lab hira

Lab-HIRA: Hazard Identification and Risk Analysis for the

Chemical Research Laboratory

Dr. David LeggettLeggett Technical Consulting

Los Angeles, CA

243rd ACS National Meeting San Diego CA, March 2012

Slide A:2

ACS March 2012LEGGETTTechnical Consulting

A straightforward technique designed to identify and assess the hazards of conducting a chemical synthesis in the research environment.

Once hazards have been recognized appropriate risk minimization or mitigation measures can be implemented by the researcher.

An additional formal hazard analysis for the synthesis reaction may be recommended.

Lab-HIRA: Hazard Identification and Risk Assessment

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• An explosion at Sussex University (UK, 1988) seriously injured a student. o UK H&SE prosecuted SU for negligence. o Today, British researchers are required to write down

risk assessments before every experiment.

• Univ. of California (Los Angeles), Texas Tech Univ. & Univ. of Florida have had well-publicized serious accidents in their chemistry labs

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• Accident rate is 10 to 50 times higher than that in industrial laboratorieso In industry scientists are required to do a careful hazard

analysis and follow strict safety precautions

o Very few [academic] scientists have taken formal courses in safety, health, and toxicology

o Most relevant safety articles are published in journals devoted outside of an academics major field of interest

A.K. Furr, Handbook of Laboratory Safety (2000)

US Chemical Safety Board, Texas Tech University Laboratory Explosion Case Study (2010)

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Chemical Industry Typically Requires Hazards Testing for New Chemistry Destined for Full Scale Manufacture

Scale of Reaction Type of Hazard Assessment Typical Approaches

Research & Development

Desktop StudySmall Scale Testing

Calculations, Literature,DSC, Mixing Cal, RSST

Pilot or Kilo Lab Qualitative and Semi-Quantitative Testing

Reaction Calorimetry, Adiabatic Calorimetry

Manufacturing Custom testing for Engineering Design

DIERS, Dust, Reaction Calorimetry, Flammability


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Lab-HIRA: Hazards Identification and Risk Analysis for New Chemistry at Research Scale

Desktop StudySmall Scale Testing

Calculations, LiteratureDSC, Mixing Calorimetry, RSST

SWIF or Simple HAZOP, if needed


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Lab-HIRA uses the physical, chemical, and health data for reactants and reactions:• Flammability – vapors, liquids, solids

• Specific Chemical Hazards

• Health Data – toxicity, exposure, carcinogenicity

• Reaction Conditions

• Equipment such as radiation sources

Lab-HIRA Step 1: Hazard Identification

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Four Classes of Data Support Lab-HIRA

Class 1: Property Expressed as Specific Value

Class 2: Hazardous Characteristic of Molecule

Class 3: Reaction Hazards, by Type or Named Rxn

Class 4: Conditions of Synthesis


Slide A:9


Properties Expressed as Discrete Values

Property Chemical / Energy Source Value

IDLH Hydrazine 50 ppm

LD50 (rats) 1,4-Dioxane 5,200 mg kg-1

TWA (OSHA) SO2 5 ppm

Flash Point THF -14 °C

Laser Source High intensity laser Class 4

Flammability Hexane Class IA


Slide A:10


For discrete values, such as LD50, map values to an index scale 0 thru’ 4

United Nations, Globally Harmonized System of Classification and Labeling of Chemicals (2005)

Hazard Index Value Hazard Min Max

0 No Hazard > 5,000

1 Minimal > 500 5,000

2 Minor > 50 500

3 Moderate 5 50

4 Major < 5


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Properties are expressed in various units:

PropertyHazard Index Value

0 1 2 3 4Flammability NF / NC IIIB II or IIIA IB or IC IA

Laser Source None Class 1 Class 2 Class 3 Class 4

UV Source, nm None 400-320 320-280 280-100 <100MIE, mJ > 5 2 - 5 0.5 - 2 0.05 - 0.5 < 0.05Auto-Ign, °C > 500 350 - 500 250 - 350 150 - 250 < 150Hazard No Haz Minimal Minor Moderate Major


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Four Classes of DataClass 1: Property Expressed as Specific Value


Class 3: Reaction Hazards, by Type or Named Reaction



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Hazardous Characteristics of Molecules

Specific Hazard Index Code

Index Value

Pyrophoric: spontaneously flammable or reactive with air < 130 °F AIR 3

Forms gaseous products during reaction –CO2, CO, H2, N2, C4H10

GAS 2

Suspected carcinogen, teratogen, mutagen or reproductive hazard HLTH 4

Impact or friction sensitive IMPT 3

Molecule requires temperature controlled storage or handling TCN 2


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Class 3: Reaction Hazards, by Type or Named Rxn



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Hazardous Characteristics of Molecules

Reaction Type Reaction Type Index Value

Decarboxylation Removal of –COOH with CO2 evolved 2

Nitration Red fuming or white HNO3, N2O4 3

ReductionsLiAlH4, N2H4 in KOH, NaBH4 in CH3OH 3

BF3 / NaBH4, H2 + catalyst 2

EsterificationsOxalyl chloride – high health hazard 3

RCOOH + SOCl2 followed by R’OH 2


Slide A:16


Hazard Levels of Named Reactions

Reaction Type Reaction Type Index Value

Wolff-KishnerReduction

Reduction of RCHO or R2CO to RH with H2NNH2

3

Grignard Reaction Reaction of R’MgCl to RCHO or RR”CO to form RR’CHOH or RR’R”COH 3

Kochi Reaction One-carbon oxidative degradation of R-COOH using a Pb(IV) reagent 1

Meerwein-Ponndorf-VerleyReduction

The aluminum-catalyzed hydride shift from the α-carbon of an alcohol reagent to RR’CO forming RR’CHOH

2


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Class 3: Reaction Hazards, by Type or Named Reaction



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Properties are expressed in various units:

Synthesis Conditions

Hazard Index Value0 1 2 3 4

TPROCESS, MAX (°C) < 75 75 - 150 150 -250 250 - 400 > 400

PPROCESS (psig) < 10 10 - 25 25 - 75 75 - 150 > 150

TFEED (°C) < 35 35 - 60 60 - 80 80 - 100 > 100

Scale-up Ratio 1 1 - 5 5 - 50 50 - 500 > 500

Reaction Mass (kg) < 0.005 0.005 – 0.1 0.1 - 1 1 - 5 > 5


Slide A:19


Lab-HIRA compared to OSHA Lab Standard (29 CFR 1910.1450)

Health Properties: Lab-HIRA and 1910.1450

Physical and Chemical Properties: Lab-HIRA only

Reaction Conditions: Lab-HIRA only


Slide A:20


Overall Hazard Index, OHI given by:

DIS_PR = Discrete property (LD50, Flash Pt.) mapped to range

DIS_CND = Discrete reaction condition (TRXN) mapped to range

CHM_HZ = Index value for specific chemical hazard (AIR, WAT)

NAME = Specific named reaction (Wolff-Kirshner)

TYPE = Type of reaction (Decarboxylation)


TYPENAMECHM ︳HZDIS ︳CNDDIS ︳PRIVIVIVIVIVOHI

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Case Study 1: Diphenylmethane from Benzophenone, using Wolff-Kishner reaction:

Populate Lab-HIRA Chemical Hazard Review form for:• Benzophenone• Potassium hydroxide pellets• Hydrazine hydrate• Ethylene glycol

KOH, HOCH2CH2OH

H2NNH2 200 °C, Reflux


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ACGIH TLVs

OSHA PEL & NIOSH IDLH

n/a Nuclear Radiation Type

5

B Pt

Dust Expl Severity: ST / Pmax / MIE

Lower Flam Limit

mg/kg

ST Dust Class n/a

Melting & Boiling Pt; AutoIgnition

Flammability (Liquid) LEL / UEL ; Fl Pt v/v%

113

Radiation Sources, Nuclear, Laser, UV

°C

ppm TWA (OSHA) n/a Exposure Limits

Toxicity LD50 oral (rat) 129

TWA (ACGIH) 40 ppm

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C (ACGIH) n/a

nmn/a UV WavelengthLaser Classn/a

ppm

ppm LC50 inhal Gas (rat)600

Upper Flam Limit

°C

AutoIgn Temp M Pt 270

7298

-52

Flash Point

mg/kg LD50 skin (rabbit) 570

°C

mJ

50

n/a n/a

Laser Type

IDLH (NIOSH)

°C

v/v%

Pmax psi Vapor MIE

ppmppm1PEL (OSHA)

STEL (ACGIH) 1 ppm

Slide A:25


Specific Hazard

Index Code Data for Hydrazine Index

Value

Flash Point FlPt 72 °C 2

Flam. Liquid FLAM Class IIIA 2

Explosion EXPL LFL = 5; UFL = 98 v/v% 4

Toxic Hazard TOXIC LD50 oral = 129mg kg-1; LC50 Inh = 570ppm; LC50 skin = 600mg kg-1 2

Exposure EXPOS IDLH = 50 ppm;PEL = 1ppm; TLV = 40ppm 4

AI Temperature AIT 270 °C 2

Fl. Pt vs BPt FPBP FlPt = 72 °C; BPt = 113 °C; Rxn T = 200 °C 2


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FlPt 2 FLAM 2 EXPL 4 TOXIC 2 EXPOS 4

AIT 2 FPBP 2

Slide A:27


Severe A formal Risk Analysis MUST be performed for this chemical

Slide A:28


Repeat data entry for other reactants

Review results of Hazard Identification and Risk Analysis on Reaction Summary:

• Potentially Hazardous Reaction Conditions

• Summary of Hazard Properties of all Reagents

• Potentially Hazardous Reaction Chemistry

• Additional Concerns

• Recommendations for Additional Hazard Review


Slide A:29


Slide A:30


200 °C

25 °C

25 °C

0 psig

0 psig

Conversion of Existing Hazardous Functional Group (y/n)

1

y

Reaction performed less than 3 times (y/n)

Hazardous Functional Group Added to Molecule (y/n)n

n

Hazard Rating for Reaction Hazard

Maximum pressure of feed Maximum pressure of reaction Maximum temperature of feed Minimum reaction temperature

Minor

Hazards of Reaction Conditions (Check all that apply)

y

Maximum reaction temperature Scale-up reaction? Enter scale-up factor (Default = 1) Reaction to be run unattended (y/n)

Slide A:31


Toxic ba

sed on

LC(D) 50 value

s for

Oral, Skin or Inh

alation

Expo

sure based

on TLV,

PEL, or IDL

H

Classification of Flammab

le or

Combu

stible Liqu

id

Minim

um Ignitio

n En

ergy

(Vap

or or G

as)

Autoignitio

n Hazard

TOXIC EXPOS FLAM MIE-V AIT

1 Hydrazine hydrate y y y n y2 Benzophenone y y n n n3 Potassium Hydroxide y n n n n4 Diethylene glycol y n y n y5

6

.

Check Safeguards Compliance

Slide A:32

ACS March 2012LEGGETTTechnical Consulting Major

The reduction of aldehydes and ketones to alkanes. Condensation of the carbonyl compound with hydrazine forms the hydrazone, and treatment with base induces the reduction of the carbon coupled with oxidation of the hydrazine to gaseous nitrogen, to yield the corresponding alkane. The Huang-Minlon modification removes water and excess hydrazine by distillation, using a Dean Stark distillation trap, so that he reaction temperature can rise to 200 C. This allows the use of the cheaper hydrazine hydrate in place of anhydrous hydrazine. The Clemmensen Reduction can effect a similar conversion under strongly acidic conditions, and is useful if the starting material is base-labile.

Wolff-Kishner Reduction

Named Reaction Hazard Rating

Hazard Rating for Named Reactions


Slide A:33


138 °C

25 °C

25 °C

0 psig

0 psig

Major

Toxic based on

LC(D) 50 values for

Oral, Skin or Inh

alation

Expo

sure based

on TLV,

PEL, or IDLH

Classification of Flammable or

Combu

stible Liqu

id

Minim

um Ignitio

n Energy

(Vapor or G

as)

Autoignition

Hazard

Explosive Va

por

Flash Po

int H

azard

Ionizing Radiatio

n (alpha, beta, gam

ma, X‐Ray)

Laser Sou

rce

(Class 1, 2, 3, or 4

)

UV Ra

diation Source

(100 to

400 nm)

Strong Oxidizer / Reducer

Static Sensitive

Easily Polym

erizes

Suspected Cancer, M

utagenic,

Birth Defects, Teratogenic Risk

Water re

active

Air Sensitive

Peroxide

Former

High Re

actio

n Ra

te

Impact / Friction Sensitive

Temp control needed for storage

Sensitizer

Second

ary Ru

naway Reaction(s)

Gas fo

rmed

during reactio

n

TOXIC EXPOS FLAM MIE-V AIT EXPL FlPt NUCL LASER UV RDOX STAT POLY HLTH WAT AIR PERX HIRR IMPT TCN SENS RUN GAS

1 Hydrazine hydrate y y y n y y y n n n y n n y n n n n n n y n n 28 Severe

2 Benzophenone y y n n n y n n n n n n n n n n n n n n y n n 8 Minor

3 Potassium Hydroxide y n n n n n n n n n n n n n y n n y n n n n n 9 Minor

4 Diethylene glycol y n y n y y y n n n n n n n n n n n n n n n n 7 Minor

5 No Hazard

6 No Hazard

7 No Hazard

8 No Hazard

9 No Hazard

10 No Hazard

Overall Hazard Ratings and Recommendations

SEVERE HAZARD: Consider substituting one or more reagents for less hazardous compounds. Perform a Risk Analysis focusing on reagent handling and use.

At least one reactant, or solvent, has a flash point 25 C, or lower, than the planned max reaction temperature (138 C)

NO HAZARD

MAJOR HAZARD: Perform a Risk Analysis focusing on the reactive chemistry and synthetic methods for this step

Additional Concerns

Maximum reaction temperature Scale-up reaction? Enter scale-up factor (Default = 1) Reaction to be run unattended (y/n) Reaction performed less than 3 times (y/n)

Standad Synthesis Protocols Followed? (Provide reference)

Named Reaction Hazard Rating

Hazardous Functional Group Added to Molecule (y/n)n

n

Hazard Rating for Reaction Hazard

Maximum pressure of feed Maximum pressure of reaction Maximum temperature of feed Minimum reaction temperature

No HazardHazard Rating for Reaction Classes Hazard Rating for Named Reactions Minimal

Hazards of Reaction Conditions (Check all that apply)

Name of Reviewer

Name of Chemist

Documentation for Hazard Review

3/2/1912

3/1/1912

y

Use Named Reactions Hazards

n

y

n

y n

COR


n

n

y

Use the named reactions hazards to evaluate the potential hazards

Lab-HIRA Hazard Assessments for Synthesis Step

Section 3: Hazard Ratings, Recommendations and Documentation for Lab-HIRA Review

Section 1: Named Reaction or Reaction Class and Reaction Conditions for Step 1 of the Diphenylmethane synthesis

Section 2: Summary Table of Reagents Used During Step 1 of the Diphenylmethane synthesis.

Chemical Hazards Score

and RatingRe

actio

n Temperature

> Flash Po

int

High Co

rrosivity

FPBP

Reaction Class Hazard Rating

Conversion of Existing Hazardous Functional Group (y/n)The reduction of aldehydes and ketones to alkanes. Condensation of the carbonyl compound with hydrazine forms the hydrazone, and treatment with base induces the reduction of the carbon coupled with oxidation of the hydrazine to gaseous nitrogen, to yield the corresponding alkane. The Huang-Minlon modification removes water and excess hydrazine by distillation, using a Dean Stark distillation trap, so that he reaction temperature can rise to 200 C. This allows the use of the cheaper hydrazine hydrate in place of anhydrous hydrazine. The Clemmensen Reduction can effect a similar conversion under strongly acidic conditions, and is useful if the starting material is base-labile.

1

y

Lab-HIRA © Copyright Leggett Technical Consulting 2008 - 2011. Version 4.5; Date November, 2011

Use of Hazardous Chemicals

Hazard Potential of Reaction Chemistry

Hazard Potential of Reaction Conditions

Date Form Completed

Date Form Reviewed

Rudolp Fittig

Ludwig Kirshner

Location of notes and other related documention for this hazard review

Check Safeguards Compliance

Use Named Reactions Hazards Wolff-Kishner Reduction

Use of Hazardous Chemicals

Hazard Potential of Reaction Chemistry

Hazard Potential of Reaction Conditions

Overall Hazard Ratings and Recommendations

SEVERE HAZARD: Consider substituting one or more reagents for less hazardous compounds. Perform a Risk Analysis focusing on reagent handling and use.

At least one reactant, or solvent, has a flash point 25 C, or lower, than the planned max reaction temperature (200 C)

MINOR HAZARD: No Additional Risk Analysis needed

MAJOR HAZARD: Perform a Risk Analysis focusing on the reactive chemistry and synthetic methods for this step

Additional Concerns

Slide A:34


Case Study 2:• Synthesis of a vinyldecane derivative using t-BuLi.

• Researcher was exposed to t-BuLi during a transfer.

• The nitrile gloves and synthetic sweater, worn by the researcher at the time of the accident, caught fire; the chemist was not wearing a lab coat at the time.

• She received burns over 40% of her body and died a few weeks later.

How would Lab-HIRA have helped in this situation?


Slide A:35


Lab-HIRA produces a Safeguards Com-pliance Checklist for each reagent, including PPE recommendations

13 Handling techniques for these chemicals have been reviewed and approved by Chemical Safety Committee Hazard Codes: AIR

14 Written contingency plans are available covering worst case accident scenarios Hazard Codes: WAT, AIR

Signed: ____________________________________ Print Name: ________________________________ Grad Student Post Doc Supervisor

Date: _________

Safeguards Required to Work With This Material Use

Safe-guard?(Y/N)

Describe other risk reduction measures

1 Confirm that only Class I Division 2 rated electrical equipment will be used during this synthesis

Hazard Codes: WAT, AIR, EXPL, FLAM

2 Consider using a glove box or bag to handle t-Bu Lithium

Hazard Codes: WAT, AIR

3 Material transfers will be done in the hood, glove box or bag. Open-bench work prohibited for this chemical

Hazard Codes: WAT, AIR, TCN


Slide A:36


Lab-HIRA Step 2: Risk Assessment

Lab-HIRA may recommend a formal risk analysis such as a What-If or procedural HAZOP

• Chose the hazard analysis technique• Assemble necessary documentation• Conduct risk analysis• Evaluate recommendations for risk reduction• Close out recommendations

o Items to be completed before beginning worko Schedule other items for timely completion

• Document Lab-HIRA findings

Slide A:37



A typical synthesis procedure for Case Study 1:In a suitable fume hood set up a nitrogen-purged multi-neck flask

equipped with an agitator, reflux condenser, Dean-Stark trap, and

temperature controller.

Suspend the ketone (85 g) in an alkylene glycol (~2 L).

Place the flask in a room temperature oil bath then add KOH (70 g).

Gradually add 80% solution of hydrazine hydrate (65 mL).

Heat the reaction mixture slowly heated to 200oC ………

Slide A:38



Action: Install and set a temperature controller for reactor

What-If Scenario 1: Temperature controller incorrectly set up or fails

Consequence: Failure to control reaction temperature; possible runaway reaction; possible loss of containment

Risk Assessment: Major, if consequence plays out

Current Safeguards: Chemist monitors reaction regularly

Recommendation: Determine if runaway is possible; consider using redundant T controller if true

Slide A:39



Action: Install and set a temperature controller for reactor

What-If Scenario 2: Runaway reaction occurs before evasive action can be taken?

Consequence: Probable loss of containment; possible fire/ explosion

Risk Assessment: Severe, if consequence plays out

Current Safeguards: None at present – no GS willing to camp out beside fume hood

Recommendation: Determine if runaway is possible; consider using redundant T controller if true; do not perform overnight runs for this reaction

Slide A:40


Lab-HIRA: Summary and Conclusions• Lab-HIRA identifies and assesses reaction hazards

and gives guidance about formal hazard review.

• Designed for use by chemists who have sufficient knowledge to safely handle the chemicals and the equipment planned for the synthesis.

• The hazard potential may be estimated from readily available physical, chemical, and health data.

• Thirty three parameters, indicative of one or more hazardous properties of molecules or synthesis conditions, are used to assess the reaction hazards.

Slide A:41


Lab-HIRA: Summary and Conclusions

• The risk-based assessments tend to be conservative.

• Once hazards have been recognized appropriate risk reduction measures can be implemented.

• If a formal hazard analysis for the synthesis reactions is indicated then techniques, such as Check-List, What-If, SWIF or HAZOP are available.

• Thermal hazards testing may be required to quantify the consequences of equipment upsets or procedural short-comings.

Slide A:42


Lab-HIRA: Summary and Conclusions

Only open literature data are used.Some hazards associated with thesynthesis reaction may be missed.

It is the responsibility of the user todetermine the adequacy of thehazard identification and riskanalysis of their synthesis.

Slide A:43


D. Leggett, Lab-HIRA: Hazard Identification and Risk Analysis for the Chemical Research Laboratory: Part 1. Preliminary Hazard Evaluation, J. Chem. Health & Safety, In pressDOI 10.1016/j.jchas. 2012.01.012

D. Leggett, Lab-HIRA: Hazard Identification and Risk Analysis for the Chemical Research Laboratory: Part 2. Risk Analysis of Laboratory Operations, J. Chem. Health & Safety, In pressDOI 10.1016/j.jchas.2012.01.013

Lab-HIRA: Publications

lab hira

Technology

labhira step

reaction class

hazard identificationlabhira

risk assessment labhira

technical consultingacs

reaction hazards

rxn class

careful hazard analysis