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Current Issues of Interest to the TLV ® -Chemical Substances Committee

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.

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Current Issues of Interest to the TLV ® -Chemical Substances Committee

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  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 moleculartype 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.

  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 don’t 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 140-215°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..

  14. RCP - Analysis Of A TypicalMineral 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

  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 - HumanChemosensory 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, onecontaining 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 < Lateralization threshold < 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: • < 3 mg/m3, respirable particles • < 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

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