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List of Chemicals with Threshold Limit Values Primarily Based on Sensory Irritation*

DOI: https://doi.org/10.22427/NTP-DATA-022-00004-0001-000-9

Inhalation Threshold Limit Values (TLVs) for 112 chemicals listed in the 2015, American Conference of Governmental Industrial Hygienists (ACGIH) booklet entitled "TLVs and BEIs Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & Biological Exposure Indices".

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ID Number Chemical Name4 CASRN Reference Date1 TLV-TWA or STEL (ppm)2 TLV Basis3

* Inhalation Toxicology Databases in Mice for QSAR and Safe Levels of Exposure for Humans

INTRODUCTION

Reported cited published

Two data tables are provided as database required to establish a Quantitative Structure-Activity Relationship (QSAR). The first table, Inhalation TLV 1993 Update, (https://cebs.niehs.nih.gov/datasets/search/updated-1993-tlvs) was updated from the database published by Schaper (1) in 1993. This table was used to prepare a QSAR. The second table, Inhalation TLV 2015 ACGIH, is a table of TLVs from a 2015 booklet (2) by the American Conference of Governmental Industrial Hygienists (ACGIH). It was used to evaluate the predictivity of the prepared QSAR. It contains 112 chemicals for separate testing. A database published in 1998, Alarie et al. (3), is available for consultation in the preparation of a new QSAR. This 1998 database was used by Gupta et al. (4) to prepare a QSAR, also available for consultation.

  1. Can results obtained in mice provide estimates of safe levels of exposure for humans to volatile organic chemicals (VOCs) of industrial importance?

Schaper’s 1993 table (1) was updated, listing the potency in mice for 89 chemicals, potencies calculated as RD50s. In this Table the available respective “safe level of exposure in humans” known as Threshold Limit Values (TLVs) are listed. These are published yearly by the American Conference of Governmental Industrial Hygienists (ACGIH) since 1946. Such values published in 1968 became the Permissible Exposure Levels (PELs) when the Occupational Health and Safety Act (OSHA) became law for the US in 1970.

A linear regression analysis was conducted using a fraction of each listed RD50 value, 0.03 x RD50, vs their respective TLV values of 1991-1992, as listed in Schaper’s table. The table, updated in 2015, also lists additional RD50s as well as updating of their respective TLVs to 2015.

Excellent correlations were found between the potencies in mice (0.03 x RD50s) and TLVs and were presented in a Lecture at the Society of Toxicology Meeting in 2016. Scientists interested in using Table 1, can listen to this Lecture for information and results with this bioassay at this link: https://vimeo.com/163860403

  1. Can Quantitative Structure-Activity Relationships (QSAR) be obtained to estimate RD50s and therefore TLVs or PELs?

In 1998, a table was published by Alarie et al. (3), now containing 145 VOCs. They were divided in nonreactive VOCs (nrVOCs) and reactive VOCs (rVOCs). The physicochemical descriptors published by M. H. Abraham were used to estimate the potency (RD50) of these VOCs. As shown in this article we were able to estimate RD50 of nrVOCs but not for rVOCs.

  1. In 2015, Gupta et al. (4) published an article using the same database published in 1998, noted above. They also used physicochemical descriptors but they added chemical reactivity descriptors. As a result, they were able to estimate RD50s for both nrVOCs and rVOCs using statistical and QSAR procedures. This progress was also presented, and discussed, at the Lecture noted above.
  2. With the data then available, an answer was prepared for NTP/NIEHS’ request for data. This answer stated that if a QSAR was to be used for “regulatory purposes” there would be a need to supply the regulator with an estimate of the possible deviation from the estimated values of RD50 for a new chemical, i.e. how good is the predictivity of this QSAR. In order to obtain this, the ACGIH 2015 Inhalation TLVs: “Table 2 List of chemicals with TLVs but with no RD50 values…..”, was included in the information submitted. How it can be used was presented and discussed here: https://ntp.niehs.nih.gov/iccvam/pubcomment/fr-2016-16840/alarie-508.pdf and also available and discussed here: https://vimeo.com/163860403

This dataset was prepared for scientists interested in QSAR in Toxicology. The two tables provide for easy access to a specific inhalation toxicity database as well as how it can be used, for in-silico methods to proceed. Basically, we need:

1) reliable animal bioassay with potency numbers from a concentration-response relationship;

2) reliable human “safe level of exposure” numbers;

3) good correlation between the animal bioassay potency and safe level of exposure in humans;

4) good physicochemical and chemical reactivity descriptors;

5) good equation to estimate potency using the descriptors for a new chemical;

6) good estimates of the variability in potency (RD50s) calculated using the QSAR procedure, so that regulators can have confidence that such estimates can be used for “safe level of exposure” for humans.

References

  1. Schaper, M. (1993). Development of a database for sensory irritants and its use in establishing occupational exposure limits. Am. Ind. Hyg. Assoc. J. 54: 488-544.    https://doi.org/10.1080/15298669391355017
  2. Booklet of The American Conference of Governmental Industrial Hygienists (2015). TLVs and BEIs Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & Biological Exposure Indices.
  3. Alarie, Y., Schaper, M., Nielsen G.D. and Abraham, M.H. (1998). Structure-Activity relationships of volatile organic chemicals as sensory irritants. Arch. Toxicol. 72: 125-140. https://doi.org/10.1007/s002040050479
  4. Gupta, S., Basant, N. and Singh, K.P. (2015). Estimating sensory irritation potency of volatile organic chemicals using QSARs based on decision tree methods for regulatory purpose. Ecotoxicology 24: 873-886. https://doi.org/10.1007/s10646-015-1431-y

Footnotes

1 From: Booklet of The American Conference of Governmental Industrial Hygienists (ACGIH) (2015). TLVs and BEIs Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & Biological Exposure Indices. For each chemical listed the last Documentation Date is listed as given in the 2015 Booklet.

2 The number listed is for TLV-TWA or STEL and the notation Ceiling (C) if applicable.  When both a TLV-TWA and TLV-Ceiling are given, the lowest value is entered. Note that for some chemicals a revision is contemplated, so check the last publication year of the Booklet.

3 The abbreviation, as written in the Booklet: URT: Upper respiratory tract; irr: irritation; CNS: Central Nervous   System; impair: impairment; LRT: Lower respiratory tract; eff: effects; pulm: pulmonary; func: function.

4 A few inorganic chemicals also with a TLV like cyanogen bromide have been added, denoted by "(4)".