Lab HIRA

Lab-HIRA: Hazard Identification
and Risk Analysis for the
Chemical Research Laboratory

Dr. David Leggett
Leggett Technical Consulting
Los Angeles, CA

243rd ACS National Meeting
San Diego CA, March 2012

Lab-HIRA: Hazard Identification and Risk Assessment

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.

LEGGETT Slide A:2
Technical Consulting ACS March 2012

• 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

LEGGETT Slide A:3

• Accident rate is 10 to 50 times higher than that in
industrial laboratories
o 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)

LEGGETT Slide A:4


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

Type of Hazard
Scale of Reaction Typical Approaches
Assessment
Research & Desktop Study Calculations, Literature,
Development Small Scale Testing DSC, Mixing Cal, RSST

Qualitative and Semi- Reaction Calorimetry,
Pilot or Kilo Lab
Quantitative Testing Adiabatic Calorimetry

Custom testing for DIERS, Dust, Reaction
Manufacturing
Engineering Design Calorimetry, Flammability

LEGGETT Slide A:5


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

Desktop Study Calculations, Literature
Small Scale Testing DSC, Mixing Calorimetry, RSST

SWIF or Simple HAZOP, if needed

LEGGETT Slide A:6

Lab-HIRA Step 1: Hazard Identification

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

LEGGETT Slide A:7


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

LEGGETT Slide A:8

Properties Expressed as Discrete Values

Chemical / Energy
Property Value
Source

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

LEGGETT Slide A:9


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

Hazard
Hazard Min Max
Index Value
0 No Hazard > 5,000
1 Minimal > 500 5,000
2 Minor > 50 500
3 Moderate 5 50
4 Major <5
United Nations, Globally Harmonized System of Classification and Labeling of
Chemicals (2005)
LEGGETT Slide A:10


Properties are expressed in various units:

Hazard Index Value
Property
0 1 2 3 4
Flammability 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 <100
MIE, mJ >5 2-5 0.5 - 2 0.05 - 0.5 < 0.05
Auto-Ign, °C > 500 350 - 500 250 - 350 150 - 250 < 150
Hazard No Haz Minimal Minor Moderate Major

LEGGETT Slide A:11


Four Classes of Data


Class 3: Reaction Hazards, by Type or Named Reaction


LEGGETT Slide A:12

Hazardous Characteristics of Molecules
Index Index
Specific Hazard Code Value
Pyrophoric: spontaneously flammable or
AIR 3
reactive with air < 130 °F
Forms gaseous products during reaction –
GAS 2
CO2, CO, H2, N2, C4H10
Suspected carcinogen, teratogen, mutagen or
HLTH 4
reproductive hazard
Impact or friction sensitive IMPT 3
Molecule requires temperature controlled
TCN 2
storage or handling

LEGGETT Slide A:13




Class 3: Reaction Hazards, by Type or Named Rxn


LEGGETT Slide A:14

Hazardous Characteristics of Molecules
Index
Reaction Type Reaction Type
Value

Decarboxylation Removal of –COOH with CO2 evolved 2

Nitration Red fuming or white HNO3, N2O4 3

LiAlH4, N2H4 in KOH, NaBH4 in CH3OH 3
Reductions
BF3 / NaBH4, H2 + catalyst 2
Oxalyl chloride – high health hazard 3
Esterifications
RCOOH + SOCl2 followed by R’OH 2

LEGGETT Slide A:15

Hazard Levels of Named Reactions
Index
Reaction Type Reaction Type
Value
Wolff-Kishner Reduction of RCHO or R2CO to RH with
3
Reduction H2NNH2

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

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

Meerwein- The aluminum-catalyzed hydride shift from the
Ponndorf-Verley α-carbon of an alcohol reagent to RR’CO 2
Reduction forming RR’CHOH

LEGGETT Slide A:16




Class 3: Reaction Hazards, by Type or Named Reaction


LEGGETT Slide A:17


Properties are expressed in various units:

Synthesis Hazard Index Value
Conditions 0 1 2 3 4
150 -
TPROCESS, MAX (°C) < 75 75 - 150 250 - 400 > 400
250

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

LEGGETT Slide A:18


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

LEGGETT Slide A:19

Overall Hazard Index, OHI given by:

O H I  I V I V I V I V I V
    D I S P R  D I S C N D  C H M H Z  N A M E  T Y P E 

 
︳

︳

︳
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)

LEGGETT Slide A:20

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

KOH, HOCH2CH2OH

H2NNH2 200 °C, Reflux

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

LEGGETT Slide A:21

LEGGETT Slide A:22

Toxicity LD50 oral (rat) 129 mg/kg

ACGIH TLVs TWA (ACGIH) 40 ppm
Exposure Limits
OSHA PEL & NIOSH IDLH TWA (OSHA) n/a ppm

Melting & Boiling Pt; AutoIgnition B Pt 113 °C

Lower Flam
Flammability (Liquid) LEL / UEL ; Fl Pt Limit
5 v/v%

Radiation Sources, Nuclear, Laser, UV Nuclear n/a Radiation Type

Dust Expl Severity: ST / Pmax / MIE ST Dust Class n/a Slide A:23
LEGGETT

LD50 skin LC50 inhal
600 mg/kg 570 ppm
(rabbit) Gas (rat)

STEL (ACGIH) 1 ppm C (ACGIH) n/a ppm

PEL (OSHA) 1 ppm IDLH (NIOSH) 50 ppm

M Pt -52 °C AutoIgn Temp 270 °C

Upper Flam
Limit
98 v/v% Flash Point 72 °C

Laser Type n/a Laser Class UV Wavelength n/a nm

Pmax n/a psi Vapor MIE n/a mJ Slide A:24
LEGGETT

Specific Index Index
Code
Data for Hydrazine Value
Hazard
Flash Point FlPt 72 °C 2
Flam. Liquid FLAM Class IIIA 2
Explosion EXPL LFL = 5; UFL = 98 v/v% 4
LD50 oral = 129mg kg-1; LC50 Inh =
Toxic Hazard TOXIC 2
570ppm; LC50 skin = 600mg kg-1
IDLH = 50 ppm;
Exposure EXPOS 4
PEL = 1ppm; TLV = 40ppm
AI Temperature AIT 270 °C 2
FlPt = 72 °C; BPt = 113 °C;
Fl. Pt vs BPt FPBP 2
Rxn T = 200 °C

LEGGETT Slide A:25

FlPt 2 FLAM 2 EXPL 4 TOXIC 2 EXPOS 4

AIT 2 FPBP 2

LEGGETT Slide A:26

Severe A formal Risk Analysis MUST be performed for this chemical

LEGGETT Slide A:27


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

LEGGETT Slide A:28

LEGGETT Slide A:29

Hazards of Reaction Conditions (Check all that apply)
Hazardous Functional Group Added to Molecule (y/n) n

Conversion of Existing Hazardous Functional Group (y/n) n

Reaction performed less than 3 times (y/n) y

Reaction to be run unattended (y/n) y

Scale-up reaction? Enter scale-up factor (Default = 1) 1

Maximum reaction temperature 200 °C

Minimum reaction temperature 25 °C

Maximum temperature of feed 25 °C

Maximum pressure of reaction 0 psig

Maximum pressure of feed 0 psig
LEGGETT Slide A:30
Hazard Rating for Reaction Hazard
Technical Consulting Minor
ACS March 2012

LEGGETT
Technical Consulting
.

6
5
4
3
2
1
Check
Safeguards

Benzophenone
Compliance

Diethylene glycol
Hydrazine hydrate

Potassium Hydroxide

Toxic based on LC(D)50 values for
y
y
y
y

Oral, Skin or Inhalation
Exposure based on TLV,
y
y

n
n

PEL, or IDLH
Classification of Flammable or
y

y
n
n
TOXIC EXPOS FLAM

Combustible Liquid
Minimum Ignition Energy
n
n
n
n

Slide A:31
MIE-V

(Vapor or Gas)
ACS March 2012
y
y

n
n

Autoignition Hazard
AIT

Named Reaction Hazard Rating
Wolff-Kishner Reduction
Wolff-Kishner Reduction
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.
LEGGETT Slide A:32
Hazard Rating for Named Reactions
Technical Consulting Major ACS March 2012

Lab-HIRA Hazard Assessments for Synthesis Step

Overall Hazard Ratings and Recommendations
Hazards of Reaction Conditions (Check all that apply)
Section 1: Named Reaction or Reaction Class and Reaction Conditions for Step 1 of the Diphenylmethane synthesis

Reaction Class Hazard Rating Named Reaction Hazard Rating
Hazardous Functional Group Added to Molecule (y/n) n Use Named Reactions Hazards Wolff-Kishner Reduction
Conversion of Existing Hazardous Functional Group (y/n) n Use Named Reactions Hazards Wolff-Kishner Reduction
Reaction performed less than 3 times (y/n) y Use the named reactions hazards to evaluate the potential hazards The reduction of aldehydes and ketones to alkanes. Condensation of the
Reaction to be run unattended (y/n)
Scale-up reaction? Enter scale-up factor (Default = 1)
y

1
SEVERE HAZARD: Consider substituting one or more 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
Use of Hazardous Chemicals
Maximum reaction temperature
Minimum reaction temperature
138

25
°C

°C
reagents for less hazardous compounds. Perform a Risk Huang-Minlon modification removes water and excess hydrazine by
distillation, using a Dean Stark distillation trap, so that he reaction

Analysis focusing on reagent handling and use.
temperature can rise to 200 C. This allows the use of the cheaper hydrazine
Maximum temperature of feed 25 °C hydrate in place of anhydrous hydrazine. The Clemmensen Reduction can
Maximum pressure of reaction 0 psig effect a similar conversion under strongly acidic conditions, and is useful if
the starting material is base-labile.
Maximum pressure of feed 0 psig

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

Hazard Potential of Reaction MAJOR HAZARD: Perform a Risk Analysis focusing on the
Chemistry Section 2:
reactive chemistry and synthetic methods for this step
Summary Table of Reagents Used During Step 1 of the Diphenylmethane synthesis
Toxic based on LC(D)50 values for

.

Temp control needed for storage

Secondary Runaway Reaction(s)
Classification of Flammable or

Suspected Cancer, Mutagenic,
Birth Defects, Teratogenic Risk
(alpha, beta, gamma, X‐Ray)

Gas formed during reaction
Minimum Ignition Energy

Impact / Friction Sensitive
Strong Oxidizer / Reducer
Exposure based on TLV,

Reaction Temperature
Oral, Skin or Inhalation

Check

UV Radiation Source
Autoignition Hazard
Combustible Liquid

Ionizing Radiation

High Reaction Rate
Flash Point Hazard

Easily Polymerizes
(Class 1, 2, 3, or 4)
Hazard Potential of Reaction
Safeguards

Peroxide Former
High Corrosivity
Explosive Vapor

(100 to 400 nm)

Static Sensitive

Water reactive
(Vapor or Gas)

Laser Source
> Flash Point
Compliance

Air Sensitive
PEL, or IDLH

MINOR HAZARD: No Additional Risk Analysis needed

Sensitizer
Conditions
Chemical
Hazards Score
At least one reactant, or solvent, has a flash point 25 C, or and Rating
Additional Concerns
1 Hydrazine hydrate
TOXIC EXPOS FLAM

y y y
MIE-V

n
AIT

y
EXPL

y
FlPt

y
lower, than the y n n max nreaction n n n n y (200 nC)28
y n n n
planned y
FPBP

n n
temperature n
NUCL LASER UV RDOX STAT POLY HLTH WAT AIR COR PERX HIRR IMPT TCN SENS RUN GAS
Severe
2 Benzophenone y y n n n y n n 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 n y n y n y n n n n n 9 Minor
4 Diethylene glycol y n y n y y y y n 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

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

Documentation for Hazard Review Overall Hazard Ratings and Recommendations
Name of Chemist Ludwig Kirshner Date Form Reviewed 3/1/1912
SEVERE HAZARD: Consider substituting one or more
Name of Reviewer Rudolp Fittig Date Form Completed 3/2/1912 Use of Hazardous Chemicals reagents for less hazardous compounds. Perform a Risk
Analysis focusing on reagent handling and use.
Standad Synthesis Protocols Followed? (Provide reference)

Hazard Potential of Reaction MAJOR HAZARD: Perform a Risk Analysis focusing on the
Chemistry reactive chemistry and synthetic methods for this step

Location of notes and other related documention for this hazard review Hazard Potential of Reaction
NO HAZARD
Conditions

LEGGETT Additional Concerns
At least one reactant, or solvent, has a flash point 25 C, or Slide A:33
lower, than the planned max reaction temperature (138 C)

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


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?

LEGGETT Slide A:34

Use Describe
Safe- other risk
Safeguards Required to Work With This Material guard? reduction
Lab-HIRA produces (Y/N) measures
Confirm that only Class I Division 2 rated electrical
a Safeguards Com- 1 equipment will be used during this synthesis
pliance Checklist Hazard Codes: WAT, AIR, EXPL, FLAM
Consider using a glove box or bag to handle t-Bu Lithium
for each reagent, 2
Hazard Codes: WAT, AIR
including PPE Material transfers will be done in the hood, glove box or
3 bag. Open-bench work prohibited for this chemical
recommendations Hazard Codes: WAT, AIR, TCN

Handling techniques for these chemicals have been
13 reviewed and approved by Chemical Safety Committee
Hazard Codes: AIR
Written contingency plans are available covering worst
14 case accident scenarios
Hazard Codes: WAT, AIR
Signed: ____________________________________
Date:
Print Name: ________________________________
_________
Grad Student  Post Doc  Supervisor 

LEGGETT Slide A:35

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 work
o Schedule other items for timely completion
• Document Lab-HIRA findings

LEGGETT Slide A:36

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 ………

LEGGETT Slide A:37


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

LEGGETT Slide A:38


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

LEGGETT Slide A:39

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.

LEGGETT Slide A:40

• 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.

LEGGETT Slide A:41


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

It is the responsibility of the user to
determine the adequacy of the
hazard identification and risk
analysis of their synthesis.

LEGGETT Slide A:42

Lab-HIRA: Publications

D. Leggett, Lab-HIRA: Hazard Identification and Risk Analysis
for the Chemical Research Laboratory: Part 1. Preliminary
Hazard Evaluation, J. Chem. Health & Safety, In press
DOI 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 press
DOI 10.1016/j.jchas.2012.01.013

LEGGETT Slide A:43

Lab HIRA

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