Current Issues of Interest to the TLVChemical Substances Committee

1
Current Issues of Interest to theTLV-Chemical
Substances Committee
Daniel J. Caldwell, Ph.D., CIH, DABT ExxonMobil
Biomedical Sciences, Inc.
2
Presentation Outline

• Mixtures
• Sensory Irritation
• Particulates Not Otherwise Specified
• Toxicology Issues

3
Mixtures

• Appendix C, TLVs for Mixtures
• Special case atmospheric composition is similar
  to original material
• Application to hydrocarbon solvents using
  Reciprocal Calculation Procedure
• Global interest MAK, ACGIH, IRSST

4
Mixtures The Reciprocal Calculation Procedure

• Hydrocarbon Solvents are Well Defined
• Reciprocal Calculation Procedure
• Known Health Effects
• Group Guidance Values
• Mineral Spirits as an Example
• Conclusions

5
Mixtures - RCP

• Objective
• To develop a generic and harmonized method for
  setting exposure limits for hydrocarbon solvents.
• Generic Include all hydrocarbon solvents
• Maximum advantage of existing data
• Minimize effects of minor differences
• Harmonized Similar solvents have similar
  TLVs
• Consistent health advice worldwide

6
Mixtures - RCP

• Properties of Hydrocarbon Solvents
• molecules composed only of hydrogen and carbon
• n- / iso-paraffins, cycloparaffins and/or
  aromatics
• may contain a single molecular type or be complex
• boil between 35-320C, although range is normally
  less
• highly refined with specific technical properties
• do not contain appreciable levels of benzene or
  carcinogenic PAHs
• olefins are not covered by method

KEY MESSAGE - Hydrocarbon solvents are a family
of materials which contain constituents with
similar chemical properties.
7
Mixtures - RCP

• Procedure To Set TLV For Hydrocarbon Solvents
• applicable to all hydrocarbon solvents
• consider the contributions of all constituents
• ensure that no component exceeds its own TLV
• produce changes in the TLV which are
  proportional to changes in composition
• sound and transparent underlying scientific
  assumptions
• readily adaptable to changes in the TLV of any
  component

8
Mixtures - RCP

• Determine Sum Of Fractional TLVs
• 1 Fractiona Fractionb Fractionn
• TLVmixture TlVa TLVb TLVn
• Inputs Include
• TLVs for single constituents e.g. cyclohexane,
  toluene
• Guidance values for groups of hydrocarbons based
  on structural and toxicological similarity

KEY MESSAGE - RCP is based on ACGIH mixtures
formula
1 Assumes similarity of vapor and liquid
compositions.
9
Mixtures - RCP

• Underlying Assumptions
• Similar chemistry ? similar toxicity
• Health effects of components are additive
• Vapor composition is similar to liquid
  composition
• Exposure limits should be based on toxicological
  properties

KEY MESSAGE - An RCP procedure can be used for
complex substances if they contain constituents
with similar physical and chemical properties
10
RCP Group Guidance Values

• or
• What do you do when you dont have a TLV?

11
Group Guidance Values

• Assigning Guidance Values for Hydrocarbon Groups
• Divide hydrocarbon components into groups with
  common health effects
• Assign common guidance values to the groups
• Calculate TLVs for complex substances from
  individual TLVs and Group Guidance Values using
  the RCP

KEY MESSAGE - If group values are developed,
TLVs can be calculated for hydrocarbon solvent
mixtures using a RCP.
12
EuropeanGroup Guidance Values
C5-C8 Aliphatics/cycloaliphatics 1500
mg/m3 C9-C15 Aliphatics/cycloaliphatics 1200
mg/m3 C7-C8 Aromatics 200
mg/m3 C9-C15 Aromatics 100
mg/m3 Others n-hexane 175
mg/m3 Naphthalene 50 mg/m3 Cyclohexane
350 mg/m3
13
RCP Example - Mineral Spirits

• Generic Term Applied To Hydrocarbon Fractions
• That boil between 140-215C
• Contain n- and iso-alkanes, cycloalkanes, and
  aromatics in varying concentrations.
• Contain lt 1 - 30 aromatics.
• Can be described by several CAS numbers.
• Are often marketed in Europe under brand names,
  not as mineral spirit.

KEY MESSAGE - Mineral spirits is a generic term
for a range of hydrocarbon solvents..
14
RCP - Analysis Of A Typical Mineral Spirit

• Boiling range 150-200C
• Flash Point 38C
• Carbon number range 8-12
• Average molecular weight 141
• w/w n-/iso-cyclo-Alkanes (C5-C8) 7.4
• w/w n-iso-cyclo-Alkanes (C9-C15) 76.5
• w/w Aromatics 16.1
• comprising C7/C8 aromatics 2.0
• C9 aromatics 8.3
• Non-listed aromatics 5.8

15
RCP Example - Mineral Spirits

• Using the proposed guidance values for mineral
  spirits and substituting these values in the RCP
  formula
• __1__ __Fra_ ___Frb__ ..... _Frn__
• TLV sol TLVa TLVb TLVn
• 0.074 0.765 0.020 0.141
  1500 1200 200 100
• 0.000049 0.00064 0.0001 0.00141

0.00219
16
RCP Example Mineral Spirits

• 1/TLV 0.00219
• TLV 456 mg/m3
• Using the rounding procedure this becomes
• 500 mg/m3
• Comparable to TLV for Stoddard Solvent of
• 600 mg/m3

17
RCP - Conclusions

• The RCP approach is
• Application of special case of the mixtures
  formula
• Accepted by ACGIH, and some EU member states

18
RCP Conclusions (cont.)

• Group Guidance Values can be used to calculate
  TLVs because
• Solvents do not contain highly toxic constituents
• A substantial toxicology database exists
• Acute CNS effects are the endpoint of greatest
  concern
• Preventing acute CNS effects will prevent chronic
  effects

19
Sensory Irritation

• What is Sensory Irritation?
• What data are used in developing TLVs?
• Differentiating irritation from odor
• Conclusions

20
Sensory Irritation

• Background Information
• Undesirable temporary effect on the eyes and
  upper respiratory tract
• Acute, concentration dependent effect
• Critical effect upon which to base a TLV
• Nearly 50 of TLVs set to prevent irritation
• Confounding of irritation response by odor

21
Sensory Irritation

• Sources of Data
• Animal models (RD50)
• Physical/Chemical properties
• Worker experience
• Social Expectations
• Irritation is an adverse effect
• Nearly all workers should be protected

22
Sensory Irritation

• Mechanism of Sensory Irritation - Human
  Chemosensory System
• olfactory (first cranial nerve) - smell
• trigeminal (fifth cranial nerve) - irritation
• Perception of Irritation Impacted By
• psychological context
• exposure duration
• inter- and intra- individual variability

23
Nasal Chemesthesis

• 2-alternative forced choice design
• Simultaneous sniff from 2 vessels, one containing
  test substance, the other a blank
• 14 trials per session

24
Ocular Chemesthesis

• 3-alternative forced choice design
• Air flow of 4 L/min to displace headspace vapor
  into eye cup
• 5 sec exposure with 10 trials per session

25
Sensory Irritation

• Current Research Areas
• Sensory scaling
• Stimulus lateralization
• Variation in sensitivity
• Adaptation
• Attitude and expectations
• Differentiation of odor from irritation

26
Sensory Irritation
27
Sensory Irritation

• Invited presentations
• Pam Dalton, Monell Institute
• Bill Cain, Univ. California

28
Sensory Irritation

• Useful Guidelines
• Threshold for sensory irritation 32 of Cs
• Acceptable human exposure 0.03 x RD50
• Odor threshold lt Lateralization threshold lt
  Irritation threshold

29
Sensory Irritation

• Conclusions
• Remains an active research area
• Effect with multiple causes
• Committee seeking reliable data on irritant
  effects

30
Particulates Not Otherwise Specified

• Appendix E Particulates (insoluble or poorly
  soluble) Not Otherwise Specified
• Do not have an applicable TLV Insoluble or
  poorly soluble in water (preferably in aqueous
  lung fluid)
• Have low toxicity (i.e., not cytotoxic,
  genotoxic, or otherwise chemically reactive with
  lung tissue)

31
Particulates Not Otherwise Specified

• Airborne concentrations should be kept
• lt 3 mg/m3, respirable particles
• lt 10 mg/m3, inhalable particles
• until such time as a TLV is set.

32
Toxicology Issues

• Reproductive Toxicity
• Separate repro notation?
• Seminar presented by MAK Commission
• Neurotoxicity
• Differentiation of neurotoxicity from
  neurobehavioral effects
• Seminar presented

33
Neurobehavioral Effects of Hydrocarbon Solvents
Research Strategy
RAT BEHAVIORAL AND PK STUDIES
HUMAN BEHAVIORAL AND PK STUDIES
ETOH
HUMAN BEHAVIORAL AND PK STUDIES
RAT BEHAVIORAL AND PK STUDIES
RAT SUBCHRONIC STUDIES
STODDARD SOLVENT/CYCLOHEXANE
Validation Complete
RAT BEHAVIORAL AND PK STUDIES
OTHER REPRESENTATIVE HYDROCARBON SUBSTANCES