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Date: February 10, 2012

From: Agency for Toxic Substances and Disease Registry / Centers for Disease

Control and Prevention

Subject: Comments on EPA’s Toxicological Review of Trimethyl benzenes

To: Environmental Protection Agency

We appreciate the opportunity to review EPA’s Toxic ological Review of trimethylbenzenes. ATSDR does not have a Toxicolog ical Profile developed for trimethylbenzenes, and CDC does not have a particul ar subject matter expert in this area. We do offer the following comments from our Divisio n of Toxicology and Environmental Medicine:

1) Pg. 19. Chemical and Physical Information. The document points out that the trimethylbenzenes are usually a mixture of three su bstances but only describes 2 of them (1,2,4 and 1,3,5). The justification (see pag e 21, Programmatic Interest ) does not describe why 1,2,3 has been left out of the ass essment or why the mixture as a

whole is not addressed. The mixture would be of mo re interest to ATSDR scientists working at superfund sites since single compounds s eem to be rarely found.

Also missing from the discussion, but of interest t o ATSDR, is why the RfD and RfC for 1,2,3 could not be adapted from study data on 1 ,2,4 as were the RfD and RfC for 1,3,5. The section on Chemical and Physical Inform ation states that all three isomers have similar chemical and physical properties.

2) Pg. 22 Executive summary . Consider writing out the full acronym for PODAD the

first time it is used in the document.

3) Pg. 23 Inhalation Reference Concentration . We suggest EPA explicitly state which PBPK model was used for this analysis. For example , was it the Hissink model?

4) One concern we have is related to the selection of “confidence levels” for the Korsak and Rydzynski paper when used to derive RfD and RfC s for trimethylbenzenes. A DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry



## Memorandumconfidence level of “medium” has been assigned to t he Korsak and Rydzynski

manuscript when the study findings were used to der ive an RfC for 1,2,4. Korsak and Rydzynski is an inhalation study on 1,2,4 that is u sed to derive an inhalation RfC for 1,2,4; therefore, we find the confidence level of “ medium” to be appropriate in this case. However, Korsak and Rydzynski is also used t o derive an oral RfD and an RfC of a different compound: 1,3,5. Our assumption wou ld be that the “confidence level” assigned to this study of 1,2,4 when used to derive the RfD and RfC for 1,3,5 would be lower than the “medium” confidence level assigne d previously when deriving an RfC for the exact compound (1,2,4) from the inhalat ion study. We have some concern that the review assigns the same “confidenc e level” to this study for all

derivations.

5) Pg 25 . Effect other than cancer observed following oral exposure . We find the wording of the first two sentences in this section to be somewhat confusing.

Wouldn’t a series of oral doses be considered a sho rt-term study?

6) Pg 25. Oral RfD for 1,2,4 TMB. Please clarify the duration (number of days) used i n the model for the oral RfD for 1,2,4.

7) Pg 26. Oral RfD for 1,2,4 TMB. The first pass effects are critical in the derivati on of the RfD. The 4-fold higher blood concentrations fo r inhalation seem reasonable but we would like to see their specific derivation. Ca n you please site reference(s) and provide justification for using these concentration s?