1. Toxicity Evaluation of Chemicals with Limited Toxicity Data Roberta L. Grant, Ph.D. Toxicology Division - Chief Engineer’s Office Texas Commission on Environmental Quality

2. Outline Toxicity assessments  Chemicals with adequate toxicity data  Chemicals with limited toxicity data

3. Toxicity Assessment The basic objective of a toxicity assessment is to identify what adverse health effects a chemical causes and how the appearance of these adverse effects depends on exposure level (dose)

4. TCEQ Exposure Durations and Averaging Times Acute – 1 hour intermittent exposure (short-term) Chronic – lifetime exposure (long-term)

5. Tiered Approach for Chemicals with Limited Toxicity Information

6. Cumulative Normal Distribution

7. Threshold of Concern Approach

8. Obtain LC 50 data and acute inhalation NOAELs from animal studies for 97 chemicals Exposure duration: 1-hour intermittent exposure, but frequently included > 1 hr studies, and in some cases multiple day studies Categorize chemicals into different acute inhalation toxicity potency classes using LC 50 data and the Globally Harmonized System (GHS) of Classification and Labeling of Chemicals (United Nations 2005)

9. Threshold of Concern (TOC) Table 3-3. Threshold of Concern Approach for Determining Tier II Generic Short-Term ESLs Globally Harmonized System of Classification and Labeling of Chemicals (GHS) Category 1Category 2Category 3Category 4Category 5 Skin IrritationCorrosiveIrritantMild Irritant Eye IrritationCauses serious eye damage Causes serious eye irritation Causes mild to moderate eye irritation d Oral LD 50 mg/kg 0 to < 5 a > 5 to < 50 a > 50 to < 300 a > 300 to < 2000 a > 2,000 a LC 50 gas ppm v 0 to < 100> 100 to < 500> 500 to < 2500> 2500 to < 5000> 5,000 LC 50 dust & mists b mg/m 3 0 to < 50> 50 to < 500> 500 to < 1000> 1000 to < 5000> 5,000 LC 50 vapors c mg/m 3 0 to < 500> 500 to < 2000 > 2000 to < 10,000> 10,000 to < 20,000> 20,000 Generic Short-Term ESL 4 µg/m 3 20 µg/m 3 125 µg/m 3 1000 µg/m 3

10. Cat 3&4 =12.6 mg/m 3 Cat 5 = 104 mg/m 3 Cat 2 = 2 mg/m 3 Cat 1 = 0.4 mg/m 3 Calculate the 10th percentile of the cumulative percentage distribution of NOAELs in each category

11. Threshold of Concern (TOC) Divide the 10 th percentile NOAEL values by 100 to account for human variability and uncertainty of animal to human extrapolation Cat 1: 0.4 mg/m 3 / 100 = 4 ug/m 3 Cat 2: 2 mg/m 3 / 100 = 20 ug/m 3 Cat 3&4: 12.6 mg/m 3 / 100 = 125 ug/m 3 Cat 5: 104 mg/m 3 / 100 = 1000 ug/m 3 Use the LC 50 data of a chemical to categorize it into a GHS category. Use the TOC for that category as a generic ESL

12. Tier II Generic ESLs NOAEL to LC 50 Ratio Approach

13. NOAEL-to-LC 50 Ratio 10 th percentile ratio = 0.0083 Calculate the ratio between acute inhalation NOAELs and LC50 Calculate the 10th percentile ratio

14. NOAEL-to-LC 50 Ratio Divide the ratio of 0.0083 by 100 to account for human variability and uncertainty of animal to human extrapolation Health-Protective Ratio = 0.000083 LC 50 data x 0.000083 = generic ESL

15. TOC or NOAEL-to- LC 50 Ratio Approach? Both approaches use LC 50 data, although the TOC approach is generally more conservative than the NOAEL-to- LC 50 Ratio approach Use information on the chemical (i.e., toxicity of chemical class or chemical structure) and a weight-of-evidence approach to decide which approach is most defensible Choose the most conservative number if there is uncertainty in the quality of the LC 50 data

16. Summary For chemicals with limited toxicity data, statistical or relative toxicity/potency approaches can be used to derive health- protective default or generic ESLs  Tier 1 – Threshold of Regulation  Tier II – Threshold of Concern toxicity potency classes or NOAEL-to-LC 50 Ratio  Tier III – Relative Toxicity/Potency Approach

17. Questions Roberta L. Grant rgrant@tceq.state.tx.us (512) 239-4115 Toxicology Division Website: http://www.tceq.state.tx.us/implementation/tox/esl/guidelines/ about.html @tceq.state.tx.us ? ? ? ? ?