Training Session Registration Reports – Toxicological Part

Dr. Christiane VleminckxScientific Institute of Public HealthDivision Toxicology23 October 2006

Toxicology

Part A – Risk Management 3 Risk management

3.1 Reasoned statement of the overall conclusions taken in accordance with the uniform Principles 3.1.3 Mammalian Toxicology

Exposure of operators: Considering the results of the risk assessments based on the German BBA-Model, the UK-POEM and field experimental data on active substance Xxx it is concluded that product XYZ can be handled safely under the recommended conditions of use. This includes that PPE (gloves).should be worn while handling the product (mixing and loading).

Part A – Risk Management Exposure of workers and bystanders: The estimation of exposure

confirms that there is no risk for bystanders exposed during application in fields of XYZ. The results of the risk assessment indicates that re-entry of treated field crops is possible after the spray solution has dried up. Workers should wear clothing and gloves to avoid dermal exposure of the active substances (particularly Xxx) deposit on the foliage. For the protection of workers, the label should carry the following instruction: “Do not re-enter treated areas/crops before the spray deposit is completely dry. Avoid dermal exposure. Re-entry should be done with working clothing and gloves.”

Label: Symbols : Xn Risk phrases: R22-38-40-63 Safety phrases: S2-13-20/21-23-24-36/37-46

Part B Detailed Summary of the Risk Assessment 4 Mammalian toxicology

4.1 Acute toxicity 4.1.1 Acute oral toxicity 4.1.2 Acute percutaneous toxicity 4.1.3 Acute inhalation toxicity 4.1.4 Skin irritation 4.1.5 Eye irritation 4.1.6 Skin sensitization 4.1.7 Supplementary studies for combinations of plant

protection products

Information that must be reported Details of the evaluation

Submitted study: species, route of exposure, duration of exposure, doses, authors, date of the report, report No

GLP status Guidelines: TM Directive 67/548/EEC, OECD TG No Materials and methods: strain, material code No, batch No,

purity, vehicle, number of animals, method used … The study is acceptable or not (justification) Findings:

Mortality Clinical signs Bodyweight Necropsy findings Cutaneous or occular reactions (scores, reversibility)

Information that must be reported Conclusions

LD50 oral and dermal (M & F) LC50 inhalation 4 h (M & F) Skin irritant or not Eye irritant or not Skin sensitizer or not According to EEC criteria the product must be

classified as …., symbol and R-phrase

Part B Detailed Summary of the Risk Assessment 4.2 Dermal absorption

Default valuesMW > 500 and logPow <-1, or >4 10%

otherwise 100 % or equivalent to oral absorption Studies

In vivo absorption study in rats In vitro absorption studies in rat and human skin

Information that must be reported Details of the evaluation

Submitted study: species, duration of exposure, doses, authors, date of the report, report No

GLP status Guidelines: OECD TG 427 (in vivo), TG 428 (in vitro) Materials and methods: material code No, batch No, purity,

formulation, concentrations, duration of exposure, sampling times, number of animals, diffusion cell, receptor fluid, …

The study is acceptable or not (justification) Findings: text + table with the results

Recovery = % of applied dose at various times (ex 6 h, 24h, 72 h, 120 h) and for the different concentrations: unabsorbed, absorbed (urine, faeces, cage wash, carcass + blood, GI tract + content), potentially absorbable (application site & stratum corneum), total absorbable dose, total recovered, …

Absorption rate (µg/cm2/h), % of the dose absorbed at various times and for the different concentrations, overall recoveries (skin wash, skin, receptor fluid, cell washings)

Or reference to Review Report

Information that must be reported Conclusions

for concentrate and dilutions % of the dose dermally absorbed in vivo in rats

(R) % of the dose absorbed through rat skin in vitro (r) % of the dose absorbed through human skin in

vitro (h) Predicted human absorption

H = R x (h / r) Or: H = h

Part B Detailed Summary of the Risk Assessment 4.3 Available toxicological data relating to non-active substances

MSDS formulation, all co-formulants

* According to Dir. 98/98/EU all preparations containing more than 10% aromatic solvent have to be labelled with R65. Such a labelling is not necessary if the kinematic viscosity at 40°C is higher than 7 x 10-6 m2/sec or if the surface tension at 25°C is higher than 33 mN/m. These requirements are fulfilled for XYZ.

Substance Classification AOEL(s)

(mg/kg bw/d)

Reference

Symbol R-phrase

Solvent naphtha petroleum (> 10%)*

Xn, N R51/53-65 MSDS

Part B Detailed Summary of the Risk Assessment 4.4 Exposure assessments

4.4.1 Operator exposure Estimation of operator exposure

UK POEM German model EUROPOEM PHED (granules)

SEEDTROPEX (protected data) GREENHOUSES: German study (protected data),

publications

Data for the active substance(s) and pertinent non active substances The estimations were compared to following data for the active

substance(s) and pertinent non active substances (e.g. safener)

Substance Classification AOEL(s)

(mg/kg bw/d)

Reference

Symbol R-phrase

Xxx T, N R23-38-50/53-63

Syst: 0.015

(NOAEL maternal

toxicity in rabbit developmental toxicity study, AF: 100, 50%

oral absorption)

Listing of endpoints (date)

Data for the active substance(s) and pertinent non active substances

Metabolites/impurities

No pertinent metabolites and impurities present or The toxicological relevance of the impurity zzz

has been addressed in addendum 2 to the draft assessment report of active substance xxx prepared by Germany (25 June 2003). zzz concentration should be at the maximum 0.0001%.

…

Details of the evaluation

Estimation of operator exposure according to UK-model

For these calculations, the following general prerequisites were considered: Water dispersible granule: SE Use  : cereals Application rate : 1.75 - 2 l (product)/ha (worst case scenario) Concentration of a.i. : 114.3 g/l xxx, 214.3 g/l yyy, 42.9 g/l zzz Spray volume : 200-400 l/ha Container size : 5 l bottle Area treated : field crop (tractor mounted), 50 ha/day Personal protective equipment (PPE):

scenario 1: none, scenario 2: gloves during mixing and loading scenario 3: gloves during mixing, loading and application

BW : 60 kg (UK)

Include spread sheets UK POEM

Details of the evaluation

Estimation of operator exposure according to the German model

For these calculations, the following general prerequisites were considered: Water dispersible granule: SE Use  : cereals Application rate : 1.75 - 2 l product/ha (worst case scenario) Concentration of a.i. : 114.3 g/l xxx, 214.3 g/l yyy, 42.9 g/l zzz Area treated : field crop, 20 ha/day (tractor mounted) Personal protective equipment (PPE):

scenario 1: none, scenario 2: gloves during mixing and loading & coverall and

boots during application BW : 70 kg

Include spread sheets German model

Conclusions concerning the estimation of the operator exposure - Does the product comply with the Uniform Principles Summary of the evaluation of operator exposure risk

Safe use or not under the recommended conditions of use (includes PPE)

Active substance

PPE POE

(mg/kg bw/d)

AOEL

(mg/kg bw/d)

% AOEL

Xxx None 0.013 0.015 87

Gloves

M & L

0.009 60

Gloves

M L A

0.003 20

References for the models

Estimation of Exposure and Absorption of Pesticides by Spray Operators, Scientific subcommittee on Pesticides and british Agrochemical association Joint Medical Panel Report (UK MAFF), 1986 and the Predictive Operator Exposure Model (POEM) V 1.0, (UK MAFF), 1992. (“UK model”).

Uniform Principles for Safeguarding the Health of applicators of Plant Protection Products (Uniform Principles for Operator Protection), Mitteilungen aus der Biologischen Bundesanstalt für Land-und Forstwirtschaft, Berlin-Dahlem, Heft 277, 1992. (“German model”).

Revised UK POEM: http://psd08.pesticides.gov.uk/uploadedfiles/Web_Assets/PSD/UK_POEM1.xls

Part B Detailed Summary of the Risk Assessment 4.4 Exposure assessments

4.4.1 Operator exposure Measurement of operator exposure

Details of the evaluation Conclusions

Overall conclusions concerning operator exposure – does the product comply with the Uniform Principles

Part B Detailed Summary of the Risk Assessment 4.4 Exposure assessments

4.4.2 Bystander exposure Estimation of bystander exposure

Details of the evaluation Conclusions - Does the product comply with the Uniform

Principles

Details of the evaluation In light of the application method used for XYZ (downward spray using

conventional tractor mounted hydraulic sprayer), bystanders are likely to be exposed (if at all) only briefly and to relatively low quantities of spray compared to operators.

Exposure of bystanders can only occur during application via drift. Bystanders walking alongside a field that is being treated are exposed only for a few seconds when the sprayer moves along the person. Repeated exposure is unlikely, since the sprayer is considered to only pass along the edge of a field for each spraying swath. It is assumed that only ordinary clothing is worn; the total uncovered area amounts to 0.4225 m2. Bystanders always stand at a larger distance from the edge of the spray boom and thus from the spray nozzle, than the operator. For example, an operator (the tractor driver) may be at 2 to 4 m distance to the nearest spraying nozzles, bystanders at least at about 8 m.

The exposure will occur by dermal and inhalatory route. It can be postulated that the dermal exposure is directly correlated to the amount of active substance applied per area (use rate), the area of the uncovered body surface contaminated and the drift distance. With regard to the inhalatory exposure of a bystander, specific exposure data can be taken from the generic data of the German model. Assumed that passing a bystander takes a minute, the exposure time is only the 360th part of the exposure time of the operator, spraying 6 hours a day.

Details of the evaluation

Inhalation exposure:

1. The inhalation exposure is calculated as for the operator I = I*A x WR x AR

I : inhalation exposure (mg a.s./person/d) I*A : spec. exposure application (mg a.s./person x ha/kg a.s.)

field crop : 0.001WR : work rate (ha/d = ha/6h)

field crop: 20 ha/dAR : application rate (kg a.s./ha)

0.228 kg xxx/haBW : 60 kg

2. adapted to 1-5 minutes (instead of 6 h for an operator)

Details of the evaluation

Dermal exposure:

D = 100 % deposition x drift deposition x exposed area

D : dermal exposure (mg a.s./person/d)

100 % deposition : AR (mg a.s./m2)drift deposition : in 7.5 m distance for a field crop : 0.13 %° exposed area : 0.4225 m2/person/d

(total uncovered area : head, back & front of neck, fore arms, 1/2 upper arms and hands)

AR : application rate0.228 kg xxx/ha

BW : 60 kg

°(Ganzelmeier et al., Studies on the spray drift of plant protection products; Federal Biological Research Centre for Agriculture and Forestry; Berlin, N° 305, 1995).

Details of the evaluation

Substance Dermal absorbed

dose

(mg/kg bw/d)

Inhalation exposure

(mg/kg bw/d)

Total systemic exposure

(mg/kg bw/d)

AOEL syst

(mg/kg bw/d)

% AOEL syst

Xxx 0.00021 0.0000126 0.00022 0.015 1.5

Conclusions

The estimation of exposure confirms that there is no risk for bystanders exposed during application in fields of XYZ.

Bystander exposure

See also the Report of the Bystander WG, A. Gilbert et al, EUROPOEM II Project FAIR3

CT96-1406, December 2002.

Part B Detailed Summary of the Risk Assessment 4.4 Exposure assessments

4.4.2 Worker exposure or re-entry exposure Estimation of worker exposure

Details of the evaluation Conclusions - Does the product comply with the Uniform

Principles Measurement of worker exposure

Details of the evaluation Conclusions - Does the product comply with the Uniform

Principles

Details of the evaluation The estimation was based on the model as developed by the German BBA

(Hoernicke et al., 1998, Hinweise in der Gebrauchsanleitung zum Schutz von Personen bei Nachfolgearbeiten in mit Planzenschutzmitteln behandelten Kulturen (worker re-entry; Nachrichtenbl. Deut. Planzenschutzd. 50, Berlin)) and the US EPA (EPA, Science Advisory Council for Exposure, 1998, Agricultural Default Transfer Coefficients, Policy 1998/11675).

The following parameters were considered:

DFR (dislodgeable foliar residue) : 1 µg/cm2 x kg a.s. appliedTF (transfer factor), according to EPA : 30,000 cm2/h x personA (working period) : 8 h/dayP (penetration factor clothing) : 0.05 (factor, equal 5%)R (rate of application) : 0.228 kg xxx/ha

Calculation of potential dermal exposure:

D (µg a.s./person/d) = DFR x TF x A x R x P

BW : 70 kg

Details of the evaluation

Substance PPE Potential dermal

exposure

(mg/kg bw/d)

Dermal absorbed

dose

(mg/kg bw/d)

AOEL syst

(mg/kg bw/d)

% AOEL syst

Xxx No 0.782 0.00782 0.015 52

Yes 0.0391 0.000391 3

Conclusions The results of the risk assessment indicates that re-entry of

treated field crops is possible after the spray solution has dried up. Workers should wear clothing and gloves to avoid dermal exposure of the active substances (particularly Xxx) deposit on the foliage. For the protection of workers, the label should carry the following instruction: “Do not re-enter treated areas/crops before the spray deposit is completely dry. Avoid dermal exposure. Re-entry should be done with working clothing and gloves.”

It is concluded that the measurement of worker exposure is not necessary and was therefore not performed.

A re-entry period for livestock does not need to be established as the product is not intended to be used in areas to be grazed. A waiting period between application and handling is not relevant here.

Worker exposure

See also the Report of the Re-entry WG, J. van Hemmen et al, EUROPOEM II Project

FAIR3 CT96-1406, December 2002.

Part B Detailed Summary of the Risk Assessment 4.5 Appropriate mammalian toxicology and

operator exposure end-points relating to the product and approved uses

Summary of acute toxicity including irritancy and skin sensitisation of product XYZ as evaluatedType of test Batch No LD50 (mg/kg

bw) or

LC50 (mg/l)

Classification Reference

Rat, oral XYZ

B: 2000-1

1200 Xn, R22 Author, year

Rat, dermal XYZ

B: 2000-1

> 2000 - Author, year

Rat inhalation, 4 h

XYZ

B: 2000-1

> 1.56 - Author, year

Rabbit, skin irritation

XYZ

B: 2000-1

Irritant Xi, R38 Author, year

Rabbit, eye irritation

XYZ

B: 2000-1

Non irritant - Author, year

Guinea pig, skin sensitization

XYZ

B: 2000-1

Not sensitizer - Author, year

4.5 Appropriate mammalian toxicology and operator exposure end-points relating to the product and approved uses According to Dir. 98/98/EU all preparations containing more than 10% aromatic

solvent have to be labelled with R65. Such a labelling is not necessary if the kinematic viscosity at 40°C is higher than 7 x 10-6 m2/sec or if the surface tension at 25°C is higher than 33 mN/m. These requirements are fulfilled for XYZ.

Based on the properties of the active substances, phrase R40 and R63 are added.

Based on the operator exposure assessment, phrases S36/37 are added In global, following instructions should be mentioned on the label:

Symbols : Xn Risk phrases: R22-38-40-63 Safety phrases: S2-13-20/21-23-24-36/37-46 Do not re-enter treated areas/crops before the spray deposit is completely dry. Avoid

dermal exposure. Re-entry should be done with working clothing and gloves

No re-entry periods need to be established.

Part B Detailed Summary of the Risk Assessment 4.6 Any other relevant toxicological data /

information