

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1.13. Environmental Fate, Ecotoxicological and other relevant data have subsequently been used to

generate environmental risk assessment and this is detailed in Appendix H.

1.14. Relevant study summaries can be found in Appendix I.

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2. Hazardous properties

Hazard classification of NOVELLUS FUNGICIDE

2.1. The hazard classifications of NOVELLUS FUNGICIDE determined by the EPA staff are 6.4A and 9.1D

(Table 1). The hazard classifications of NOVELLUS FUNGICIDE were determined based on the

information provided by the applicant (including toxicity and ecotoxicity studies), information on the

individual components of NOVELLUS FUNGICIDE, mixture rules and other available information (EU

registration reports), Table 4 in Appendix F shows the method used for classification and indicates the

main component that contributes to each hazard classification).

Table 1: Hazard classification of NOVELLUS FUNGICIDE

Hazard EPA classification

Eye irritancy 6.4A

Aquatic ecotoxicity 9.1D

2.2. Mammalian toxicity studies with NOVELLUS FUNGICIDE indicate that the substance is not classified

for acute toxicity (oral, dermal or inhalation). The substance is not irritating to the skin but is an irritant

to the eyes (6.4A), and is not a contact sensitiser.

2.3. Data available on the formulation and on the active ingredients indicate that the substance can be

classified as 9.1D.

3. Risk assessment context

3.1. It is considered that there is potential for significant exposure to people and the environment during

the use phase of the lifecycle of NOVELLUS FUNGICIDE. As such, quantitative risk assessments

have been undertaken to understand the likely exposures to the substance under the use conditions

proposed by the applicant, using the endpoint data available and the standard risk assessment

methodologies used by the EPA (EPA 2018)

3.2. During the importation, manufacture, transportation, storage and disposal of this substance, it is

estimated that the proposed controls and other legislative requirements will sufficiently mitigate risks to

a negligible level. This assessment takes into account the existing EPA Notices around packaging,

identification and disposal of hazardous substances. In addition, the Land Transport Rule 45001, Civil

Aviation Act 1990, Maritime Transport Act 1994 and New Zealand’s Health and Safety at Work (HSW)

requirements all have provisions for the safe management of hazardous substances.

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4. Human health risk assessment

4.1. The risks from the use of eugenol, geraniol and thymol are considered as a proxy for NOVELLUS

FUNGICIDE on users and operators of the substance, re-entry workers and bystanders. Full details

can be found in Appendix G: Human health risk assessment

4.2. Operator Exposure:

Predicted operator exposures to thymol are below the Acceptable Operator Exposure Level (AOEL)

for airblast application to grapes, even without the use of personal protective equipment (PPE).

Therefore operator exposures are not expected to result in adverse health effects.

Although the quantitative risk assessment indicates that PPE is not required to ensure that exposures

are below the AOEL, the requirements under HSW (HS), and in particular Regulations 13.7 and 13.8,

state that personal protective equipment is to be used to minimise risks to the health and safety of

workers.

4.3. Worker Re-Entry:

Predicted exposures to eugenol for workers re-entering and working in areas where NOVELLUS

FUNGICIDE has been applied are below the AOEL. No re-entry intervals are necessary.

4.4. Bystanders:

Estimated bystander exposure from spray drift after application of NOVELLUS FUNGICIDE to grape

vines is below the AOEL. No buffer zone is required to protect bystanders.

4.5. Impurities:

Methyleugenol has been identified as an impurity of toxicological concern in eugenol by European

Commission (EC 2013a). It must remain below 0.1% in the active substance.

No impurities of toxicological concern have been identified in geraniol and thymol.

4.6. Overall human health conclusion:


acceptable even without the use of appropriate Personal Protective Equipment (PPE). There is no

need for an application of a re-entry interval control or a need for a buffer zone to protect bystanders.

5. Environmental risk assessment

5.1. The risks to a range of environmental receptors from the use of eugenol, thymol and geraniol are

considered as proxies for the risks from NOVELLUS FUNGICIDE. Full details can be found in

Appendix H: Environmental risk assessment

5.2. Aquatic environment:

Predicted exposure concentrations of eugenol, geraniol, and thymol, applied as NOVELLUS

FUNGICIDE to grapevines resulted in calculated acute risk quotients (RQs) below the level of concern

(LOC) for the aquatic environment. The scenario modelled for application of NOVELLUS FUNGICIDE

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to grapevines is worst-case, assuming the maximum application rate, maximum frequency of

applications and worst-case assumptions for parameters where either reliable data were not available,

or no data were available. No additional controls were determined necessary to mitigate adverse

effects to the aquatic environment

5.3. Groundwater:

For eugenol, geraniol, and thymol, the PECgw values are well below the 0.1 µg/L trigger level set by

the European regulators. The scenario modelled was worst-case using the maximum application rate,

maximum number of applications, no crop interception, and a worst-case default Koc value assuming

the active ingredients are very mobile in soil. Risks to groundwater are therefore considered below the

level of concern following application of NOVELLUS FUNGICIDE to grapevines

5.4. Sediment:

Given the assumptions made regarding likelihood of rapid volatilisation, and that all three active

substances are readily biodegradable, exposure of water/sediment systems is unlikely to be

significant. Based on the available data, toxicity of eugenol, geraniol, thymol, and the substance

NOVELLUS FUNGICIDE in the aquatic environment is low. No assessment of toxicity to sediment-

dwelling organisms for applications of NOVELLUS FUNGICIDE to grapevines was considered

necessary.

5.5. Soil organisms:

Acute toxicity exposure ratios for soil macro-organisms following application of NOVELLUS

FUNGICIDE to grapevines are below the level of concern (LOC), and no risks are expected. Risks to

soil microflora are also considered to be below the level of concern.

5.6. Non-target Plants: Information gained during the course of efficacy trials have been used to show

that effects to non-target flora were nil or negligible. This information is considered sufficient to

address any potential concerns about the phytotoxic activity of NOVELLUS FUNGICIDE to non-target

plants.

5.7. Birds:

Toxicity exposure ratios determined to assess to birds from application of NOVELLUS FUNGICIDE to

grapevines are below the level of concern, and any risks to birds are considered negligible

5.8. Pollinators:

Acute contact risks to adult honeybees are below the level of concern following application of

NOVELLUS FUNGICIDE to grapevines. The risk quotient (RQ) for acute oral toxicity to adult

honeybees is also considered below the level of concern following application of NOVELLUS

FUNGICIDE in grapevines when crop interception is taken into account. Acute risks to adult honey

bees from use of NOVELLUS FUNGICIDE are considered to be low overall

5.9. Non-target Arthropods:

Risks to non-target arthropods are below the level of concern both in-field and off-field following use of

NOVELLUS FUNGICIDE in grapevines.

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5.10. Overall Ecological risk assessment conclusion:

It is considered that the risks to the environment from the proposed use of NOVELLUS FUNGICIDE

are acceptable with the proposed controls.

6. Proposed controls

Application rate

6.1. A maximum of 0.13 kg/ha of eugenol, 0.26 kg/ha of geraniol and 0.26 kg/ha of thymol with a maximum

frequency of 4 applications per year and a minimum of 7 days interval.

Application method

6.2. NOVELLUS fungicide must only be applied by ground-based application methods.

Impurities

6.3. The following maximum limit is set for toxicologically relevant impurity in the active ingredient eugenol

used to manufacture NOVELLUS FUNGICIDE: methyl-eugenol: 0.1% of eugenol.

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Appendix A: Identity of the active ingredient, use pattern and mode of action

Regulatory status

The regulatory history of eugenol, thymol and geraniol are summarised in Table 2 below.

Table 2: Active ingredient regulatory status

Active

ingredient

name

Regulatory history in New

Zealand

International regulatory history

(Australia, Canada, Europe,

Japan, USA)

Eugenol Approved in New Zealand

(HSR003486)

Approved in EU, Australia, US

Not approved in Canada and Japan

Thymol Approved in New Zealand

(HSR003803)

Approved in EU, Australia, Canada,

US

Not approved in Japan

Geraniol Approved in New Zealand

(HSR003176)

Approved in EU and US

Pending in Canada and Australia

Not approved in Japan

All three active ingredients are essential oils commonly found in plants. Eugenol is naturally occurring in the

environment, being found in many plant extracts (in particular, cloves and clove oil, where it constitutes up to

80% dry matter). Geraniol is a plant oil, which is found naturally in the environment in a variety of fruits,

vegetables, herbs and spices. Geraniol is one of the main components found in citronella oil and is a

naturally occurring terpene substance synthesized by a wide range of plants. Thymol is a plant oil, which is

found naturally in the environment in a variety of fruits, vegetables and herbs. All three active ingredients

have been approved in the European Union as fungicides. 3EAY (=Novellus Fungicide) was the

representative formulation for the assessment of eugenol (EC 2011a), geraniol (EC 2011b) and thymol (EC

2011c) with the same use pattern being considered (fungicide for the control of Botrytis cinerea on grapes).

Impurities and or restrictions on purity or composition

Methyleugenol has been identified as an impurity of toxicological concern in eugenol by the European

Commission (EC 2013b). It must remain below 0.1% in the active ingredient.

No impurities of toxicological concern have been identified in geraniol and thymol.

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Use pattern and mode of action

Use pattern

NOVELLUS FUNGICIDE is capsule suspension (CS) which is diluted in water (500-1000 litres of water per

hectare). The applicant seeks to have NOVELLUS FUNGICIDE approved for ground-based application only.

NOVELLUS FUNGICIDE is typically applied using industry commercial tractor mounted/trailed boom or air

blast sprayer with hydraulic nozzles. Depending upon the rig size, the prepared spray volume can range

between 400-4000 L capacity with an average spray tank size being 2000 L. The sprayer size used will also

dictate the number of re-fills and mixing required per day for the treated crop.

Application will be at the rate of 1.5-4 Litres of product per hectare (L/ha) which is equivalent to 0.13 kg/ha of

eugenol, 0.26 kg/ha of geraniol and 0.26 kg/ha of thymol with a maximum frequency of 4 applications per

year a minimum of 7 days apart. More details on the intended uses for NOVELLUS FUNGICIDE are given in

Table 5.

Mode of action

Terpene compounds such as eugenol, geraniol and thymol generally possess antifungal activity and it is

believed that they have a single mode of action that is very similar to that of benzyl alcohol, phenol and

polyphenols. From widespread research carried out on terpenes, it is evident that eugenol, geraniol and

thymol all have the same general mode of action against fungi, having effects on spore germination, hyphal

penetration, mycelial growth and hyphal growth.

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Table 3: List of intended uses for NOVELLUS FUNGICIDE

Crop and/or

situation (a)

Use

pattern

(b)

Pests or

group of

pests

controlled

(c)

Mixture Application Application rate per treatment Remarks

(l) Type (d-f) Conc of ai

(g)

Method and

kind (h-i)

Growth stage

& season (j)

Number

Min

max (k)

Interval

between

applications –

days

(minimum)

kg ai/hL

min max

water

L/ha

min max

kg ai/ha

max

Grapes for

wine or table

grapes (fresh)

F

Grey mould /

bunch rot

(Botrytis

cinerea)

Dilute

spray

33 g/L (E)

66 g/L (G)

66 g/L (T)

Ground

based

Flowering

(EL19/BBCH60)

to 7 days prior

to harvest)

4 7

0.013 (E)

0.026 (G)

0.026 (T)

500 -

1000

0.06 –

0.13 (E)

0.13 –

0.26 (G)

0.13 –

0.26 (T)

a Where relevant, the use situation should be described (eg fumigation of soil) b Outdoor or field use (F), glasshouse application (G) or indoor application (I). c eg biting and sucking insects, soil borne insects, foliar fungi, weeds d eg wettable powder (WP), emulsifiable concentrate (EC), granule (GR) e CropLife international, 2008. Technical Monograph no 2, 6th edition. Catalogue of pesticide formulation types and international coding system f All abbreviations used must be explained g g/kg or g/l or others h Method, eg high volume spraying, low volume spraying, spreading, dusting, drench, aerial, etc i Kind, eg overall, broadcast, aerial spraying, row, individual plant, between the plant - type of equipment used must be indicated. If spraying include droplet size spectrum j growth stage at last treatment (BBCH Monograph, Growth Stages of Plants, 1997, Blackwell (ISBN 3-8263-3152-4) , including where relevant, information on season at time of application k Indicate the minimum and maximum number of application possible under practical conditions of use l Remarks may include: Extent of use/economic importance/restrictions

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Appendix B: Physico-chemical properties of NOVELLUS FUNGICIDE

The physico-chemical properties of NOVELLUS FUNGICIDE are listed in Table 6.

Table 4: Physical and chemical properties of NOVELLUS FUNGICIDE

Property Value Reference

Colour Dark cream (beige) Application form

Odour Aromatic Application form

Physical state Viscous liquid Application form

Flash point Not applicable SDS

Vapour pressure Not available Application form

Water Solubility (20°C) Miscible in water SDS

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Appendix C: Mammalian toxicology

Unless otherwise noted, all studies were conducted according to GLP and were fully compliant with the

requirements of the international test guidelines followed.

Executive summaries and list of endpoints for NOVELLUS FUNGICIDE

The mammalian toxicology data for NOVELLUS FUNGICIDE are summarised in Table 5.

Table 5: Summary of mammalian toxicology data for NOVELLUS FUNGICIDE

Endpoint

(Test Guideline)

Klimisch

score Result

HSNO

Classification Reference

Acute oral toxicity

(OECD 423) 1 LD50 > 2000 mg/kg bw No

Appendix I; Table 30;

Report number: 6733

Acute dermal toxicity

(OECD 402) 1 LD50 > 2000 mg/kg bw No


Report number: 6734

Acute inhalation toxicity

(OECD 403) 1 LC50 > 2.28 mg/L No

Appendix I; Table 32

Report number: 6735

Skin irritation/corrosion

(OECD 404) 1

Mean irritation score

(24, 48, and 72 hrs) –

Erythema: 1.33

Oedema: 0.0

No Appendix I; Table 33;

Report number: 6736

Eye irritation/corrosion

(OECD 405) 1

Mean Draize Score (24,

48, 72 hrs) –

Conjunctiva

-Redness: 2

-Chemosis: 2

Corneal opacity: 1.22

iritis: 0.0

6.4A Appendix I; Table 34;

Report number: 6737

Contact sensitisation

(OECD 429) 1

SI< 3 for undiluted test

substance treated

group and SI> 3 for 25

and 50% treated

groups.

No


Project number: I-

2408/0001

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Appendix D: Environmental fate

Executive summaries and list of endpoints

All studies on the environmental fate of eugenol, geraniol, and thymol provided by the applicant have been

reviewed. Unless otherwise noted, all environmental fate laboratory studies were conducted in accordance

with GLP and were fully compliant with all requirements of the standard international test methods.

In this case, the majority of environmental fate studies submitted to the EPA by the applicant were also

reviewed as part of the European assessments of eugenol (EC 2011a), geraniol (EC 2011b), and thymol (EC

2011c).

Where the EPA has not agreed with the European review or has additional comments, a study summary has

been provided in Appendix I. Where the EPA fully agrees with the review in the European assessment, no

study summary has been included in Appendix I as the summary is available in the publicly available DAR

(EC 2011a, EC 2011b, EC 2011c). Finally, where additional environmental studies have been submitted to

the EPA, which were not part of the European assessment, a detailed study summary has been written and

included in Appendix I.

The environmental fate endpoints and conclusions for eugenol, geraniol, and thymol are presented under the

following sub-sections. These endpoints are then used to parameterise the models and generate the

predicted environmental concentrations of eugenol, geraniol, and thymol following application of the end-use

product NOVELLUS FUNGICIDE in grapevines.

Applicant’s environmental risk assessment

The applicant has provided the EPA with their own New Zealand specific environmental risk assessment to

support registration of NOVELLUS FUNGICIDE for use in New Zealand (Australian Environment Agency

Proprietary Limited 2018). The environmental risk assessment was performed by the Australian Environment

Agency Proprietary Limited. Environmental fate endpoints were determined during this assessment.

All environmental fate endpoints are largely in agreement so minor differences, while they are noted in the

endpoint table and text below, have not been discussed in detail in this case as they make no difference to

the overall conclusions given that the actives are so short lived in the environment in this case.

Residues relevant to the environment

No major metabolites of eugenol, geraniol or thymol were identified (ie. no degradates individually accounted

for >10% AR at a single time point).

Degradation and fate of eugenol, geraniol and thymol in aquatic environments

Information on the degradation and fate of the three active ingredients eugenol, geraniol and thymol in the

aquatic environment is summarised in Table 6. Information on bioaccumulation potential is listed in Table 7.

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Table 6: Degradation and fate of the three active ingredients in aquatic environments

Test type Value or conclusion Reference

Eugenol

Ready biodegradation Readily biodegradable EU DAR (EC 2011a); Report B65160

Water solubility at 20°C [mg/L] 1850 (pH 7) EU DAR (EC 2011a); Report J16548

Geraniol

Ready biodegradation Readily biodegradable EU DAR (EC 2011b); Report B34424

Water solubility at 20°C [mg/L] 572 (pH 7) EU DAR (EC 2011b); Report J16315

Thymol

Ready biodegradation Readily biodegradable EU DAR (EC 2011c); Report B34435

Water solubility at 20°C [mg/L] 596 (pH 7) EU DAR (EC 2011c); Report J16318

Table 7: Bioaccumulation potential of the three active ingredients

Test type Values Reference

Eugenol

Partition coefficient octanol/water [Log Pow] 2.39 EU DAR (EC 2011a); Report J16548

Geraniol

Partition coefficient octanol/water [Log Pow] 3.79 EU DAR (EC 2011b); Report J16315

Thymol

Partition coefficient octanol/water [Log Pow] 3.97 EU DAR (EC 2011c); Report J16318

Degradation and fate of eugenol, geraniol and thymol in soil

Information on the degradation and fate of the three active ingredients eugenol, geraniol and thymol in the

soil environment is summarised in Table 8.

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Table 8: Degradation and fate of the three active ingredients in soil


Eugenol

Aerobic half-life in soil (DT50lab)

Range: 0.5 days (Calke), 0.6 days (Ingleby),

<1 day (Brierlow) and <3 days (Empingham)

80th percentile: 1.80 days1

Appendix I, Table 36; Report

number PIF0002

Sorption to soil (Kd / Koc) Study not considered reliable due to instability

of the test item (see Appendix I, Table 39)2


number PIF0003

Geraniol

Aerobic half-life in soil (DT50lab)


0.4 days (Brierlow) and 0.2 days (Empingham)



number PIF0005

Sorption to soil (Kd / Koc) Study not considered reliable (see Appendix I,

Table 40)2


number PIF0006

Thymol

Aerobic half-life in soil (DT50lab)1


0.6 days (Brierlow) and 0.6 days (Empingham)



number PIF0008

Sorption to soil (Kd / Koc) Study not considered reliable (see Appendix I,

Table 41)2


number PIF0009

1 Non-normalised upper 80% lab DT50 of 0.5, 0.6, 1 and 3 days

2 The applicant’s risk assessment also concluded the sorption studies were unreliable due to instability of the actives. In

the absence of reliable data, in the exposure modelling it will be assumed that all active ingredients are mobile.

3 Non-normalised upper 80% lab DT50 of 0.3, 0.3, 0.4 and 0.2 days

4 Non-normalised upper 80% lab DT50 of 0.6, 0.8, 0.6 and 0.6 days

The EPA uses the 80th percentile lab DT50 for exposure modelling, and as such the soil DT50 values listed in

the table above are slightly different to those selected in the applicant’s environmental risk assessment

(which were 1.0, 1.43 and 1.0 days for eugenol, geraniol and thymol, respectively). Since in this case

eugenol, geraniol, and thymol are rapidly degraded in the soil environment, and minor differences in these

values make no difference to the overall conclusions, the EPA has remained in alignment with the standard

risk assessment methodology (EPA 2018).

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Rates of release of active substances from the formulated product

Premise for the test

The formulation of NOVELLUS FUNGICIDE is unique in that the active substances are held within ‘capsules’

formed from dead yeast cells. As a result of this, the active substances are likely to be released more slowly

into the environment compared with if the three active substances were simply applied as a “free” active

substance in a more typical spray solution.

The volatile rates of release of the terpene substances geraniol, eugenol and thymol from NOVELLUS

FUNGICIDE (referred to as “Mevalone 3AEY” in the study, but these are the same formulation) were studied

in a novel experiment by Kant (2008). This study aimed to investigate the volatile rate of release of the three

active substances under laboratory conditions but simulating three different types of environmental

conditions that might be encountered during practical use. Three different post-application environmental

conditions were simulated using the formulated product NOVELLUS at the proposed spray-strength

concentration (diluted to 4.08 g product/L) as described under the following sub-headings.

Continuously wet

The “continuously wet” scenario mimics behaviour of the three active substances following formulation

overspray onto the surface of a body of water. An aqueous suspension of NOVELLUS FUNGICIDE was

used to simulate “continuously wet” conditions.

Continuously dry

The “continuously dry” scenario simulates application of the formulation NOVELLUS FUNGICIDE on a solid

surface under dry conditions to assess behaviour of the three active substances in the terrestrial

environment in the absence of precipitation. The formulation was applied to a piece of filter paper suspended

inside a sampling vessel and allowed to dry to represent “continuously dry” conditions.

Dry-wet-dry

The “dry-wet-dry” cycling scenario mimics behaviour of the three active substances under conditions of

short-term wetting events, eg. dew, humidity, precipitation, irrigation. Dried filter paper was re-wetted and

dried several times to mimic wetting and drying cycles in the natural environment.

General overview of the method

Air movement around the samples in all three systems was simulated by constant air-flow through sample

vessels (60 mL/min), and in the wet system, natural water currents were reproduced using a magnetic stirrer

(60 rpm). Release of terpenes (geraniol, eugenol and thymol) into the headspace of sampling vessels was

quantified by atmospheric pressure chemical ionisation-mass spectrometry (APcI-MS) and further analysis of

residual geraniol, eugenol and thymol was performed after solvent extraction of the aqueous NOVELLUS

solution or filter papers using GC-MS. The parameters for sample preparation, treatment conditions and

analysis were validated and verified in a previous pilot study.

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In order to investigate the stability of a diluted NOVELLUS spray mix, the total and free concentrations of

geraniol, eugenol and thymol in freshly prepared NOVELLUS suspension (diluted with water to 4.08 g

product/L, with no headspace) were measured before and after an incubation period of 24 hours. The

conditions of this trial were intended to mimic the potential storage of spray-strength NOVELLUS in a sealed

spraying machine prior to application in the field.

Results

Continuous wet conditions

The relatively large reservoir of terpenes applied to the wet system (ie, 15 mL at 4.08 g product/L compared

with 0.35 mL used in the filter paper studies) resulted in a relatively small decrease in the headspace

concentrations of geraniol, eugenol and thymol above aqueous NOVELLUS suspension during the first 24

hours of constant air-flow and gentle stirring.

After the first 24 hours, headspace concentrations for geraniol and thymol decreased rapidly, and at the end

of the 7-day experimental period the headspace signal for geraniol and thymol had reached the lower limit of

detection (LOD).

The rate of eugenol release was slower than that of geraniol and thymol. At the end of the 7-day

experimental period, the headspace concentrations for geraniol and thymol were below the LOD, but the

eugenol headspace concentration was slightly above the LOD and the limit of quantification (LOQ).

Gas chromatography mass spectrometry (GC-MS) analysis of the residual aqueous suspension remaining

after 168 hours (7 days) showed that levels of geraniol and thymol were below the LOD, and that trace levels

of eugenol were below the limit of quantitation (LOQ).

Complete release of geraniol and thymol from the encapsulated formulation had been achieved after 7 days

and it was calculated that approximately 91% release of eugenol had been achieved.

Continuous dry conditions

Headspace concentrations for geraniol and thymol decreased rapidly during the first six hours of the

experiment, but the rate of decrease for eugenol headspace concentrations was comparatively slow over the

same period of time. After 20 hours, headspace levels of all three terpenes were very low, eventually falling

below detection limits after 46 and 72 hours. The author postulated that visual observations indicated that

the filter paper was dry after 3-4 hours of air-flow (under the experimental conditions).

GC-MS analysis showed that geraniol, eugenol and thymol were present in the dried NOVELLUS formulation

residue, suggesting that when dry, the yeast particles were incapable of releasing measureable levels of the

three terpenes into the headspace of the vessel ie. the residual active substance remained in the formulation

rather than volatilising.

Mass balance calculations indicated that 81% of geraniol, 79% of thymol and 60% of eugenol had been

released into the headspace after three days. At the end of the study, it was calculated that 19% of geraniol,

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21% of thymol and 40% of eugenol remained in the dry formulation on the filter papers at the end of the

three-day experiment.

Dry-wet-dry cycling

Similar to terpene release in continuous dry conditions, headspace concentrations for geraniol and thymol

decreased rapidly during the first six hours, but the rate of decrease for eugenol headspace concentrations

was comparatively slow during the same period of time. After 24 hours, the headspace above filter paper

samples in the dry-wet-dry system contained barely detectable levels of all three terpenes.

Re-wetting the filter paper resulted in further geraniol, eugenol and thymol release, which confirmed that the

presence of water was required for the release of detectable geraniol, eugenol and thymol from residual

NOVELLUS formulation.

A total of four re-wetting events were required before headspace concentrations of geraniol, eugenol and

thymol decreased to a level that was below the LOD.

Following four re-wetting events and 96 hours of constant air-flow, GC-MS analysis confirmed that geraniol

and thymol were below the LOD, and trace levels of eugenol (below the LOQ) were present in the dried

NOVELLUS formulation residue.

Mass balance calculations indicated that complete release of geraniol and thymol from the encapsulated

formulation had been achieved after four days. It was calculated that approximately 98% release of eugenol

had been achieved after four days, with approximately 2% remaining in the formulation on the filter paper at

the end of the four-day experiment.

Conclusion

This experiment was performed with a novel methodology with no formal guideline. Although the study was

not performed according to GLP, conduct and reporting appear to be of a sufficiently high standard for this

study to be considered acceptable.

Under “continuous wet” conditions, complete release of geraniol and thymol from the encapsulated

formulation had been achieved after 7 days, and approximately 91% release of eugenol had been achieved.

Under “continuous dry” conditions 81% of geraniol, 79% of thymol and 60% of eugenol had been released

into the headspace after three days. It was calculated that 19% of geraniol, 21% of thymol and 40% of

eugenol remained in the dry formulation on the filter papers at the end of the three-day experiment.

Finally, under dry-wet-dry cycling conditions, complete release of geraniol and thymol from the encapsulated

formulation had been achieved after four days. It was calculated that approximately 98% release of eugenol

had been achieved after four days, with approximately 2% remaining in the formulation on the filter paper at

the end of the four-day experiment.

The results of this study indicate that the vast majority (if not all) eugenol, geraniol and thymol will be

released from the encapsulated formulation between three and seven days, depending on environmental

conditions. Therefore it is considered unlikely that NOVELLUS FUNGICIDE will retain levels of the active

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constituents for prolonged periods of time following application. The same conclusion was reached by the

applicant in their environmental risk assessment.

Fate and behaviour of eugenol, geraniol and thymol in air

Information on the fate and behaviour of the three active ingredients eugenol, geraniol and thymol in air is

summarised in Table 9.

Table 9: Fate and behaviour of the three active ingredients in air


Eugenol

Vapour Pressure (20°C) 2.7 Pa EU DAR (EC 2011a); Report J16548

Volatility, Henry’s Law Constant (20°C) 0.24 Pa.m3.mol-1 EU DAR (EC 2011a); Report J16548

Atmospheric half-life (Atkinson method) 0.165 days (1.975 hours) EU DAR (EC 2011a); Report EDR/02/01c

Geraniol

Vapour Pressure (20°C) 4.6 Pa EU DAR (EC 2011b); Report J16315

Volatility, Henry’s Law Constant (20°C) 1.22 Pa.m3.mol-1 EU DAR (EC 2011b); Report J16315

Atmospheric half-life (Atkinson method) 0.059 days (0.713 hours) EU DAR (EC 2011b); Report EDR/02/01b

Thymol

Vapour Pressure (20°C) 3.4 Pa EU DAR (EC 2011c); Report J16318

Volatility, Henry’s Law Constant (20°C) 0.86 Pa.m3.mol-1 EU DAR (EC 2011c); Report J16318

Atmospheric half-life (Atkinson method) 0.100 days (1.197 hours) EU DAR (EC 2011c); Report EDR/02/01a

General conclusion about environmental fate

Fate and behaviour in aquatic environments

The three active ingredients eugenol, geraniol, and thymol contained within the formulated product

NOVELLUS FUNGICIDE are all readily biodegradable. Eugenol, geraniol and thymol are expected to be

very short-lived in the environment therefore.

No aerobic/anaerobic transformation in aquatic sediment systems studies were submitted. Given the

assumptions made regarding likelihood of rapid volatilisation (see fate and behaviour in air conclusions

below) and that the active substances are readily biodegradable, exposure of water/sediment systems is

unlikely to be significant and this is not considered a data gap.

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Finally, the Log Pow values for the three active substances indicate that potential for bioaccumulation is low

for all three actives (Log Pow <4). Although Log Pow values are closer to the threshold of 4 for geraniol

(3.79) and thymol (3.97), it is considered unlikely that either geraniol or thymol will persist or accumulate in

soil or natural water systems due to its rapid volatilisation properties and ready biodegradability in the

environment.

Fate and behaviour in the soil environment

Eugenol, geraniol and thymol degraded rapidly in the soil environment. DT50 values ranged from 0.5 to <3

days (n=4) for eugenol, from 0.2 to 0.4 days (n=4) for geraniol, and from 0.6 to 0.8 days (n=4) for thymol.

The three new (2015) adsorption/desorption studies submitted were considered unreliable by the EPA as a

result of instability of the test substances in the studies (see Appendix I, Table 36 to Table 41 for further

discussion).

It is noted in the DARs (EC 2011a, EC 2011b, EC 2011c) for eugenol, geraniol and thymol that the applicant

submitted Koc values calculated by the US EPA software “PCKOCWIN”. Using this software Koc values of

1124 mL/g, 70.79 mL/g and 2188 mL/g were estimated for eugenol, geraniol and thymol, respectively. This is

not a normally accepted method of Koc determination however, and due to the lack of reliable sorption data

the EPA will assume eugenol, geraniol and thymol are mobile in soil, and use worst-case default Kd and Koc

values of 0.1 and 10 mL/g, respectively.

Rate of release from the formulation

The results of the study by Kant (2008) indicate that under simulated “continuous wet” conditions, complete

release of geraniol and thymol from the encapsulated formulation had been achieved after seven days, and

approximately 91% release of eugenol had been achieved.

Under simulated “continuous dry” conditions 81% of geraniol, 79% of thymol and 60% of eugenol had been

released into the headspace after three days. It was calculated that 19% of geraniol, 21% of thymol and 40%

of eugenol remained in the dry formulation on the filter papers at the end of the three-day experiment.

Finally, under simulated dry-wet-dry cycling conditions, complete release of geraniol and thymol from the

encapsulated formulation had been achieved after four days. It was calculated that approximately 98%

release of eugenol had been achieved after four days, with approximately 2% remaining in the formulation

on the filter paper at the end of the four-day experiment.

These results indicate that the vast majority (if not all) eugenol, geraniol and thymol will be released from the

encapsulated formulation between three and seven days, depending on environmental conditions. It is highly

unlikely therefore that the formulation will retain levels of the active constituents for prolonged periods of time

following application.

Fate and behaviour in air

Information on vapour pressure and Henry’s Law Constant suggest that volatilisation is likely to be a major

route of dissipation for eugenol, geraniol and thymol.

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Atmospheric half-lives for eugenol, geraniol and thymol using the Atkinson method were determined to be

0.165 days (1.975 hours), 0.059 days (0.713 hours) and 0.100 days (1.197 hours), respectively, under

environmental conditions with a diurnal cycle of 12 hours.

These data suggest that eugenol, geraniol and thymol will be rapidly degraded. In addition, it is noted in the

DAR that it is likely than quantities of eugenol, geraniol and thymol volatilised from the formulation will be

insignificant given the probable emission levels from the apparently wide range of plants producing, and

emitting eugenol, geraniol and thymol.

Metabolites

No major metabolites of eugenol, geraniol or thymol were identified (ie no degradates individually accounted

for >10% AR at a single time point).

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Appendix E: Ecotoxicity

Executive summaries and list of endpoints

Unless otherwise noted, all ecotoxicity laboratory studies were conducted in accordance with GLP and were

fully compliant with all requirements of the standard international test methods.

All studies on the ecotoxicity of eugenol, geraniol and thymol provided by the applicant on environmental

receptors have been reviewed. In this case, all of the ecotoxicity studies submitted to the EPA by the

applicant were also reviewed as part of the European assessments of eugenol, geraniol and thymol.

Where the EPA has not agreed with the European review or had additional comments, a study summary has

been provided in Appendix I. Where the EPA fully agrees with the review in the European assessment, no

study summary has been included in Appendix I as the summary is available in the publicly available draft

assessment report (DAR) (EC 2011a, EC 2011b, EC 2011c).

The ecotoxicity endpoints and conclusions for eugenol, geraniol, thymol, and substance NOVELLUS

FUNGICIDE are presented under the following sub-sections.

These studies are used to describe the key impacts of eugenol, geraniol, thymol or substance NOVELLUS

FUNGICIDE on different environmental receptors. The data from the studies have been used for classifying

the active ingredient and in relevant areas of the risk assessment.

Applicant’s environmental risk assessment

The applicant has provided the EPA with their own New Zealand specific environmental risk assessment to

support registration of NOVELLUS FUNGICIDE for use in New Zealand. The environmental risk assessment

was performed by the Australian Environment Agency Proprietary Limited. Ecotoxicity endpoints were

determined during this assessment.

All ecotoxicity endpoints are essentially in agreement so very minor differences have not been noted or

discussed in detail in this case since they make no difference to the overall conclusions given that the

actives are so short lived in the environment, and have a low ecotoxicity profile.

Aquatic toxicity

Table 10 contains the aquatic toxicity test results for the three active ingredients eugenol, geraniol and

thymol. Table 11 contains the aquatic toxicity test results for the formulated product NOVELLUS

FUNGICIDE.

Values in bold are those used for the risk assessment. Underlined values are those used to determine the

classification.

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Table 10: Summary of aquatic toxicity data for the three active ingredients

Test species Test type and

duration Endpoint value Reference

Eugenol

Fish

Rainbow trout, Oncorhynchus mykiss 96-hr LC50 (semi-

static system)

>10 mg eugenol/L (nominal) EU DAR (EC 2011a); Study no. 37984230

Zebra fish, Danio rerio 11.9 mg eugenol/L (nominal) EU DAR (EC 2011a); Study no. 37984230

Invertebrates

Daphnia magna 48-hr EC50 1.11 mg eugenol/L (nominal) EU DAR (EC 2011a); Study no. 37982220

Algae

Green alga, Pseudokirchneriella subcapitata 72-hr ErC50 15.4 mg eugenol/L (mean measured) EU DAR (EC 2011a); Study no. 37981210

Geraniol

Fish


static system)

11.6 mg geraniol/L (nominal) EU DAR (EC 2011b); Study no. 34291230

Zebra fish, Danio rerio 23.6 mg geraniol/L (nominal) EU DAR (EC 2011b); Study no. 34292230

Invertebrates

Daphnia magna 48-hr EC50 16.1 mg geraniol/L (nominal) EU DAR (EC 2011b); Study no. 34293220

Algae

Green alga, Pseudokirchneriella subcapitata 72-hr ErC50 48.0 mg geraniol/L (nominal) EU DAR (EC 2011b); Study no. 34294210

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Thymol

Fish


static system)

3.0 mg thymol/L (mean measured) EU DAR (EC 2011c); Study no. 34281230

Zebra fish, Danio rerio 7.1 mg thymol/L (nominal) EU DAR (EC 2011c); Study no. 34282230

Invertebrates

Daphnia magna 48-hr EC50 4.9 mg thymol/L (nominal) EU DAR (EC 2011c); Study no. 34283220

Algae

Green alga, Pseudokirchneriella subcapitata 72-hr ErC50 11.1 mg thymol/L (nominal) EU DAR (EC 2011c); Study no. 34284210

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Table 11: Summary of acute aquatic toxicity data for formulated product NOVELLUS FUNGICIDE


duration Value Reference

Fish


static system) 31.1 mg formulation/L (nominal)

(EC 2011a, EC 2011b, EC 2011c); Study no.

34301230

Invertebrates

Daphnia magna 48-hr EC50 35.4 mg formulation/L (nominal) (EC 2011a, EC 2011b, EC 2011c); Study no.

34302220

Algae

Green alga, Pseudokirchneriella subcapitata 72-hr ErC50 100.8 mg formulation/L (nominal) (EC 2011a, EC 2011b, EC 2011c); Study no.

34303210

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Uncertainties and data gaps

Chronic aquatic toxicity data

No data on the long-term effects of eugenol, geraniol, or thymol in the aquatic environment have been

submitted. Chronic toxicity data for active ingredients are normally required for fish and Daphnia as

per the EPA’s data requirements (EPA 2018). The applicant argues that eugenol, geraniol, and

thymol are very short-lived, and very volatile so chronic exposure of the actives to the aquatic

environment is not anticipated. The EPA also conclude that the persistence of eugenol, geraniol, and

thymol will be very short in water (all actives are readily biodegradable), and little or no accumulation

in soil is expected to occur between applications of NOVELLUS FUNGICIDE to grapevines at 7-day

intervals (80th percentile lab DT50 values <1.8 days in soil). Based on the data available, the acute

aquatic toxicity of the end-use product NOVELLUS FUNGICIDE and its active constituents is low, and

it is unlikely that repeat applications to grapevines will cause unacceptable effects to the aquatic

environment in the long-term. Additionally, the rate of release study by Kant (2008) demonstrates it is

unlikely that NOVELLUS FUNGICIDE will retain the active constituents for prolonged periods of time

following its use in vineyards.

In conclusion, chronic exposure of the aquatic environment is not considered likely following

application of NOVELLUS FUNGICIDE to grapevines. As such, the absence of chronic aquatic

toxicity data is not considered an uncertainty or data gap, and no chronic aquatic risk assessment is

considered necessary for eugenol, geraniol or thymol. Only an acute aquatic risk assessment will be

performed for the individual active constituents of NOVELLUS FUNGICIDE since this is the most

relevant exposure scenario.

Toxicity to sediment-dwelling organisms

No studies in regard to toxicity to sediment-dwelling organisms were submitted. Sediment ecotoxicity

data are a conditional requirement for both the active ingredient and formulated substance as per the

EPA’s data requirements (EPA 2018). As described in the environmental fate section above, given

the assumptions made regarding likelihood of rapid volatilisation (also see fate and behaviour in air in

the environmental fate section), and that all three active substances are readily biodegradable,

exposure of water/sediment systems is unlikely to be significant, and absence of these data is not

considered an uncertainty or data gap therefore. No assessment of toxicity to sediment-dwelling

organisms for applications of NOVELLUS FUNGICIDE to grapevines is considered necessary in this

case.

General conclusion about aquatic toxicity

The end-use product NOVELLUS FUNGICIDE falls into the endpoint categories for 9.1C and 9.1D

HSNO classifications based on a 96-hr LC50 of 31.1 mg formulation/L determined for the rainbow trout

Oncorhynchus mykiss. If the substance is bioaccumulative or persistent, the substance triggers a

9.1C, if the substance is not bioaccumulative or persistent, the substance triggers a 9.1D.

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No bioaccumulation or persistence data are available for the end-use product NOVELLUS

FUNGICIDE however, since these data are only ever generated for individual active ingredient(s).

In regard to the individual active ingredients, eugenol triggers a 9.1B HSNO classification (48-hr EC50

of 1.11 mg eugenol/L for Daphnia magna), geraniol triggers a 9.1C HSNO classification (96-hr LC50 of

11.6 mg geraniol/L for the rainbow trout Onchorhynchus mykiss), and thymol triggers a 9.1B HSNO

classification (96-hr LC50 of 3.0 mg thymol/L for the rainbow trout Onchorhynchus mykiss). All of these

hazard classifications would be downgraded to a 9.1D however, since none of the individual active

ingredients are considered bioaccumulative or persistent based on their respective environmental fate

parameters (see Appendix D for endpoints).

In addition, after taking into consideration the co-formulants of the substance, these are not

considered likely to be bioaccumulative or persistent, with a low (9.1D) or no hazard classification.

In this specific case therefore, it is considered appropriate that the hazard classification for the

substance NOVELLUS FUNGICIDE should also be downgraded from a 9.1C to a 9.1D as based on

expert judgement, the substance is not considered to be bioaccumulative or persistent.

Soil toxicity

Table 12 contains the soil toxicity test results for the formulated product NOVELLUS FUNGICIDE.

Values in bold are those used for the risk assessment. Underlined values are those used to

determine the classification.

Table 12: Summary of soil toxicity data for NOVELLUS FUNGICIDE



Soil macro-organisms

Earthworm, Eisenia

fetida

Acute, 14-d

LC50

>500 mg product/kg soil dw1

[uncorrected value >1000 mg product

kg soil dw (nominal)]

(EC 2011a, EC 2011b,

EC 2011c); Study no.

34307021

Soil microbial function

Soil microflora

Respiration and

nitrogen

mineralisation,

28 days

<25% effects at up to 54.4 mg

formulation/kg soil

(EC 2011a, EC 2011b,

EC 2011c); Study no.

34308080

1 Original toxicity endpoints from the artificial soil tests have been divided by 2 to account for different soil

characteristics and the possibility of reduced bioavailability for soil organisms of lipophilic substances (Log Pow

>2) as per the EFSA Technical Report (EFSA 2015)

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Toxicity of active ingredients to soil-dwelling organisms

No data on soil toxicity are available for active ingredients eugenol, geraniol, or thymol. Soil toxicity

data are usually available for active ingredients, and the risk assessment is usually performed using

the active ingredient endpoints. Since soil toxicity data are available for the end-use product

NOVELLUS FUNGICIDE, the quantitative risk assessment has been performed with these endpoints.

It should be noted this is not the standard approach however. Since a soil DT50 is required for

assessing toxicity to soil-dwelling organisms, the longest lab DT50 determined for an active ingredient

will be used as a worst-case scenario (80th percentile DT50 of 1.8 days for eugenol in this case).

Chronic soil toxicity data

No data on the long-term toxicity of eugenol, geraniol, or thymol, in the soil environment have been

submitted. Chronic toxicity data for active ingredients are usually required in regard to effects on

earthworm reproduction as per the EPA’s data requirements. The applicant argues that eugenol,

geraniol, and thymol are very short-lived in soil and water, and very volatile so chronic exposure of the

soil environment is not anticipated following application of NOVELLUS FUNGICIDE to grapevines.

The EPA also conclude that the persistence of eugenol, geraniol, and thymol will be short, and little or

no accumulation in soil is expected to occur between applications of NOVELLUS FUNGICIDE to

grapevines at 7-day intervals (80th percentile lab DT50 values <1.8 days in soil). Based on the data

available, the acute toxicity of end-use product NOVELLUS FUNGICIDE to soil organisms is low, and

it is unlikely that repeat applications to grapevines will cause unacceptable effects to the soil

environment in the long-term. Additionally, the rate of release study by Kant (2008) demonstrated that

it is unlikely NOVELLUS FUNGICIDE will retain the active constituents for prolonged periods of time

following its use in vineyards.

In conclusion, chronic exposure of the soil environment is not considered likely following application of

NOVELLUS FUNGICIDE in grapevines. As such, the absence of chronic soil toxicity data is not

considered an uncertainty or data gap, and no assessment of chronic risks to soil organisms is

considered necessary. Only an acute soil organism risk assessment will be performed for the end-use

product NOVELLUS FUNGICIDE since this is considered the most relevant exposure scenario.

Toxicity to non-target plants

No data have been submitted in regard to toxicity of NOVELLUS FUNGICIDE to non-target plants.

Seedling emergence and vegetative vigour data for the formulated substance are usually required as

per the EPA’s data requirements. The applicant states that NOVELLUS is a fungicide treatment and

according to European guidelines data on the effects on non-target flora are not required. It is known

however, that geraniol is a component of citronella oil, which has known plant toxicity. Furthermore, it

appears that eugenol has herbicidal activity since it is the active ingredient in the formulated product

“Matran® EC”, which is approved for use as non-selective weed control in the US. Information gained

during the course of efficacy trials have been used to show that flora effects are nil or negligible. This

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has been discussed further qualitatively in the Environmental Risk Assessment in Appendix I. This

information is considered sufficient to address any potential concerns about the phytotoxic activity of

NOVELLUS FUNGICIDE to non-target plants. Absence of specific non-target plant studies is not

considered an uncertainty or data gap therefore.

General conclusion about soil toxicity

NOVELLUS FUNGICIDE does not trigger the HSNO thresholds for toxicity to the soil environment

based on the data available.

No soil toxicity data were available for the individual active ingredients eugenol, geraniol or thymol,

and as such no soil toxicity hazard classification could be made for these components. Since data are

available for the end-use product however, and these take precedence, this is not considered an

issue.

Terrestrial vertebrate toxicity

For effects on terrestrial vertebrates other than birds, refer to the mammalian toxicity section.

Table 13 contains the avian toxicity test results for the formulated product NOVELLUS FUNGICIDE.

Table 13: Summary of terrestrial vertebrate toxicity data for NOVELLUS FUNGICIDE


duration

NOVELLUS

FUNGICIDE Reference

Bobwhite quail,

Colinus virginianus

Acute oral LD50 >10000 mg

formulation/kg bw

(EC 2011a, EC 2011b, EC 2011c);

Study no. 648-101

8-d dietary LC50 >20000 ppm in diet (EC 2011a, EC 2011b, EC 2011c);

Study no. 648-102 [648C-101]


Toxicity of active ingredients to terrestrial vertebrates

No toxicity data for terrestrial vertebrates are available for the active ingredients eugenol, geraniol, or

thymol. Terrestrial vertebrate toxicity data are required for active ingredients as per the EPA’s data

requirements (EPA 2018), and the risk assessment is usually performed using the active ingredient

endpoints. Since data are available for the end-use product NOVELLUS FUNGICIDE, the quantitative

risk assessment will be performed using these endpoints. It should be noted this is not the standard

approach however.

Chronic toxicity to terrestrial vertebrates

No data on the long-term toxicity of eugenol, geraniol, or thymol have been submitted for birds. An

avian reproduction test is usually required for active ingredients as per the EPA’s data requirements

(EPA 2018). The applicant argues that eugenol, geraniol, and thymol are very short-lived in soil and

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water, and very volatile so chronic exposure of these actives to birds is not anticipated. The EPA also

conclude that the persistence of eugenol, geraniol, and thymol will be short in the environment, and

little or no accumulation in soil is expected to occur between applications of NOVELLUS FUNGICIDE

to grapevines at 7-day intervals (80th percentile lab DT50 values <1.8 days in soil). Based on the data

available, acute toxicity of the end-use product NOVELLUS FUNGICIDE to birds is low, and it is

considered unlikely that repeat applications to grapevines will cause unacceptable effects to birds in

the long-term. Additionally, the rate of release study by Kant (2008) demonstrates it is unlikely that

NOVELLUS FUNGICIDE will retain the active constituents for prolonged periods of time following its

use in vineyards.

In conclusion, chronic exposure to birds is not considered likely following application of NOVELLUS

FUNGICIDE to grapevines. As such, the absence of chronic bird toxicity data is not considered an

uncertainty or data gap, and no assessment of chronic risks to birds is considered necessary. Only an

acute risk assessment will be performed to evaluate risks to birds from use of the end-use product

NOVELLUS FUNGICIDE in grapevines since this is the most relevant exposure scenario.

General conclusion about ecotoxicity to terrestrial vertebrates

NOVELLUS FUNGICIDE does not trigger the HSNO thresholds for toxicity to the terrestrial

vertebrates based on the data available.

No bird toxicity data were available for the individual active ingredients eugenol, geraniol or thymol,

and as such no terrestrial vertebrate hazard classification could be made for these components. Since

data are available for the end-use product however, and these take precedence, this is not

considered an issue.

Ecotoxicity to bees and other terrestrial invertebrates

Table 14 contains the toxicity test results for NOVELLUS FUNGICIDE on non-target terrestrial

invertebrates.

Table 14: Summary of terrestrial invertebrate toxicity data for NOVELLUS FUNGICIDE



Pollinators

Honeybee, Apis mellifera

Acute oral, 48-hr

LD50

>224.6 µg

formulation/bee EC DAR (2011); Study no.

3430403

Acute contact, LD50 >200 µg formulation/bee

Non-target arthropods

Parasitic wasp, Aphidius

rhopalosiphi

48-hr LR50,

laboratory glass

plate study

>12,000 mL product/ha,

equivalent to 12,420 g

product/ha1,2

EC DAR (2011); Study no.

34305001

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Predatory mite,

Typhlodromus pyri

48-hr LR50,

laboratory glass

plate study

>12,000 mL product/ha,

equivalent to 12,420 g

product/ha1,2

EC DAR (2011); Study no.

34306063

1 Based on a specific density of 1.035 mL/cm3

2 Note in the EFSA conclusions it states that these endpoints should be treated with caution due to volatilisation

from glass plates but these endpoints were used in the risk assessment


Toxicity of active ingredients to honeybees

No toxicity data for honeybees are available for active ingredients eugenol, geraniol, or thymol. Honey

bee toxicity data are usually required for the individual active ingredient(s) as per the EPA’s data

requirements, and the risk assessment is usually performed using the active ingredient toxicity

endpoints. Since data are available for the end-use product NOVELLUS FUNGICIDE, risks to

honeybees will be assessed using these endpoints. It should be noted this is not the normal approach

however.

Chronic toxicity to honeybees

No data on the long-term effects of NOVELLUS FUNGICIDE have been submitted for honeybees.

This is normally required for active ingredients as per the EPA’s data requirements. The applicant

argues that eugenol, geraniol, and thymol are very short-lived in the environment, and very volatile so

chronic exposure of these actives following use of NOVELLUS FUNGICIDE in grapevines is not

anticipated. The EPA also conclude that the persistence of eugenol, geraniol, and thymol will be

short. Based on the data available, acute toxicity of the end-use product NOVELLUS FUNGICIDE to

honeybees is low, and it is considered unlikely that repeat applications will cause unacceptable

effects to pollinators in the long-term. Additionally, the rate of release study by Kant (2008)

demonstrates that NOVELLUS FUNGICIDE is unlikely to the active constituents for prolonged periods

of time following its use in vineyards. It should also be noted that NOVELLUS FUNGICIDE has no

insecticidal activity.

In conclusion, chronic exposure to honeybees from use of NOVELLUS FUNGICIDE in grapevines is

not considered likely. The absence of chronic toxicity data for honeybees is not considered an

uncertainty or data gap therefore. Only an acute risk assessment will be performed to evaluate risks

to honeybees from application of the end-use product NOVELLUS FUNGICIDE to grapevines since

this is considered the most relevant exposure scenario.

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General conclusion about ecotoxicity to bees and terrestrial invertebrate

toxicity

NOVELLUS FUNGICIDE does not trigger the HSNO thresholds for toxicity to terrestrial invertebrates

based on the data available (lowest LD50 of >200 µg formulation/bee, acute contact).

No pollinator toxicity data were available for the individual active ingredients eugenol, geraniol or

thymol, and as such no terrestrial invertebrate hazard classification could be made for these

components. Since data are available for the end-use product however, and these take precedence,

this is not considered an issue.

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Appendix F: Hazard classification of NOVELLUS FUNGICIDE

The hazard classifications of NOVELLUS FUNGICIDE are listed in Table 15.

Table 15: Applicant and Staff classifications of the NOVELLUS FUNGICIDE

Hazard Class/Subclass

Active ingredient

classification by:

Method of

classification

Remarks A

pp

lican

t

EP

A S

taff

Test

resu

lts

Read

acro

ss

Class 1 Explosiveness No No Aqueous based

Class 2, 3 & 4 Flammability No No Flashpoint >100 ºC

Class 5 Oxidisers/Organic

Peroxides No ND

Subclass 8.1 Metallic

corrosiveness ND ND

Subclass 6.1 Acute toxicity (oral) No No LD50 > 2000 mg/kg

bw

Subclass 6.1Acute toxicity (dermal) No No LD50 > 2000 mg/kg

bw

Subclass 6.1 Acute toxicity

(inhalation) No No LC50 > 2.28 mg/L

Subclass 6.1 Aspiration hazard No ND

Subclass 6.3/8.2 Skin

irritancy/corrosion 8.2B No

The Mean Draize

Scores: 1.33 for

erythema and 0.0

for oedema at 24,

48 and 72 hours

Subclass 6.4/8.3 Eye

irritancy/corrosion 8.3A 6.4A

The Mean Draize

Scores (24, 48, 72

hours) were 1.22

for corneal opacity,

0.0 for iritis and 2

for conjunctival

redness and

chemosis

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Subclass 6.5A Respiratory

sensitisation 6.5A ND

Subclass 6.5B Contact

sensitisation 6.5B No*

SI< 3 for undiluted

test substance

treated group and

SI> 3 for 25 and

50% treated

groups which are

higher than their

level in the

substance

Subclass 6.6 Mutagenicity No ND

Subclass 6.7 Carcinogenicity No ND

Subclass 6.8 Reproductive/

developmental toxicity No ND

Subclass 6.8 Reproductive/

developmental toxicity (via

lactation)

No ND

Subclass 6.9 Target organ

systemic toxicity (oral) No ND


systemic toxicity (dermal) No ND


systemic toxicity (inhalation) No ND

Subclass 9.1 Aquatic ecotoxicity 9.1C 9.1D

9.1C based on a

96-hr LC50 of 31.1

mg product/L for

the rainbow trout

but downgraded to

a 9.1D as the

substance is not

considered

bioaccumulative or

persistent

Subclass 9.2 Soil ecotoxicity No No

Subclass 9.3 Terrestrial vertebrate

ecotoxicity No No

Subclass 9.4 Terrestrial

invertebrate ecotoxicity No No

NA: Not Applicable.

ND: No Data or poor quality data [according to Klimisch criteria (Klimisch, Andreae et al. 1997)]. There is a lack

of data for one or more components.

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No: Not classified based on actual relevant data available for the substance. The data are conclusive and

indicate the threshold for classification is not triggered.

* The positive result at 25 and 50% test concentrations were due to the encapsulated active ingredients being

extracted by DMF and therefore becoming more bioavailable. Refer Appendix I for more details.

Human health hazard classification

The proposed classification of NOVELLUS FUNGICIDE is eye irritant (6.4A)

The EPA staff classification of NOVELLUS FUNGICIDE differed from that of the applicant in that it is

classified as an eye irritant (6.4A) whereas the applicant classified it as skin corrosive (8.2B), eye

corrosive (8.3A), respiratory sensitiser (6.5A) and contact sensitiser (6.5B).

Ecotoxicity hazard classification

As described above in Appendix E, the end-use product NOVELLUS FUNGICIDE falls into the

endpoint categories for 9.1C and 9.1D HSNO classifications based on a 96-hr LC50 of 31.1 mg

formulation/L determined for the rainbow trout Oncorhynchus mykiss. If the substance is

bioaccumulative or persistent, the substance triggers a 9.1C, if the substance is not bioaccumulative

or persistent, the substance triggers a 9.1D.

No bioaccumulation or persistence data are available for the end-use product NOVELLUS

FUNGICIDE however, since these data are only ever generated for individual active ingredient(s).

In regard to the individual active ingredients, eugenol triggers a 9.1B HSNO classification (48-hr EC50

of 1.11 mg eugenol/L for Daphnia magna), geraniol triggers a 9.1C HSNO classification (96-hr LC50 of

11.6 mg geraniol/L for the rainbow trout Oncorhynchus mykiss), and thymol triggers a 9.1B HSNO

classification (96-hr LC50 of 3.0 mg thymol/L for the rainbow trout Oncorhynchus mykiss). All of these

hazard classifications would be downgraded to a 9.1D however, since none of the individual active

ingredients are considered bioaccumulative or persistent based on their respective environmental fate

parameters (see Appendix D for endpoints).

In addition, after taking into consideration the co-formulants of the substance, these are not

considered likely to be bioaccumulative or persistent, with a low (9.1D) or no hazard classification.

In this specific case therefore, it is considered appropriate that the hazard classification for the

substance NOVELLUS FUNGICIDE should also be downgraded from a 9.1C to a 9.1D as based on

expert judgement, the substance is not considered to be bioaccumulative or persistent.

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Appendix G: Human health risk assessment

Qualitative risk assessment

NOVELLUS FUNGICIDE is a water-based capsule suspension formulation containing three terpenes:

eugenol, geraniol and thymol, as active ingredients. They occur naturally in plants such as cloves,

thyme, basil, lemongrass and in rose oil. Their safety has been thoroughly reviewed as they are used

primarily as fragrances and as flavours in food. They are also functional ingredients of numerous

pharmaceutical and cosmetic products. Due to their long safe history of human ingestion dermal

exposure from their use in Novellus is unlikely to result in adverse effects on human health. Worker

exposure to the terpenes is also minimised by their water-based capsule suspension that results in a

slow controlled release of the terpenes.

Quantitative risk assessment

The operator exposure assessment is based on a modification of the approach used by European

regulators, taking into account New Zealand specific factors. The model is based on the results of

actual measurements carried out in the field and has an established history of providing reliable and

reproducible results.

The re-entry worker exposure assessment is based on a modification of the approach used by

European regulators and the US-EPA. The parameters for the modelling are based on empirical data

relating to measurements of dermal exposure of workers from contact with residues on foliage for

various activities and the amount of foliar residues that are dislodgeable.

The bystander exposure assessment is based on a modification of the approaches used by European

regulators and the US-EPA. Spray drift deposition from ground based application is estimated using

the AgDrift model using the curves produced by the Australian Pesticides and Veterinary Medicines

Authority [APVMA, (APVMA 2010)]. The parameters are based on empirical data. Spray drift

deposition from aerial application is estimated using the AGDISP model along with appropriate New

Zealand input parameters.

Full details of the methodology can be found in the EPA risk assessment methodology document

(EPA 2018).

To assess risks the predicted systemic exposures to the active ingredient(s) are compared with an

acceptable operator exposure limit (AOEL) for the active ingredient and a risk quotient (RQ) is

calculated. RQ values greater than one indicate that predicted exposures are greater than the AOEL

and potentially of concern. RQ values below one indicate that predicted exposures are less than the

AOEL and are not expected to result in adverse effects.

Input values for the human health risk assessment

Novellus is a water-based capsule suspension formulation containing three terpenes: eugenol,

geraniol and thymol, as active ingredients. However, thymol was only quantitatively risk assessed

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because it is present at highest concentration (66 g/L), has maximum application rate (0.13 – 0.26 kg

as/ha) along with geraniol but with the most conservative NOAEL (40 mg/kg bw) identified.

Reference doses for thymol established by internationally reputable regulatory authorities are

summarised in Table 16.

Table 16: Reference doses established by regulators

Available

international

Reference doses

Key systemic

effect

NOAEL

mg/kg

bw/d

Uncertainty

factors

Reference

value (nature

of the value)

mg/kg bw/d

Staff’s

modifications Remarks

ADI – Thymol (EC

2013b)

Based on a

threshold of

toxicological

concern (TTC)

concept

Acceptable

intake -

1800

μg/person/

day

- 0.03 None None

ARfD – Thymol EU

DAR (EC 2013b)

Forestomach

effects like

oedema, erosion

and hyperplasia

8 100 0.08 None None

The reference value for thymol was derived by the EPA.

The relevant toxicity studies that were considered to derive an acceptable operator exposure level

(AOEL) for thymol is summarised in Table 17.

Table 17: Summary of studies relevant for establishing an AOEL

Key systemic

effect

NOAEL

mg/kg bw/d

Uncertainty

factors

Absorption

factor

AOEL

mg/kg

bw/d

Justification

Reproductive

toxicity study:

slightly reduced

pup weights and

pup weight gain

over four day

lactation period

(EC 2013b)

40 100 - 0.4

NOAEL for effects on offspring

compares favourably with

estimated exposures to

consumers, spray operators,

bystanders and residents.

Other input values for the exposure assessment are summarised in Table 18.

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No dermal absorption data were provided for NOVELLUS FUNGICIDE so default values have been

used in the risk assessment. For pesticides, default dermal absorption values proposed by Aggarwal

et al. (Aggarwal, Fisher et al. 2015) have been adopted, which are based on a review of a robust data

set of 295 in vitro human dermal absorption studies with over 150 agrochemical active ingredients.

These default values are 2% for solid concentrates, 6% for liquid concentrates and 30% for spray

dilutions.

Table 18: Input values for human exposure modelling

Active

ingredient

Physical

form

Concentration

of each active

(%)

Maximum

application rate (for

each active, for

each method of

application)

g ai/ha

Dermal absorption (%) AOEL

mg/kg bw/d

Concen

trate

Spray

Thymol liquid 6.86 260 30 30 0.4

Operator exposure assessment

The results of the operator exposure assessment are shown in Table 19.

Table 19: Output of operator mixing, loading and application exposure assessment for Thymol

Exposure Scenario Estimated operator

exposure (mg/kg bw/d)

Risk

Quotient

Boom

No personal protective equipment (PPE)1 during mixing, loading and

application

0.0281 0.0703

Gloves only during mixing and loading 0.0233 0.0583

Gloves only during application 0.0243 0.0608

Full PPE during mixing, loading and application (excluding respirator) 0.0019 0.0049

Full PPE during mixing, loading and application (including FP1, P1 and

similar respirator achieving 75 % inhalation exposure reduction)

0.0019 0.0047



0.0019 0.0047

1 ‘Full PPE’ includes: gloves, hood/visor, coveralls, and heavy boots during application and gloves during mixing and loading.

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Airblast

No PPE during mixing, loading and application 0.1342 0.335

Gloves only during mixing and loading 0.1294 0.323

Gloves only during application 0.1272 0.318

Full PPE during mixing, loading and application (excluding respirator) 0.0080 0.0201



0.0074 0.0184



0.0073 0.0182

Predicted operator exposures to thymol are below the Acceptable Operator Exposure Level (AOEL)

for airblast application to grapes, even without the use of personal protective equipment (PPE).

Therefore operator exposures are not expected to result in adverse health effects.

Although the quantitative risk assessment indicates that PPE is not required to ensure that exposures

are below the AOEL, the requirements under HSW (HS), and in particular Regulations 13.7 and 13.8,

state that personal protective equipment is to be used to minimise risks to the health and safety of

workers.

Re-entry worker exposure assessment

The results of the re-entry worker exposure assessment are summarised in Table 20.

Table 20: Output of the re-entry worker exposure assessment for thymol

Active

ingredient Crop/activity

Internal

(absorbed) dose

available for

systemic

distribution

(mg/kg bw/8

hours)

AOEL

(mg/kg

bw/d)

Risk Quotient

immediately

after

application

Re-entry

interval

without

gloves

Re-entry

interval

with

gloves

Thymol grapes:

reach/pick

0.18 (boom)/0.20

(airblast)

0.4 0.45/0.5 0.0/0.0 0.0/0.0

Predicted exposures to eugenol for workers re-entering and working in areas where NOVELLUS

FUNGICIDE has been applied are below the AOEL. No re-entry intervals are necessary.

Quantitative bystander risk assessment

It is considered that the main potential source of exposure to the general public for substances of this

type (other than via food residues which will be considered as part of the registration of this substance

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under the Agricultural Compounds and Veterinary Medicines (ACVM) Act 1997) is via spray drift. In

terms of bystander exposure, toddlers are regarded as the most sensitive sub-population and are

regarded as having the greatest exposures. For these reasons, the risk of bystander exposure is

assessed in this sub-population. The AOEL calculated for the operator and re-entry worker exposure

assessments has been used for the bystander assessment, as the use of an oral chronic reference

dose (CRfD) is usually likely to be over precautionary.

The results of the bystander exposure assessment are summarised in Table 21.

Table 21: Output of the bystander exposure assessment for thymol

Exposure Scenario

Estimated exposure of

15 kg toddler exposed

through contact to

surfaces 8 m from an

application area

(µg/kg bw/d)

Risk Quotient

Buffer zone needed

to reduce toddler

exposure to the

AOEL

Boom

High boom, fine droplets 3.48 0.0087 0.0

High boom, coarse droplets 0.55 0.0014 0.0

Low boom, fine droplets 1.18 0.0029 0.0

Low boom, coarse droplets 0.28 0.0007 0.0

Airblast

Airblast vineyard 0.53 0.0013 0.0

Estimated bystander exposure from spray drift after application of NOVELLUS FUNGICIDE to grape

vines is below the AOEL. No buffer zone is required to protect bystanders.

Conclusions of the human health risk assessment


acceptable even without the use of appropriate Personal Protective Equipment (PPE). There is no

need for an application of a re-entry interval control or a need for a buffer zone to protect bystanders.

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Appendix H: Environmental risk assessment

Applicant’s environmental risks assessment

The applicant has provided the EPA with its own New Zealand specific environmental risk

assessment to support registration of NOVELLUS FUNGICIDE for use in New Zealand (Australian

Environment Agency Proprietary Limited 2018). This has been reviewed and integrated/referred to

throughout this document.

Evaluation of toxicity of the mixture

No quantitative evaluation of mixture toxicity has been performed for the active ingredients eugenol,

geraniol, and thymol, and end-use product NOVELLUS FUNGICIDE.

When the toxicity endpoints determined for the end-use product NOVELLUS FUNGICIDE are

expressed on an active ingredient basis, toxicity of the individual active ingredients appears to be

higher when part of the formulated substance (ranging from 1.5 to 9.9 times more toxic depending on

the active ingredient and species).

The aquatic risk assessment is always performed using the toxicity endpoints derived for the active

ingredient(s). This is because environmental fate data are only ever generated for active ingredients

(worldwide). An indication that the active ingredients are more toxic when part of the formulation may

mean risks to the aquatic environment are underestimated when the assessment is based on the

endpoints derived for the individual active ingredients. In this case it is important to note, as reiterated

below for the aquatic risk assessment, even if the endpoints derived for the individual active

ingredients were of 10 times greater toxicity, risks would still be below the level of concern (non-

threatened and threatened species).

The soil toxicity, terrestrial vertebrate toxicity, and terrestrial invertebrate toxicity risk assessments

have all been performed with endpoints derived for the end-use product NOVELLUS FUNGICIDE

since no toxicity data are available for the individual active ingredients. An evaluation of the toxicity of

the mixture cannot be performed for these environmental receptors.

Aquatic risk assessment

The basis for the aquatic risk assessment is a comparison of the expected environmental

concentrations (EEC) with toxicity endpoints to which safety factors have been applied. The EEC is

divided by the toxicity endpoint to calculate a risk quotient (RQ) value. The methodology for the aquatic

risk assessment, including the level of concern (LOC) ascribed to specific RQ values, is described in

detail in the EPA standard risk assessment methodology (EPA 2018).

Calculation of expected environmental concentrations

The parameters used in GENEEC2 modelling are listed in Table 22.

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Table 22: Input parameters for GENEEC2 analysis

Parameter Application method for NOVELLUS FUNGICIDE

Active substance Eugenol Geraniol Thymol

Crop Grapevines

Application rate (g/ha)1 132 264 264

Application frequency 4

Application interval (days) 7

Kd1 0.1 L/kg (default assumption in absence of reliable data)

Aerobic soil DT50 (days) 1.8 0.34 0.68

Pesticide wetted in? No

Methods of application Air blast spray (orchard and vineyard), foliated vineyard

‘No spray’ zone (width) 0 m

Water solubility (ppm, pH 7) 1850 572 596

Aerobic aquatic DT50 whole system(days)2 3.6 (default) 0.68 (default) 1.36 (default)

Aqueous photolysis DT50 (days)3 0 (stable, default assumption in absence of data)

1 The maximum application rates take into account the specific density of 1.035 mL/cm3

2 Active ingredients are assumed to be mobile in soil in absence of reliable data

3 If parameter unavailable, GENEEC2 user manual recommends to use 2 x the aerobic soil half-life

4 Assumed actives are stable to photolysis as a worst-case scenario, although this is unlikely to be the case in

reality based on their ready biodegradability and rapid degradation in soil

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Output from the GENEEC2 model

Eugenol

RUN No. 1 FOR eugenol ON grapes * INPUT VALUES *

--------------------------------------------------------------------

RATE (#/AC) No.APPS & SOIL SOLUBIL APPL TYPE NO-SPRAY INCORP

ONE(MULT) INTERVAL Kd (PPM ) (%DRIFT) ZONE(FT) (IN)

--------------------------------------------------------------------

0.118( 0.126) 4 7 0.1 1850.0 VINYAR( 1.5) 0.0 0.0

FIELD AND STANDARD POND HALFLIFE VALUES (DAYS)

--------------------------------------------------------------------

METABOLIC DAYS UNTIL HYDROLYSIS PHOTOLYSIS METABOLIC COMBINED

(FIELD) RAIN/RUNOFF (POND) (POND-EFF) (POND) (POND)

--------------------------------------------------------------------

1.80 2 0.00 0.00- 0.00 3.60 3.60

GENERIC EECs (IN MICROGRAMS/LITER (PPB)) Version 2.0 Aug 1, 2001

--------------------------------------------------------------------

PEAK MAX 4 DAY MAX 21 DAY MAX 60 DAY MAX 90 DAY

GEEC AVG GEEC AVG GEEC AVG GEEC AVG GEEC

--------------------------------------------------------------------

3.33 2.87 1.41 0.55 0.37

Geraniol

RUN No. 1 FOR geraniol ON grapes * INPUT VALUES *

--------------------------------------------------------------------



--------------------------------------------------------------------

0.235( 0.235) 4 7 0.1 572.0 VINYAR( 1.5) 0.0 0.0


--------------------------------------------------------------------



--------------------------------------------------------------------

0.34 2 0.00 0.00- 0.00 0.68 0.68

GENERIC EECs (IN NANOGRAMS/LITER (PPTr)) Version 2.0 Aug 1, 2001

--------------------------------------------------------------------



--------------------------------------------------------------------

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257.05 141.70 30.36 10.63 7.08

Thymol

RUN No. 1 FOR thymol ON grapes * INPUT VALUES *

--------------------------------------------------------------------



--------------------------------------------------------------------

0.235( 0.235) 4 7 0.1 596.0 VINYAR( 1.5) 0.0 0.0


--------------------------------------------------------------------



--------------------------------------------------------------------

0.68 2 0.00 0.00- 0.00 1.36 1.36

GENERIC EECs (IN MICROGRAMS/LITER (PPB)) Version 2.0 Aug 1, 2001

--------------------------------------------------------------------



--------------------------------------------------------------------

1.78 1.24 0.35 0.12 0.08

The maximum estimated environmental concentrations (EECs) of eugenol, geraniol, and thymol

following application of NOVELLUS FUNGICIDE as estimated by GENEEC2 are 0.00333, 0.000257

and 0.00178 mg/L, respectively.

Calculated risk quotients

The calculated acute risk quotients for each trophic level considering the above EECs, and lowest

relevant toxicity figures are presented in Table 23.

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Table 23: Acute risk quotients derived from the GENEEC2 model and toxicity data

Species

Peak EEC

from

GENEEC2

(mg/L)

LC50 or

EC50

(mg/L)

Acute

RQ Conclusion

Eugenol

Fish, Oncorhynchus mykiss 0.00333 >10 0.00033 Below LOC for threatened/non-

threatened species

Crustacea, Daphnia magna 0.00333 1.11 0.0030 Below LOC for threatened/non-

threatened species

Algae, Pseudokirchneriella

subcapitata

0.00333 15.4 0.00022 Below LOC for threatened/non-

threatened species

Geraniol

Fish, Oncorhynchus mykiss 0.000257 11.6 0.000022 Below LOC for threatened/non-

threatened species


threatened species


subcapitata


threatened species

Thymol

Fish, Oncorhynchus mykiss 0.00178 3.0 0.00059 Below LOC for threatened/non-

threatened species


threatened species


subcapitata


threatened species

Predicted acute exposures are considerably below the LOC for all aquatic species (threatened and

non-threatened) for eugenol, geraniol and thymol. The scenario modelled for application of

NOVELLUS FUNGICIDE to grapevines is worst-case, assuming the maximum application rate,

maximum frequency of applications and worst-case assumptions for parameters where either reliable

data were not available, or no data were available.

As discussed above in regard to mixture toxicity, it is important to note that even if risks to the aquatic

environment have potentially been underestimated since the risk assessment was performed using

toxicity endpoints derived for the individual active ingredients, even if the aquatic endpoints had 10

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times greater toxicity, risks to aquatic species (threatened and non-threatened) would still be below

the LOC.

Since no risks were identified, no further spray drift or runoff modelling is required.

This conclusion is in agreement with that made in the environmental risk assessment submitted by

the applicant.

Conclusions of the aquatic risk assessment


FUNGICIDE to grapevines resulted in calculated acute risk quotients (RQs) below the level of

concern (LOC) for the aquatic environment. The scenario modelled for application of NOVELLUS

FUNGICIDE to grapevines is worst-case, assuming the maximum application rate, maximum

frequency of applications and worst-case assumptions for parameters where either reliable data were

not available, or no data were available. No additional controls were determined necessary to mitigate

adverse effects to the aquatic environment.

Groundwater risk assessment

The predicted environmental concentrations in groundwater (PECgw) of eugenol, geraniol, and

thymol, calculated using the Sci-Grow model, are shown in Table 24. The PECgw values are

compared to the EU limit for maximum permissible concentration of pesticide active ingredients of 0.1

µg/L.

Table 24: Input parameters for Sci-Grow analysis and resulting PECgw values

Input parameters Eugenol Geraniol Thymol

Application rate (kg ai/ha)1 0.132 0.264 0.264

Application rate (lb ai/acre)2 0.118 0.235 0.235

Number of applications 4

Koc3 10

Aerobic soil DT50 (days) 1.8 0.34 0.68

PECgw (µg/L) 0.00114 0.00069 0.00113

1 The maximum application rates take into account the specific density of 1.035 mL/cm3

2 The application rate is conversion from kg ai/ha to lb/acre (the units required to be entered into the model) by

multiplying it by 0.892

3 Default worst-case Koc selected for use in the modelling due to lack of reliable data

Using worst-case assumptions (maximum application rate, maximum number of applications, no crop

interception, and a worst-case default Koc value assuming the active ingredients are very mobile in

soil) PECgw values for eugenol, geraniol, and thymol are well below the 0.1 µg/L trigger level set by

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the European regulators. Risks to groundwater are therefore considered below the level of concern

following application of NOVELLUS FUNGICIDE to grapevines.


the applicant.

Conclusions of the groundwater risk assessment





level of concern following application of NOVELLUS FUNGICIDE to grapevines.

Sediment risk assessment

As described in the environmental fate section above (Appendix D), given the assumptions made

regarding likelihood of rapid volatilisation, and that all three active substances are readily

biodegradable, exposure of water/sediment systems is unlikely to be significant. Based on the

available data, toxicity of eugenol, geraniol, thymol, and the substance NOVELLUS FUNGICIDE in

the aquatic environment is low. No assessment of toxicity to sediment-dwelling organisms for

applications of NOVELLUS FUNGICIDE to grapevines is considered necessary.


the applicant.

Terrestrial risk assessment

The terrestrial risk assessment considers the risks to soil organisms, terrestrial plants, birds, bees,

and non-target arthropods.

The methodology for the terrestrial risk assessment is described in the EPA standard risk assessment

methodology (EPA 2018).

Soil macro-organisms

The soil organism risk assessment is based on a comparison of the PEC with toxicity values for the

substance NOVELLUS FUNGICIDE. The toxicity value is divided by the PEC to give a toxicity

exposure ratio (TER). The different levels of concern assigned to TER values are listed in the EPA

standard risk assessment methodology (EPA 2018).

The results of the acute risk assessment for soil organisms are summarised in Table 25.

Note this assessment was performed using the acute toxicity endpoint obtained for the end-use

product NOVELLUS FUNGICIDE since there are sufficient data. Toxicity of the individual active

ingredients has not been considered separately. It should be noted that this is not the standard

approach since this assessment is typically performed using the soil toxicity endpoints derived for the

individual active ingredient(s) as discussed previously in Appendix E. In addition, since all actives are

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short-lived in the environment (discussed in Appendix D), only an acute assessment of risks to

earthworms has been performed as this is considered the most relevant exposure scenario

(discussed in Appendix E).

It should also be noted that two tiers of assessment were considered to assess in-field risks to soil

organisms. At the first tier crop interception is not taken into account, whilst the second tier introduces

more realism into the risk assessment by considering that a proportion of the applied substance will

be intercepted by the grapevines, and therefore not reach the soil.

Table 25: Acute TER values for soil organisms

Species

LC50

(mg

product/kg

soil)

Drift (%)

PEC (mg

product/kg

soil)3

TER

acute Conclusion

Tier I “in-field” scenario – 4140 g product/ha1, four applications with 7-day interval (without crop

interception)

Earthworm,

Eisenia fetida >5002 NA 5.92 84

Below LOC for non-threatened

species

Above LOC for threatened

species

Tier II “in-field” scenario – 4140 g product/ha1, four applications with 7-day interval (60% crop

interception, corresponding to flowering BBCH 53-69; (EFSA 2013)

Earthworm,

Eisenia fetida >5002 NA 2.37 211

Below LOC for threatened/non-

threatened species

Tier I “off-field” scenario – 4140 g product/ha, four applications with 7-day interval (without crop

interception)

Earthworm,

Eisenia fetida >5002 6.714 0.397 1259

Below LOC for threatened/non-

threatened species

1 The maximum application rate listed in the draft label is 400 mL product per 100 L. In combination with a

maximum water rate of 1000 L/ha as listed in the GAP, this is equivalent to 4000 mL product/ha. Taking into

account a specific density of 1.035 mL/cm3, this equates to a maximum application rate of 4140 g product/ha).

2 Original toxicity endpoints from the artificial soil tests have been divided by 2 to account for different soil

characteristics and the possibility of reduced bioavailability for soil organisms of lipophilic substances (Log Kow

>2) as per the EFSA Technical Report (EFSA 2015)

3 Note that the longest 80th percentile DT50 was used in this calculation as a worst-case scenario (1.8 days as

determined for the active ingredient eugenol)

4 Basic drift value for four late applications to grapevines at 3 m (worst-case drift value selected)

Using worst-case assumptions (maximum application rate, maximum number of applications, no crop

interception, and longest 80th percentile lab DT50 in soil), acute risks to soil organisms are determined

to be below the level of concern for non-threatened species and above the level of concern for

threatened species. When considered crop interception, risks are below the LOC for both threatened

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species species in-field (when crop interception is taken into account) and off-field, following use of

NOVELLUS FUNGICIDE in grapevines.


the applicant.

Soil micro-organisms

For NOVELLUS FUNGICIDE the data indicate there was no impact on respiration activity and <25%

effects on nitrogen transformation at application rates up to 54.4 mg formulation/ha (highest

concentration tested, and corresponds to 10 times the maximum predicted environmental

concentration in soil in-field). Risks to soil microflora following use of NOVELLUS FUNGICIDE in

grapevines are therefore considered below the level of concern.

Conclusions of the soil organism risk assessment




Non-target plant risk assessment

No data have been submitted in regard to toxicity of NOVELLUS FUNGICIDE to non-target plants and

no quantitative risk assessment could therefore be performed.

The applicant states that NOVELLUS is a fungicide treatment and according to European guidelines

data on the effects on non-target flora are not required. It is known however, that geraniol is a

component of citronella oil, which has known plant toxicity. Furthermore, it appears that eugenol has

herbicidal activity since it is the active ingredient in the formulated product “Matran® EC”, which is

approved for use as non-selective weed control in the US.

Information gained during the course of efficacy trials have been used to show that effects to non-

target flora were nil or negligible, as described as follows.

Although no specific studies were undertaken to evaluate for any effects on other plants, no adverse

effects were observed on any crops adjacent to those on which any of the efficacy or taint trials were

located. The efficacy of “3AEY” (NOVELLUS FUNGICIDE) against diseases on other crop types was

investigated in glasshouse and field trial studies, and these trials have not reported any observed

phytotoxic effects at rates equivalent or higher than that proposed for "3AEY” (NOVELLUS

FUNGICIDE). The crops in question include potato, oilseed rape, winter wheat, strawberry, courgette,

cucumber, watermelon, lettuce, capsicum, cacao, papaya, walnut, Lúcumo, and grasses including

turf, and general pasture grass. Due to the relative crop safety of “3AEY” (NOVELLUS FUNGICIDE) it

is considered unlikely that “3AEY” (NOVELLUS FUNGICIDE), applied as per the proposed label

recommendations, would have any deleterious impact on other plants, including succeeding crops.

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This information is considered sufficient to address any potential concerns about the phytotoxic

activity of NOVELLUS FUNGICIDE to non-target plants.

Conclusion for non-target plant risk assessment


target flora were nil or negligible. This information is considered sufficient to address any potential

concerns about the phytotoxic activity of NOVELLUS FUNGICIDE to non-target plants.

Bird risk assessment

The bird risk assessment is based on a comparison of the PEC with toxicity values for the substance

NOVELLUS FUNGICIDE. The toxicity value is divided by the PEC to give a toxicity exposure ratio

(TER). The different levels of concern assigned to specific TER values are listed in the EPA standard

risk assessment methodology (EPA 2018).

Screening assessment

Predicted exposure of birds to NOVELLUS FUNGICIDE is assessed using an acute screening

assessment, and the results are shown in Table 26.

Note this assessment was performed using the acute toxicity endpoint obtained for the end-use

product NOVELLUS FUNGICIDE since there are sufficient data. Toxicity of the individual active

ingredients has not been considered separately. It should be noted that this is not the standard

approach, and this assessment is typically performed on the endpoints derived for the active

ingredient(s) as previously discussed in Appendix E. In addition, since all active ingredients are short-

lived in the environment (discussed in Appendix D), only an acute assessment of risks to birds has

been performed as this is considered the most relevant exposure scenario (discussed in Appendix E).

Table 26: Exposure of birds via the acute screening assessment

Screening

type2

Indicator

species3

Short-cut

value

(90th%)4

TWA5 MAF

(90th %)6

Daily

dietary

dose

(DDD)

TER

Application rate of 4.14 kg product/ha1, four applications with a 7-day application interval

Acute

Small

omnivorous

bird

95.3 1 1.8 710.18 14.1




2 EFSA, (EFSA 2009), Table 5 p27

3 EFSA, (EFSA 2009), Table 6 p28

4 90th %ile short-cut value used for the acute assessment, EFSA, (EFSA 2009), Table 6 p28

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5 A time-weighted average (TWA) is used for the acute screening assessment. EFSA, (EFSA 2009), p34.

6 90th %ile MAF value used for the acute assessment, EFSA, (EFSA 2009), Table 7 p29

Using worst-case assumptions (maximum application rate, maximum number of applications, and no

crop interception), the acute screening risk assessment indicates an acute risk below the level of

concern to birds following use of NOVELLUS FUNGICIDE in grapevines. As no risks were above the

level of concern, it is not necessary to progress to performing a Tier 1 risk assessment.


the applicant.

Secondary poisoning

The Log Pow values for the three active ingredients indicate that potential for bioaccumulation is low

in all cases (Log Pow <4). Although Log Pow values are closer to the threshold of 4 for geraniol (3.79)

and thymol (3.97), it is considered unlikely that either geraniol or thymol will persist or accumulate in

soil or natural water systems due to its rapid volatilisation properties, and ready biodegradability in the

environment. Accumulation in worms and fish and exposure of birds from consumption of these is

considered unlikely, and no risk assessment via secondary poisoning is required therefore.

Conclusions for bird risk assessment


grapevines are below the level of concern, and any risks to birds are considered negligible.

Pollinator risk assessment

The basis for the pollinator risk assessment is a comparison of the environmental exposure

concentration (EEC) with toxicity endpoints to which safety factors have been applied. The EEC is

divided by the toxicity endpoint to calculate a risk quotient (RQ) value. The methodology for the

pollinator risk assessment, including the level of concern (LOC) ascribed to specific RQ values, is

described in detail in the EPA standard risk assessment methodology (EPA 2018). The results of the

bee risk assessment are shown in Table 27.

Note this assessment was performed using the acute contact and oral toxicity endpoints obtained for

the end-use product NOVELLUS FUNGICIDE since there are sufficient data. Toxicity of the individual

active ingredients has not been considered separately. It should be noted that this is not the standard

approach, and this assessment is typically performed using endpoints derived for the individual active

ingredient(s) as discussed previously in Appendix E. In addition, since all active ingredients are short-

lived in the environment (discussed in Appendix D), only an acute assessment of risks to honeybees

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has been performed as this is considered the most relevant exposure scenario (as previously

discussed in Appendix E).

Table 27: Bee exposure estimates and RQ values

Use scenario

Application

rate (kg

product/ha)1

EEC (µg

product/bee)

Toxicity

endpoint

value (µg

product/bee)

RQ Conclusion

Tier I (without crop interception)

Acute / adult bees – contact

Grapevines 4.14 9.936 >200.0 0.050 Below the LOC

Acute / adult bees – oral

Grapevines 4.14 118.49 >224.6 0.528 Potentially above

the LOC

Tier II (with 60% crop interception, corresponding to flowering BBCH 53-69; (EFSA 2013))

Acute / adult bees – oral

Grapevines 2.48 70.98 >224.6 0.316 Below the LOC




The acute risk quotient (RQ) calculated for contact toxicity to adult honeybees following application of

NOVELLUS FUNGICIDE in grapevines is below the level of concern (LOC).

The acute RQ for oral toxicity to adult honeybees following application of NOVELLUS FUNGICIDE to

grapevines (without considering crop interception) is “potentially” above the LOC since using the

minimum LD50 results in an RQ 1.3 times above the LOC (0.4). Since the acute oral toxicity endpoint

is not an absolute value however, the calculated RQ of 0.528 is a worst-case estimate. Taking into

account crop interception (60%, corresponding to flowering at BBCH 53 to 69), the acute RQ for oral

toxicity to adult honeybees is below the LOC.

The risk to adult honeybees following use of NOVELLUS FUNGICIDE in grapevines is considered to

be low overall.

This conclusion is in agreement with that of the applicant in regard to oral toxicity. The applicant’s risk

assessment states that “contact toxicity is not very likely as the application will be on bare soil.

Therefore, this route of exposure is not assessed”. The EPA considers that contact exposure is a

relevant route of exposure of bees however, following application to grapevines, and has assessed

the risk from contact exposure accordingly.

Conclusions of the pollinator risk assessment

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bees from use of NOVELLUS FUNGICIDE are considered to be low overall.

Non-target arthropod risk assessment

The non-target arthropod risk assessment is a comparison of the predicted environmental

concentration (PEC) with toxicity endpoints to which safety factors have been applied. The PEC is

divided by the toxicity endpoint to calculate a hazard quotient (HQ) value. The methodology for the

non-target arthropods risk assessment, including the level of concern (LOC) ascribed to specific HQ

values, is described in detail in the EPA standard risk assessment methodology (EPA 2018).

Results of the in-field and off-field non-target arthropod risk assessment are shown in Table 28 and

Table 29, respectively.

Note toxicity to non-target arthropods was performed using the endpoints obtained for the end-use

product NOVELLUS FUNGICIDE, which is the standard approach in this case.

Table 28: In-field HQ values for non-target arthropods

Species

LR50

(g

product/ha)1,2

Application

rate

(g product/ha)1

MAF Hazard

Quotient Conclusion


rhopalosiphi >12,420 4140 2.7 0.90 Below the LOC

Predatory mite,

Typhlodromus pyri >12,420 4140 2.7 0.90 Below the LOC

1 The endpoints, and maximum application rate takes into account the specific density of 1.035 mL/cm3



Table 29: Off-field HQ values for non-target arthropods (drift factor = 6.71%1)

Species

LR50

(g

product/ha)2,3

Application

rate

(g product/ha)2

MAF Hazard

Quotient Conclusion


rhopalosiphi >12,420 4140 2.7 0.06 Below the LOC

Predatory mite,

Typhlodromus pyri >12,420 4140 2.7 0.06 Below the LOC

1 Basic drift value for four late applications to grapevines at 3 m (worst-case drift value selected)

2 The endpoints, and maximum application rate takes into account the specific density of 1.035 mL/cm3

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Using worst case assumptions (maximum application rate, and a worst-case drift factor), risks to non-

target arthropods were determined to be below the level of concern both in-field and off-field following

use of NOVELLUS FUNGICIDE in grapevines.


the applicant.

Conclusion for non-target arthropod risk assessments

Risks to non-target arthropods are below the level of concern both in-field and off-field following use

of NOVELLUS FUNGICIDE in grapevines.

Conclusions of the ecological risk assessment

The EPA staff assessed the potential risks to the environment following use of NOVELLUS

FUNGICIDE following the instructions captured in the proposed label and GAP table.

Aquatic risk assessment


FUNGICIDE to grapevines resulted in calculated acute risk quotients (RQs) below the level of

concern (LOC) for the aquatic environment. The scenario modelled for application of NOVELLUS

FUNGICIDE to grapevines is worst-case, assuming the maximum application rate, maximum

frequency of applications and worst-case assumptions for parameters where either reliable data were

not available, or no data were available. No additional controls were determined necessary to mitigate

adverse effects to the aquatic environment

Groundwater





level of concern following application of NOVELLUS FUNGICIDE to grapevines.

Sediment

Given the assumptions made regarding likelihood of rapid volatilisation, and that all three active

substances are readily biodegradable, exposure of water/sediment systems is unlikely to be

significant. Based on the available data, toxicity of eugenol, geraniol, thymol, and the substance

NOVELLUS FUNGICIDE in the aquatic environment is low. No assessment of toxicity to sediment-

dwelling organisms for applications of NOVELLUS FUNGICIDE to grapevines was considered

necessary.

Terrestrial risk assessment

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Soil




Non-target plants


target flora were nil or negligible. This information is considered sufficient to address any potential

concerns about the phytotoxic activity of NOVELLUS FUNGICIDE to non-target plants.

Birds


grapevines are below the level of concern. The scenario modelled was worst-case (maximum

application rate, maximum number of applications, and no crop interception) and therefore, any risks

to birds are considered negligible.

Pollinators





bees from use of NOVELLUS FUNGICIDE are considered to be low overall.

Non-target arthropods

Risks to non-target arthropods are below the level of concern both in-field and off-field following use

of NOVELLUS FUNGICIDE in grapevines. The scenario modelled was worst-case (maximum

application rate, and a worst-case drift factor).

Overall, it is considered that risks to the environment from the proposed use of NOVELLUS

FUNGICIDE are acceptable with the proposed controls. These conclusions are in agreement with

those made in the environmental risk assessment submitted by the applicant.

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Appendix I: Study summaries

Manufacturer code name for NOVELLUS FUNGICIDE is Product 3AEY

Toxicity study summaries

Mammalian toxicity studies on NOVELLUS FUNGICIDE have been reviewed. These studies are used

to describe potential risks to human health. The effects on mammals in these studies are used as

proxies for the impact on humans. Data from the studies have been used for classifying the

formulated substance and for derivation of appropriate health-based criteria which are used in risk

assessment. The summary of the studies is provided in Table 30 to Table 35.

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Mammalian toxicology - Robust study summaries for NOVELLUS

FUNGICIDE

Acute toxicity [6.1]

Table 30: Acute Oral Toxicity [6.1 (oral)]

Type of study Acute oral toxicity in rats

Flag Key study

Test Substance Product 3AEY

Endpoint Acute lethality (LD50), signs of toxicity

Value LD50 > 2000 mg/kg bw

Reference Shinde, K.; 2007. Acute oral toxicity study of 3AEY in rats. Jai Research

Foundation. Gujarat, India; Report number: 6733.

Klimisch Score 1

Amendments/Deviations None of significance

GLP Yes

Test Guideline OECD 423

Species Rat

Strain Wistar

No/Sex/Group 6F; 3/group

Dose Levels 300, 2000 mg/kg bw

Exposure Type Oral by gavage

Study Summary

An acute oral toxicity test was conducted in female Wistar rats (3/group)

to determine the potential for 3AEY to produce toxicity from single dose.

Set I animals received test substance at the dose of 300 mg/kg bw. Set

II animals were dosed at the same dose level as no mortality was

observed in set I. As no mortality was observed again, set III animals

were administered 2000 mg/kg bw of test substance. No mortality was

observed and set IV animals were administered 2000 mg/kg bw of test

substance. Animals were observed for mortality, signs of gross toxicity

and individual body weights. At the end of the 14 days observation

period, all animals were sacrificed and subjected to gross pathological

examinations.

Lethargy was observed in animals dosed at 300 mg/kg bw, and both

lethargy and abdominal breathing were observed in animals treated with

2000 mg/kg bw. Slight reduction in bodyweight gain was noted at 2000

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mg/kg bw dose level. There were no treated–related gross lesions

present at necropsy.

Additional Comments No additional comments

Conclusion The LD50 of 3AEY in Wistar rats was estimated to be greater than 2000

mg/kg bw

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Table 31: Acute Dermal Toxicity [6.1 (dermal)]

Type of study Acute dermal toxicity in rats

Flag Key study


Endpoint Acute lethality (LD50), signs of toxicity

Value LD50 > 2000 mg/kg bw

Reference Shinde, K.; 2007. Acute dermal toxicity study of product 3AEY in rats.

Jai Research Foundation. Gujarat, India; Report number: 6734.

Klimisch Score 1

Amendments/Deviations None of significance

GLP Yes

Test Guideline/s OECD 402

Species Rat

Strain Wistar

No/Sex/Group 5/sex/group

Dose Levels 0, 2000 mg/kg bw

Exposure Type Dermal using a porous gauze dressing

Study Summary

An acute dermal toxicity study was conducted in Wistar rats

(5/sex/group). Undiluted test substance was applied over the clipper

area of rats at the dose of 2000 mg/kg bw for 24 hours and observed for

14 days. The test substance was held in contact with skin using a

porous gauze dressing and a non-irritating tape to prevent loss of test

substance due to evaporation and also to ensure that the animals did

not lick or ingest it.

All animals survived and body weight was comparable to that of control.

No signs of gross toxicity and dermal irritation was observed. No gross

abnormalities were noted in any animal when necropsied in 14-day

observation period.


Conclusion The LD50 of Product 3AEY in Wistar rats was estimated to be greater

than 2000 mg/kg bw for each sex.

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Table 32: Acute Inhalation Toxicity [6.1 (inhalation)]

Type of study Acute inhalation toxicity in rats

Flag Key study


Endpoint Acute lethality (LC50), signs of toxicity

Value LC50 > 2.28 mg/L

Reference Patel, U.; 2007. Acute inhalation toxicity study of product 3AEY in rats.


Klimisch Score 1

Amendments/Deviations None

GLP Yes


Species Rat

Strain Wistar

No/Sex/Group 10/sex/group

Dose Levels 2.280 mg/L; mass median aerodynamic diameter (MMAD): 2.94 µm;

geometric standard deviation (GSD): 2.77 µm

Exposure Type Nose only

Study summary

An acute inhalation toxicity study was conducted in rats (10/sex/group)

which were exposed for 4 hours using nose/head exposure system

followed by 14 days observation period. The maximal achievable

gravimetric chamber concentration was 2.280 mg/L. The average

MMAD was estimated to be 2.94 µm with an average GSD of 2.77 µm.

Animals were observed for mortality, any signs of toxicity and gross

pathological changes.

The test substance was well tolerated at dose level of 2.280 mg/L and no

mortality was observed. Toxic signs like nasal irritation and nasal

discharge were observed at the end of exposure but not on subsequent

days. At terminal sacrifice animals did not reveal any abnormality of

pathological significance except uterine distension. Mild lesions were also

noted but were considered a spontaneous finding, unrelated to the

treatment.


Conclusion The LC50 was greater than 2.280 mg/L in combined male and female

groups.

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Table 33: Skin Irritation [6.3/8.2]

Type of study Acute skin irritation in rabbits

Flag Key study


Endpoint The Mean Draize Scores

Value 1.33 for erythema and 0.0 for oedema at 24, 48 and 72 hours

Reference Shinde, K.; 2007. Acute dermal irritation study of product 3AEY in

rabbits. Jai Research Foundation. Gujarat, India; Report number: 6736.

Klimisch Score 1


GLP Yes


Species Rabbit

Strain New Zealand White

No/Sex/Group 3/M/group

Dose Levels 0.5 mL (undiluted)

Exposure Type Dermal , semi-occlusive wrap

Study Summary

In a skin irritation study, 0.5 mL of undiluted test substance was applied

evenly to the clipped intact skin of rabbits for a period of 4 hours. 0.5 mL

of distilled water was applied on the other clipped side which served as

a control site. Both the sites were covered with gauze patches and were

secured at margins by non-irritating tape to prevent the evaporation of

the test substance and to ensure that the animals do not ingest it. After 4

hours of exposure, the residual test substance was removed with cotton

soaked in distilled water. The skin of each rabbit was observed and

scored for erythema and oedema at 1, 24, 48, 72 hours and on Day 7.

No toxic signs other than dermal irritation were observed during the

study. Well defined erythema was seen at 24 hours on the treated skin

site of all three rabbits. However on Day 7, all animals recovered

completely and appeared normal.

The Mean dermal irritation scores (24, 48, 72 hours) were 1.33 for

erythema and 0.0 for oedema.


Conclusion The substance was non-irritant.

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Table 34: Eye Irritation [6.4/8.3]

Type of study Acute eye irritation in rabbits

Flag Key study


Endpoint The Mean Draize Scores

Value The Mean Draize Scores (24, 48, 72 hours) were 1.22 for corneal

opacity, 0.0 for iritis and 2 for conjunctival redness and chemosis.

Reference Shinde, K.; 2007. Acute eye irritation study of product 3AEY in rabbits.


Klimisch Score 1


GLP Yes


Species Rabbit

Strain New Zealand White

No/Sex/Group 3/M/group

Dose Levels 0.1 mL

Exposure Type Ocular (Instillation in the conjunctival sac)

Study Summary

An acute eye toxicity irritation study was performed on male New

Zealand white rabbits (n=3). 0.1 mL of test substance was instilled into

one eye of each animals and the other eye served as control was

instilled with 0.1 mL of normal saline. After 24 hours, both the eyes of all

animals were washed with normal saline. Animals were observed for

ocular irritation at 1, 24, 48 and 72 hours and Day 7, 14 and 21 after

instillation.

Conjunctival redness and chemosis was observed after 1, 24, 48 and 72

hours and Day 7, in all animals after instillation of the test substance

which disappeared after fourteen days. The ocular lesions were found to

be reversible and treated eyes appeared normal after by Day 21 post

instillation. The iris of all animals were unaffected throughout the study

and there were no treatment related clinical signs other than irritation.

The scores for conjunctival redness and chemosis were:

Conjunctival redness (1 hour), 24, 48, 72 hours

Animal 1: (2), 2, 2, 2

Animal 2: (2), 2, 2, 2

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Animal 3: (2), 2, 2, 2

The Mean Draize Score (24, 48, 72 hours) for conjunctival redness was

18/9 = 2

Chemosis (1 hour), 24, 48, 72 hours

Animal 1: (1), 2, 2, 2

Animal 2: (2), 2, 2, 2

Animal 3: (2), 2, 2, 2

The Mean Draize Score (24, 48, 72 hours) for chemosis was 18/9 = 2

The scores for cornea opacity was:

Cornea opacity (1 hour), 24, 48, 72 hours

Animal 1: (0), 1, 1, 2

Animal 2: (0), 1, 1, 1

Animal 3: (0), 1, 1, 2

The Mean Draize Score (24, 48, 72 hours) for cornea opacity was 11/9 =

1.22


Conclusion The test substance is an eye irritant and is classified as 6.4A

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Table 35: Contact Sensitisation [6.5]

Type of study Sensitisation in mice

Flag Key study

Test Substance 3AEY

Endpoint Stimulation Index (SI)

Value SI< 3 for undiluted test substance treated group and SI> 3 for 25 and

50% treated groups.

Reference

Sanders, A.; 2007. 3AEY: Local lymph node assay in the mouse.

Safepharm Laboratories Limited, Derbyshire, UK; SPL project number: I-

2408/0001

Klimisch Score 1


GLP Yes


EC No 2004/73; B42

Species Mouse

Strain CBA/CaBkl

No/Sex/Group 4/F/group

Dose Levels 25 µL/ear of 25, 50, and 100% v/v of test substance in dimethyl

formamide (DMF)

Exposure Type Topical (Dorsal surface of each ear using a micropipette)

Study Summary

The sensitisation potential of 3AEY was determined in mice after

repeated topical applications. 25 µL of test substance undiluted or 25%,

and 50% v/v in DMF was applied to dorsum of both ears of each mouse

once per day for three consecutive days (Days 1, 2, 3) using a

micropipette. Another group of four mice were treated with DMF alone in

same manner. After 5 days of first application all mice were injected with

250 µL of phosphate buffered saline containing 3H-methyl thymidine via

the tail vein.

No signs of toxicity or mortality was observed in test or control animals

during the study. Fur loss around the base of ears and neck was noted

post dose on Day 3 and for remainder of the study in the animals treated

with undiluted test substance.

SI is expressed as the mean radioactive incorporation for each

treatment group divided by the mean radioactive incorporation of vehicle

control group are as given below:

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Concentration (%

v/v)

SI Result

Vehicle - -

25 5.40 positive

50 3.08 positive

100 1.92 negative

SI obtained at each concentration resulted in an inverse dose response.

Additional Comments

The positive result at 25 and 50% test concentrations was maybe due to

the encapsulated active ingredients being extracted by DMF and

therefore becoming more bioavailable. As the undiluted test substance

is an aqueous suspension containing high proportion of water it is

considered that the epidermal barrier is preventing the encapsulated

active ingredients reaching and activating the relevant cellular targets in

the skin. Hence, the results with undiluted test substance is therefore

considered more relevant for human risk assessment.

Conclusion The test substance was not considered positive for dermal sensitisation

potential.

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Environmental fate studies

All studies on the environmental fate of eugenol, geraniol, and thymol provided by the applicant have

been reviewed. These studies are used to understand how eugenol, geraniol, and thymol behave and

move through the environment. Data from these studies have been used in relevant areas of the risk

assessment to parameterise the models, predict environmental concentrations of eugenol, geraniol,

and thymol in the environment following use of NOVELLUS FUNGICIDE and thus, the likely exposure

of environmental receptors.

In this case, the EPA has reviewed the studies and the summaries of these studies provided as part

of the European reviews of eugenol, geraniol, and thymol (EFSA 2011). Where the EPA has not

agreed with the European reviews of the environmental fate study or had additional comments these

are described below. When the EPA fully agrees with the review in the European assessment, no

summary has been made as the summary is available in the publicly available Draft Assessment

Report (DAR).

Summaries of additional environmental fate studies provided by the applicant, which were not part of

the European review are presented in Table 36 to Table 41.

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Aerobic soil metabolism

Table 36: Aerobic degradation in soil (eugenol): key study summary

Study type


Flag

Key study

Test Substance

Active ingredient eugenol

Endpoint

DT50

Value

Eugenol declined rapidly in each soil type. DT50 values of 0.5 and 0.6 days were

observed for the Calke and Ingleby soils, respectively. Insufficient data were

available to calculate DT50 values in the Brierlow and Empingham soil (by

observation these were <1 day and <3 days, respectively).

Reference

Jones (2015). Eugenol: Aerobic Soil Metabolism. Study number: PIF0002.

Klimisch Score

2 (reliable with restriction, see comments below)

Amendments/Devia

tions

There is an Amendment to this study, which corrects errors in the summary and

reported DT50 values for the Brierlow soil.

Two very minor deviations are noted but these are not considered to have impacted

the performance or results of the study.

GLP

Yes

Test Guideline/s

OECD 307

Dose Levels

0.52 mg/kg (nominal concentration, equivalent to an application rate of 520 g

eugenol/ha)

Analytical

measurements

Liquid scintillation counting (LSC), high performance liquid chromatography (HPLC)

and thin layer chromatography (TLC)

Quality criteria met No (see comments below)

Study Summary

The route and rate of degradation of eugenol were studied in four soils (Calke

sandy loam, Brierlow clay loam/silty clay loam, Empingham clay and Ingleby loamy

sand), in the laboratory under aerobic conditions. The soils were selected to

represent a range of textural characteristics, pH (5.0 - 7.7) and organic carbon

contents (1.6 – 3.6%). Soil samples were set up and allowed to acclimatise before

being treated with [14C]-eugenol at a nominal concentration of 0.52 mg/kg,

approximately equivalent to a use rate of 520 g ai/ha. The samples were incubated

under aerobic conditions in the dark at about 20°C at a moisture content equivalent

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to pF 2 for periods of up to 120 days after application. Combined soil extracts were

analysed by HPLC with fraction collection.

The overall recoveries of applied radioactivity (AR) were in the range 81.2 – 116.1%

AR. The variable recoveries of radioactivity may be due to the inhomogeneous

nature of the non-extractable residue, and the difficulties in accurately quantifying

this fraction.

The proportion of radioactivity extracted from soil decreased with time with a

corresponding increase in the levels of non-extractable radioactivity and 14CO2

evolution. Extractable radioactivity declined with time from mean values of 46.2 –

74.4% AR in each soil at zero-time to mean values of 7.6 – 14.2% AR after three

days incubation before plateau through the remainder of the incubation period.

Non-extractable radioactivity accounted for mean values of 65.6 – 70.4% AR after

120 days. Volatile radioactivity, characterised as 14CO2, represented 19.1 – 20.2%

AR after 120 days.





Eugenol degraded to multiple minor unidentified degradates (none of which

individually accounted for >10% AR at a single time point), bound residues and

carbon dioxide.

Comments

Recoveries should range from 90% to 110% for labelled chemicals. Recoveries

were outside this range for this study (81.2 to 116.1%). The author states that the

recoveries of ten vessels had lower recoveries (81.2 to 89.2%) than the specified

range.

The author states the data suggests that the variable recoveries may be due to

difficulties accurately quantifying the high level of bound residues. They state that

due to the volatile nature of the test substance the solid residues were not dried

prior to combustion and this made it difficult (after several attempts) to obtain a

homogeneous sample for analysis and led to high variance in the non-extractable

residue combustion.

The EPA considers this a reasonable explanation, and since the test substance is

readily biodegradable and appears to degrade rapidly in soil. The study is

considered reliable (with restriction due to the low recoveries) but adequate for risk

assessment purposes overall.

The Australian Environment Agency (who performed the environmental risk

assessment on behalf of the applicant) also considered this study reliable and

adequate for risk assessment purposes. In their review they note that “it is apparent

that there is rapid degradation of eugenol and its metabolites. After three days

degradation slows considerably with relatively constant levels of radioactivity found

over the period to 120 days. In the two soils where eugenol was quantified through

to 120 days, levels remained at around 2-3% of radioactivity. It is clear that the

initial half-life of eugenol is <1 days in all soils tested”.

Conclusion





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Table 37: Aerobic degradation in soil (geraniol): key study summary

Study type


Flag

Key study

Test Substance

Active ingredient geraniol

Endpoint

DT50

Value

Values for the Empingham, Brierlow, Ingleby and Calke soils were 0.2, 0.4,

0.3 and 0.3 days, respectively.

Reference

Jones (2015). Geraniol: Aerobic Soil Metabolism. Study number: PIF0005.

Klimisch Score


Amendments/Deviations

None noted

GLP

Yes

Test Guideline/s

OECD 307

Dose Levels


geraniol/ha)

Analytical

measurements

Liquid scintillation counting (LSC) and high performance liquid

chromatography (HPLC)


Study Summary

The route and rate of degradation of geraniol were studied in four soils (Calke

sandy loam, Brierlow clay loam/silty clay loam, Empingham clay and Ingleby

loamy sand) in the laboratory under aerobic conditions. The soils were

selected to represent a range of textural characteristics, pH (5.6 - 7.8) and

organic carbon contents (1.8 – 4.4 %). Soil samples were set up and allowed

to acclimatise before being treated with [14C]-geraniol at a nominal

concentration of 1.04 mg/kg, approximately equivalent to a use rate of 1040 g

ai/ha. The samples were incubated under aerobic conditions in the dark at

about 20°C at a moisture content equivalent to pF 2 for periods of up to 120

days after application. Extracts of soil were analysed by HPLC with fraction

collection.

The overall recoveries of applied radioactivity (AR) were in the range 69.9 –

122.3% AR. The variable recoveries of radioactivity may be due to the

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inhomogeneous nature of the nonextractable residue, and the difficulties in

accurately quantifying this fraction.

The proportion of radioactivity extracted from soil decreased with time with a

corresponding increase in the levels of non-extractable radioactivity and 14CO2

evolution. Extractable radioactivity declined with time from means of 80.0 –

109.6% AR in each soil at zero-time to means of 1.7 – 4.0% after 3 days

incubation and 0.5 – 0.8% AR after 120 days. Nonextractable radioactivity

accounted for means of 30.1 – 39.8% AR after 120 days. Volatile radioactivity,

characterised as 14CO2, represented 43.8 – 57.2% AR after 120 days.

Geraniol degraded rapidly in each soil type. DT50 values for the Empingham,

Brierlow, Ingleby and Calke soils were 0.2, 0.4, 0.3 and 0.3 days, respectively.

Geraniol degraded to four minor unidentified degradates (none of which

individually accounted for >10% AR at a single time point), bound residues

and carbon dioxide.

Comments

Recoveries should range from 90% to 110% for labelled chemicals.

Recoveries were outside this range (69.9 to 113.6%).

The author states the data suggests that the variable recoveries may be due

to difficulties accurately quantifying the high level of bound residues. They

state that due to the volatile nature of the test substance the solid residues

were not dried prior to combustion and this made it difficult (after several

attempts) to obtain a homogeneous sample for analysis and led to high

variance in the non-extractable residue combustion.

The EPA considers this a reasonable explanation, and since the test

substance is readily biodegradable, and appears to degrade rapidly in soil.

The study is considered reliable (with restriction due to the low recoveries) but

adequate for risk assessment purposes overall.



adequate for risk assessment purposes. In their review they note that “It was

clear that geraniol rapidly metabolised over the first three days of incubation.

While the study authors calculated DT50 values applying SFO, these were

done on two time points as geraniol was not quantified from three days

onwards”. Based on the total radioactivity extracted, the Australian

Environment Agency noted that degradation of all radioactive components

continued to follow SFO kinetics, and a DT50 was calculated for the 120 day

profile by the Australian Environment Agency. They used the longest DT50

value of 1.43 days determined for the Brierlow soil in the exposure modelling.

Conclusion

DT50 values for the Empingham, Brierlow, Ingleby and Calke soils were 0.2,

0.4, 0.3 and 0.3 days, respectively.

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Table 38: Aerobic degradation in soil (thymol): key study summary

Study type


Flag

Key study

Test Substance

Active ingredient thymol

Endpoint

DT50

Value

Thymol declined rapidly in each soil type. DT50 values for the Empingham,


Reference

Jones (2015). Thymol: Aerobic Soil Metabolism. Study number: PIF0008.

Klimisch Score



One very minor deviation was noted but this not considered to have impacted

the performance or results of the study.

GLP

Yes

Test Guideline/s

OECD 307

Dose Levels


thymol/ha)

Analytical

measurements

Liquid scintillation counting (LSC), high performance liquid chromatography

(HPLC) and liquid chromatography-mass spectrometry (LC-MS)


Study Summary

The route and rate of degradation of thymol were studied in four soils (Calke

sandy loam, Brierlow clay loam/silty clay loam, Empingham clay and Ingleby

loamy sand) in the laboratory under aerobic conditions. The soils were

selected to represent a range of textural characteristics, pH (5.6 - 7.8 in water)

and organic carbon contents (1.8 – 4.4%). Soil samples were set up and

allowed to acclimatise before being treated with [14C]-thymol at a nominal

concentration of 1.04 mg/kg, approximately equivalent to a use rate of 1040 g

ai/ha. The samples were incubated under aerobic conditions in the dark at

to pF 2 for periods of up to 120

days after application. Combined soil extracts were analysed by HPLC with

fraction collection.

The overall recoveries of applied radioactivity (AR) ranged from 90.9 – 109.6%

AR except on four occasions where recoveries were 85.1 to 113%. The

variable recoveries of radioactivity may be due to the inhomogeneous nature

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of the non-extractable residue, and the difficulties in accurately quantifying this

fraction.

Extractable radioactivity decreased concomitantly with an increase in the

levels of non-extractable radioactivity and evolved 14CO2. Extractable

radioactivity declined rapidly from mean values of 80.8 – 91.8% AR in each

soil at zero-time to mean values of 11.4 – 25.5% after three days incubation

and then remained at a similar level throughout the incubation period.

Non-extractable radioactivity increased to mean values of 72.4 – 78.2% AR

after three days and accounted for 62.0 – 78.2% AR after 120 days. Volatile

radioactivity, characterised as 14CO2, represented 11.9 – 28.2% AR after 120

days.



Thymol degraded to five minor unidentified degradates (none of which

individually accounted for >10% AR), bound residues and carbon dioxide.

Comments

Recoveries should range from 90% to 110% for labelled chemicals. The

majority of recoveries were in this range with the exception of four replicates,

which were outside (85.1 to 113%).

The author states the data suggests that the variable recoveries may be due

to difficulties accurately quantifying the high level of bound residues. They

state that due to the volatile nature of the test substance the solid residues

were not dried prior to combustion and this made it difficult (after several

attempts) to obtain a homogeneous sample for analysis and led to high

variance in the non-extractable residue combustion.

The EPA considers this a reasonable explanation, and since the test

substance is readily biodegradable, and appears to degrade rapidly in soil.

The study is considered reliable (with restriction due to the low recoveries) but

adequate for risk assessment purposes overall.



adequate for risk assessment purposes. In their review they note that “It is

apparent that there is rapid degradation of thymol and its metabolites. After

three days, degradation slows considerably with relatively constant levels of

radioactivity found over the period to 120 days. Thymol was quantified through

to 120 days in three soils and levels remained at around 2.2 to 6.4% of

radioactivity. It is clear the initial half-life of thymol is <1 days in all soils tested

in this study”.

Conclusion



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Adsorption/desorption

Table 39: Adsorption/desorption in soil (eugenol): key study summary

Study type


Flag

Key study

Test Substance

Active ingredient eugenol

Endpoint

NA

Value

The sorption parameters determined in this study are not considered reliable for

the reasons outlined below in the comments section

Reference

Jones (2015). Eugenol: Adsorption/desorption in five soils. Study number:

PIF0003.

Klimisch Score

3 (not reliable, see comments below). Note that this was also the conclusion

reached by the Applicant’s Environmental Risk Assessment.

Amendments/Deviatio

ns

One very minor deviation was noted by the author in the study report but this is

not considered to have impacted the performance or results of the study.

GLP

Yes

Test Guideline/s

OECD 106

Test concentrations

5.0, 1.5, 0.5, 0.15 and 0.05 mg/mL (nominal)

Analytical

measurements

Liquid scintillation counting (LSC) and high performance liquid chromatography

(HPLC)

Quality criteria met No (see comments)

Study Summary

The sorption properties of eugenol were studied in five soils (Elmton sandy clay

loam, Bromsgrove sandy loam, Warsop sand, Calke sandy loam and Evesham

3 clay loam) using the batch equilibrium method. The test soils included a range

of textural classes, with pH values between 3.9 and 7.2 and organic carbon

contents between 1.1 and 3.9%. Eugenol radiolabelled with carbon-14 was

used.

Preliminary experiments were conducted to ascertain (1) an appropriate soil-to-

solution ratio, (2) the time required to achieve equilibrium between eugenol in

solution and that adsorbed to soil and (3) the extent of any binding of eugenol to

the glass test vessels.

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Nominal initial solution concentrations of eugenol in the range 0.05 – 5 mg/L in

aqueous 0.01 M calcium chloride were studied. Soil-to-solution ratios of 1 : 50

w/v (Bromsgrove, Warsop and Evesham 3) or 1 : 20 w/v (Elmton and Calke)

were used. For the adsorption phase all five soils were equilibrated for 24 hours.

Soil samples were then desorbed once with fresh calcium chloride solution for

24 hours. All equilibrations were carried out at 25°C in the dark.

Concentrations of radioactivity in solution were measured directly by LSC and,

from these results, the concentration of radioactivity in the soil was determined.

Both values were corrected for actual proportions of eugenol present in solution

and soil exacts, as determined by chromatographic analysis.

Recoveries of radioactivity were in the range 93.1 to 98.1% of the amounts

applied.

The following Kd and Koc values were measured for the test item in each soil:

Soil Kd (mL/g)1 Koc (mL/g)1

Bromsgrove 6.5 434

Evesham 3 7.2 483

Elmton 55.8 3723

Warsop 6.1 404

Calke 60.1 4007

1 Average values

It should be noted that the adsorption/desorption results presented in the study

report were expressed as the Freundlich sorption parameters Kf, Kfoc and 1/n.

For use in the risk assessment the EPA has calculated the sorption parameter

Koc from the raw data included in the study report.

There was no correlation between soil pH and the degree of adsorption /

desorption. For each soil, the desorption coefficient was higher than the

adsorption coefficient, indicating some degree of irreversibility to the adsorption

of eugenol.

Comments

This study is not considered reliable because the test substance cannot be

considered stable during the study period (24 hours).

Although it is stated in the laboratory report that recoveries of radioactivity were

in the range 93.1 to 98.1% of the amounts applied, this is somewhat misleading.

A mass balance was only performed for the highest test concentration (ie. no

mass balance was performed for the other four test concentrations). For two of

the soils (Elmton and Calke) for which the mass balance was performed, the

amount of non-extractable radioactivity was a significant amount (65.1% and

69.0%, respectively). Since this radioactivity was measured by soil combustion

and liquid scintillation counting (LSC), the nature of these residues has not been

characterised. For the Evesham 3 soil, 17.6% of the total applied radioactivity

was also determined to be non-extractable residue. Although this is a lot lower

than for the Elmton and Calke soils, this is still a significant amount.

Sorption of eugenol appears to increase significantly with soil organic carbon

content (the greatest adsorption was observed for the Elmton and Calke soils),

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which had the highest organic carbon contents of 3.9% and 3.5%, respectively.

A lower soil solution ratio was used for these soils however (1:20), compared

with 1:50 for the Bromsgrove, Evesham 3 and Warsop soils, which may

artificially increase the amount of adsorption observed for these two soils.

Amounts of soil used in this test were very low overall (0.4 g for the

Bromsgrove, Evesham 3 and Warsop soils to achieve a 1:50 soil:solution ratio,

and 1 g for the Elmton and Calke soils to achieve a 1:20 soil:solution ratio). The

OECD Guideline 106 recommends to use at least 1 g of soil and preferably 2 g,

in order to obtain reliable results.

OECD Guideline 106 states that if the mass balance is less than 90% after the

soil extraction step of the experiment then the substance is considered unstable.

Although this study has ostensibly been performed in accordance with OECD

Guideline 106, which states that that the test can be continued for unstable

compounds if both phases have been analysed, the high level of non-

extractable residues identified by soil combustion is concerning as these have

not been characterised (so the nature of these residues is unknown), and a

mass balance was only determined for the soil tested at the highest

concentration. It is therefore unclear whether the soil extraction method was

unsuitable, or what this residue is comprised of (ie. whether it is the result of

degradation). Furthermore, whether the same pattern is observed at the other

concentrations is unknown.

In addition, it is noted in the preliminary experiment that “equilibrium was

generally not reached due to degradation in most soils however an equilibration

time of 24 hours was used for all soils”. It is also noted in OECD Guideline 106

that in order to perform a mass balance, adsorption equilibrium should have

been reached within the time period of the experiment.

As a result of the aforementioned points, the test substance cannot be

considered stable, and the results are therefore not considered reliable or

suitable for use in the risk assessment.

Conclusion

The sorption parameters determined in this study are not considered reliable for

the reasons outlined above in the comments section

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Table 40: Adsorption/desorption in soil (geraniol): key study summary

Study type


Flag

Key study

Test Substance

Active ingredient geraniol

Endpoint

NA

Value

The sorption parameters determined in this study are not considered

reliable for the reasons outlined above in the comments section

Reference

Jones (2015). Geraniol: Adsorption/desorption in five soils. Study number:

PIF0006.

Klimisch Score

3 (not reliable, see comments below). Note that this was also the

conclusion reached in the Applicant’s Environmental Risk Assessment.


Three minor deviations were noted by the author in the study report but

these are not considered to have impacted the performance or results of

the study.

GLP

Yes

Test Guideline/s

OECD 106

Test concentrations

5.0, 1.5, 0.5, 0.15 and 0.05 mg/mL (nominal)

Analytical measurements




Study Summary

The sorption properties of geraniol were studied in five soils (Elmton sandy

clay loam, Bromsgrove sandy loam, Warsop sand, Calke sandy loam and

Evesham 3 clay loam) using the batch equilibrium method. The test soils

included a range of textural classes, with pH values between 3.9 and 7.3

and organic carbon content between 1.1 and 4.4%. Geraniol radiolabelled

with carbon-14 was used.

Preliminary experiments were conducted to ascertain (1) an appropriate

soil-to-solution ratio, (2) the time required to achieve equilibrium between

geraniol in solution and that adsorbed to soil and (3) the extent of any

binding of geraniol to the glass test vessels, mass balance and stability of

the geraniol.

Nominal initial solution concentrations of geraniol in the range 0.05 – 5

mg/L in aqueous 0.01 M calcium chloride were studied. Soil-to-solution

ratios of 1 : 100 w/v (Bromsgrove) or 1 : 20 w/v (Elmton, Evesham 3,

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Warsop and Calke) were used. For the adsorption phase all Calke and

Elmton soils were equilibrated for 24 hours and Evesham, Warsop and

Bromsgrove soils were equilibrated for 48 hours. Soil samples were then

desorbed once with fresh calcium chloride solution for either 24 or 48

hours, as appropriate. All equilibrations were carried out at 25°C in the

dark.

Concentrations of radioactivity in solution were measured directly by LSC

and, from these, the concentration of radioactivity in the soil was

determined. Both values were corrected for actual proportions of geraniol

present in solution and soil exacts, as determined by chromatographic

analysis.

Recoveries of radioactivity were in the range 92.1 to 93.1% of the amounts

applied for Evesham 3, Calke and Elmton soils, and 63.0 to 64.8% for

Bromsgrove and Warsop soils.

The following Kd and Koc values were measured for the test item in each

soil:


Bromsgrove 440 29313

Evesham 3 70.6 4707

Elmton 6.6 438

Warsop 26.6 1774

Calke 27.3 1820

1 Average values

It should be noted that the adsorption/desorption results presented in the

study report were expressed as the Freundlich sorption parameters Kf,

Kfoc and 1/n. For use in the risk assessment the EPA has calculated the

sorption parameter Koc from the raw data included in the study report.

There was no correlation between soil pH and the degree of adsorption.

For the Elmton soil, the desorption coefficient was higher than the

adsorption coefficient, indicating some degree of irreversibility to the

adsorption of geraniol. It was not possible to determine the desorption

coefficients for the other soils as geraniol was not detected in the

desorption supernatant.

Comments

This study is not considered reliable because the test substance cannot be

considered stable during the study period (24 hours).

It is stated in the laboratory report that recoveries of radioactivity were in

the range 92.1 to 93.1% of the amounts applied for Evesham 3, Calke and

Elmton soils, and 63.0 to 64.8% for Bromsgrove and Warsop soils. Agin,

the high recoveries for the Evesham 3, Calke and Elmton soils is

somewhat misleading.

Again, a mass balance was only performed for the highest test

concentration (ie. no mass balance was performed for the other four test

concentrations). Again, amounts of non-extractable residue were

significant for all five soils, ranging from 27.1% for the Warsop soil to 39%

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for the Evesham 3 soil. Again, this radioactivity was measured by soil

combustion and liquid scintillation counting (LSC), the nature of these

residues has not been characterised.

Amounts of soil used in this test were also very low overall (1 g for the

Elmton, Evesham 3, Warsop and Calke soils to achieve a 1:20 soil:solution

ratio, and 0.2 g for the Bromsgrove soil to achieve a 1:100 soil:solution

ratio). The OECD Guideline 106 recommends to use at least 1 g of soil

and preferably 2 g, in order to obtain reliable results.

OECD Guideline 106 states that if the mass balance is less than 90% after

the soil extraction step of the experiment then the substance is considered

unstable.

Although this study has ostensibly been performed in accordance with

OECD Guideline 106, which states that that the test can be continued for

unstable compounds if both phases have been analysed, the high level of

non-extractable residues identified by soil combustion is concerning as

these have not been characterised (so the nature of these residues is

unknown), and a mass balance was only determined for the soil tested at

the highest concentration. It is therefore unclear whether the soil extraction

method was unsuitable, or what this residue is comprised of (ie. whether it

is the result of degradation). Furthermore, whether the same pattern is

observed at the other concentrations is unknown.

In addition, it is noted in the preliminary experiment that “degradation of

geraniol was observed in the soil and supernatant after 24 and 48 hours

equilibration”. It is therefore anticipated this would also be the case for the

main isotherm experiment although this was not discussed in the study

report. It is also noted in OECD Guideline 106 that in order to perform a

mass balance, adsorption equilibrium should have been reached within the

time period of the experiment.


considered stable, and the results are therefore not considered reliable or

suitable for use in the risk assessment.

Conclusion



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Table 41: Adsorption/desorption in soil (thymol): key study summary

Study type


Flag

Key study

Test Substance

Active ingredient thymol

Endpoint

NA

Value



Reference

Jones (2015). Thymol: Adsorption/desorption in five soils. Study number:

PIF0009.

Klimisch Score

3 (not reliable, see comments below). Note that this was also the

conclusion reached in the Applicant’s Environmental Risk Assessment.


Two minor deviations were noted by the author in the study report but

these are not considered to have impacted the performance or results of

the study.

GLP

Yes

Test Guideline/s

OECD 106

Test concentrations

5.0, 1.5, 0.5, 0.15 and 0.05 mg/mL (nominal)

Analytical measurements




Study Summary

The sorption properties of thymol were studied in five soils (Elmton sandy

clay loam, Bromsgrove sandy loam, Warsop sand, Calke sandy loam

and Evesham 3 clay loam) using the batch equilibrium method. The test

soils included a range of textural classes, with pH values between 3.9

and 7.3 and organic carbon content between 1.1 and 4.4%. Thymol

radiolabelled with carbon-14 was used.

Preliminary experiments were conducted to ascertain (1) an appropriate

soil-to-solution ratio, (2) the time required to achieve equilibrium between

thymol in solution and that adsorbed to soil and (3) the extent of any

binding of thymol to the glass test vessels, mass balance and stability of

the thymol.

Nominal initial solution concentrations of thymol in the range 0.05 – 5

mg/L in aqueous 0.01 M calcium chloride were studied. Soil-to-solution

ratios of 1 : 10 w/v (Bromsgrove and Warsop) or 1 : 20 w/v (Elmton,

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Evesham 3 and Calke) were used. For the adsorption phase all five soils

were equilibrated for 24 hours. Soil samples were then desorbed once

with fresh calcium chloride solution for 24 hours. All equilibrations were

carried out at 25°C in the dark.

Concentrations of radioactivity in solution were measured directly by LSC

and, from these, the concentration of radioactivity in the soil was

determined. Both values were corrected for actual proportions of thymol

present in solution and soil exacts, as determined by chromatographic

analysis.

Recoveries of radioactivity were in the range 92.1 to 93.1% of the

amounts applied for Evesham 3, Calke and Elmton soils, and 63.0 to

64.8% for Bromsgrove and Warsop soils.

The following Kd and Koc values were measured for the test item in each

soil:


Bromsgrove 12.1 807

Evesham 3 11.7 778

Elmton 43.2 2880

Warsop 3.1 206

Calke 25.9 1728

1 Average values

It should be noted that the adsorption/desorption results presented in the

study report were expressed as the Freundlich sorption parameters Kf,

Kfoc and 1/n. For use in the risk assessment the EPA has calculated the

sorption parameter Koc from the raw data included in the study report.

There was no correlation between soil pH and the degree of adsorption /

desorption. For each soil, the desorption coefficient was higher than the

adsorption coefficient, indicating some degree of irreversibility to the

adsorption of thymol.

Comments

This study is not considered reliable because the test substance cannot

be considered stable during the study period (24 hours).

Although it is stated in the laboratory report that recoveries of

radioactivity were in the range 88.8 to 95.0% of the amounts applied, this

is somewhat misleading.

A mass balance was only performed for the highest test concentration

(ie. no mass balance was performed for the other four test

concentrations). Levels of non-extractable residue varied, ranging from

only 1.9% for the Warsop soil up to 45.9% for the Calke soil. Again

suggesting instability of the test item with the exception for the Warsop

soil in this case.

Slightly higher amounts of soil were used in this test (1 g Elmton,

Evesham 3 and Calke soils to achieve a 1:20 soil:solution ratio, and 2 g

for the Bromsgrove and Warsop soils to achieve a 1:10 soil:solution

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ratio). The OECD Guideline 106 recommends to use at least 1 g of soil

and preferably 2 g, in order to obtain reliable results.

OECD Guideline 106 states that if the mass balance is less than 90%

after the soil extraction step of the experiment then the substance is

considered unstable.

Although this study has ostensibly been performed in accordance with

OECD Guideline 106, which states that that the test can be continued for

unstable compounds if both phases have been analysed, the high level

of non-extractable residues identified by soil combustion is concerning as

these have not been characterised (so the nature of these residues is

unknown), and a mass balance was only determined for the soil tested at

the highest concentration. It is therefore unclear whether the soil

extraction method was unsuitable, or what this residue is comprised of

(ie. whether it is the result of degradation). Furthermore, whether the

same pattern is observed at the other concentrations is unknown.

In addition, it is noted in the preliminary experiment that “degradation of

thymol was observed in the soil and supernatant at 24 hours”. It is

therefore anticipated this would also be the case for the main isotherm

experiment although this was not discussed in the study report. It is also

noted in OECD Guideline 106 that in order to perform a mass balance,

adsorption equilibrium should have been reached within the time period

of the experiment.


considered stable, and the results are therefore not considered reliable

or suitable for use in the risk assessment.

Conclusion



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Appendix J: References

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and R. Billington (2015). "Assessment of an extended dataset of in vitro human dermal absorption

studies on pesticides to determine default values, opportunities for read-across and influence of

dilution on absorption." Regul Toxicol Pharmacol 72(1): 58-70.

APVMA (2010). "Standard spray drift risk assessment scenarios."

Australian Environment Agency Property Limited (2018). Novellus Fungicide - New Zealand

Environmental Risk Assessment Report to Support Registration.

EC (2011a). "Draft Assessment Report (DAR) - Initial risk assessment provided by the rapporteur

Member State the United Kingdom for the new active substance EUGENOL."

EC (2011b). "Draft Assessment Report (DAR) - Initial risk assessment provided by the rapporteur

Member State the United Kingdom for the new active substance GERANIOL."

EC (2011c). "Draft Assessment Report (DAR) - Initial risk assessment provided by the rapporteur

Member State the United Kingdom for the new active substance THYMOL."

EC (2013a). FINAL Review report for the active substance eugenol. Brussels, European Commission,

Health & Consumers Directorate-General.

EC (2013b). FINAL Review report for the active substance thymol. Brussels, European Commission,

Health & Consumers Directorate-General.

EFSA (2009). "Risk Assessment for Birds and Mammals." EFSA Journal 7(12): 1438.

EFSA (2013). "Guidance on tiered risk assessment for plant protection products for aquatic organisms

in edge-of-field surface waters." EFSA Journal 11(7): 3290.

EFSA (2015). "Outcome of the pesticides peer review meeting on general recurring issues in

ecotoxicology." EFSA Supporting Publications 12(12): 924E.

EPA (2018). Risk Assessment Methodology for Hazardous Substances ; Draft for Consultation.

HSNO

Klimisch, H. J., M. Andreae and U. Tillmann (1997). "A systematic approach for evaluating the quality

of experimental toxicological and ecotoxicological data." Regul Toxicol Pharmacol 25(1): 1-5.

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Appendix K: Confidential Composition

app203836 novellus fungicide - epa

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