Transcript Document

Current Issues of Interest to
the
TLV®-Chemical Substances
Committee
Daniel J. Caldwell, Ph.D., CIH, DABT
ExxonMobil Biomedical Sciences, Inc.
Presentation
Outline
•Mixtures
•Sensory Irritation
•Particulates Not Otherwise Specified
•Toxicology Issues
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
Mixtures: The Reciprocal
Calculation Procedure
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Hydrocarbon Solvents are Well Defined
Reciprocal Calculation Procedure
Known Health Effects
Group Guidance Values
Mineral Spirits as an Example
Conclusions
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
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 35-320°C, 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.
Mixtures - RCP
Procedure To Set TLV® For Hydrocarbon Solvents:
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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
Mixtures - RCP
Determine Sum Of Fractional TLVs® :
1
=
TLVmixture
Fractiona
TlVa
+
Fractionb
TLVb
+
Fractionn
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.
Mixtures - RCP
Underlying Assumptions:
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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
RCP –
Group Guidance Values
or
What do you do when you
don’t have a TLV®?
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.
European
Group 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
Naphthalene
Cyclohexane
175 mg/m3
50 mg/m3
350 mg/m3
RCP Example - Mineral
Spirits
Generic Term Applied To Hydrocarbon
Fractions:
• That boil between 140-215°C
• Contain n- and iso-alkanes, cycloalkanes, and
aromatics in varying concentrations.
• Contain < 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..
RCP - Analysis Of A
Typical Mineral Spirit
Boiling range
150-200°C
Flash Point
~38°C
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
RCP Example Mineral Spirits
Using the proposed guidance values for mineral spirits and
substituting these values in the RCP formula:
__1__
TLV sol
= __Fra_+
TLVa
___Frb__
TLVb
= 0.074 +
1500
0.765
1200
+
+ ..... _Frn__
TLVn
0.020
200
+ 0.141
100
= 0.000049 + 0.00064 + 0.0001 + 0.00141
= 0.00219
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
RCP - Conclusions
The RCP approach is:
• Application of special case of the mixtures
formula
• Accepted by ACGIH®, and some EU member
states
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
Sensory Irritation
• What is Sensory Irritation?
• What data are used in developing
TLVs®?
• Differentiating irritation from odor
• Conclusions
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
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
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
Nasal Chemesthesis
• 2-alternative forced choice design
• Simultaneous sniff from 2 vessels, one containing test
substance, the other a blank
• 14 trials per session
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
Sensory Irritation
Current Research Areas
• Sensory scaling
• Stimulus lateralization
• Variation in sensitivity
• Adaptation
• Attitude and expectations
• Differentiation of odor from irritation
Sensory Irritation
ODOR SOURCE
EXPOSURE
PERCEPTION
APPRAISAL
AVOIDANCE
BEHAVIOR
ANNOYANCE
STRESS RELATED
HEALTH EFFECTS
ADAPTATION
HABITUATION
Sensory Irritation
Invited presentations:
• Pam Dalton, Monell Institute
• Bill Cain, Univ. California
Sensory Irritation
Useful Guidelines
• Threshold for sensory irritation: ~ 32% of Cs
• Acceptable human exposure:
~ 0.03 x
RD50
• Odor threshold < Lateralization threshold <
Irritation threshold
Sensory Irritation
Conclusions:
• Remains an active research area
• Effect with multiple causes
• Committee seeking reliable data on irritant
effects
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)
Particulates Not
Otherwise Specified
Airborne concentrations should be kept:
• < 3 mg/m3, respirable particles
• < 10 mg/m3, inhalable particles
until such time as a TLV® is set.
Toxicology Issues
Reproductive Toxicity
• Separate “repro” notation?
• Seminar presented by MAK Commission
Neurotoxicity
• Differentiation of neurotoxicity from
neurobehavioral effects
• Seminar presented
Neurobehavioral Effects of
Hydrocarbon Solvents:
Research Strategy
ETOH
“STODDARD
SOLVENT”/
CYCLOHEXANE
HUMAN BEHAVIORAL
RAT BEHAVIORAL
AND
AND
PK STUDIES
PK STUDIES
HUMAN BEHAVIORAL
RAT BEHAVIORAL
RAT
AND
AND
SUBCHRONIC
PK STUDIES
PK STUDIES
STUDIES
Validation Complete
OTHER REPRESENTATIVE
HYDROCARBON SUBSTANCES
RAT BEHAVIORAL
AND
PK STUDIES