### April 22, 2009

Note to Pam

Mosley: RE: 3 Reviews of dermal absorption studies to add to Docket No. EPA-HQ-OPPT2003-0006 Attached are 3 reviews of dermal absorption rate studies conducted to comply with a TSCA section 4test rule. Please add each reviewas a separate document to the docket for that rule, EPA-HQ-OPPT-2003-0006 . Following is a description of each review : 1 . Review

ofIn Vitro Dermal Absorption Rate Testing for Dicyclopentadiene (77-73-6) . 2. Review

of In Vitro Dermal Absorption Rate Testing for Diphenylamine (122-39-4) . 3. Review

of In Vitro Dermal Absorption Rate Testing for Diacetone Alcohol (123-42- 2) . Catherine Roman Project Manager, CITB, CCD, OPPT 202-564-8172



## CONTAINS NOCC! 

# 3r~6~~OCCUPATIONAL SAFETY AND HEALTHADMINISTRATION 200 CONSTITUTIONAVENUE, NW WASHINGTON D

.C. 20210 October 14, 2008 

### TO : Catherine Roman

Chemical Information and Testing Branch (7405M) Office ofPollution, Prevention and Toxics US EPA FROM : Loretta Schuman Directorate of Standards and Guidance OSHA SUBJECT: Review ofDetermination of the In Vitro Absorption Rate of Diphenylamine (122- 39-4) Areviewofthe study report entitled "Determination of the In Vitro Absorption Rate of Diphenylamine" is provided below . The report was submitted by the Chemtura Corporation, in response to EPAconcerns with the original report submitted in response to the TSCA Section 4 Test Rule requiring in vitro dermal absorption rate determinations for several chemicals used in the workplace (69 FR 22402, 4/26/2004) . Study Summary In vitro dermal absorption testing of diphenylamine was undertaken at SafePharm Laboratories using atest standard specified in the TSCA Section 4Test Rule (section 799 .5115(h)) . Skin membranes that had been obtained by cutting human cadaver abdominal skin with adermatome to a thickness of 200to 500 [Lm were mounted in a static diffusion cell maintained at 32° Cusing 0 .9 % saline as receptor fluid. Radiolabeled [14C] diphenylamine at a concentration of 32 gg/mL in an aqueous solution was applied over the epidermal surface under infinite dose and occluded conditions. There was no explanation provided as to why the diphenylamine was diluted rather than applied neat. At infinite dose, a lag-time ofbetween 1 and 2 hours was observed before the absorption ofradioactivity approached steady state. Receptor fluid was sampled for radioactivity at regular intervals for up to 24 hours. Skin membrane integrity was evaluated by measuring electrical impedance before and after testing. The permeability coefficient (Kp) was calculated fromthe steady state flux of diphenylamine using six skin experiments representing three human subjects. The mean Kp was reported to be 7.7 x 10"3 cm/h (SD = 2

.3 x 10-3) . Prior to the determination ofpercutaneous absorption, the membrane



## CONTAINS NOCBl

### integrity of each skin membrane was evaluated by measuring the electrical resistence (ER) .

Membrane integrity was deemed acceptable if the ER across each membrane was ~2.8 kSZ . There was a slight loss in skin integrity in only one ofthe six preparations over the course of the testing . The ratios of post-ERvalues to pre-ER values for the six samples were 1 .49, 1 .10, 1 .72, 0 .79, 1 .12, and 1 .56

. Short-termdermal penetration experiments with [14C] diphenylamine in aqueous solution usingthe in vitro diffusion cell method were also conducted under finite dosing (i .e.25 ~L/cm2) and occluded conditions. These tests were intended to approximate brief skin contact rather than the more prolonged exposures often necessary to achieve steady state . Six skin experiments were carried out for durations of 10 and 60 minutes, respectively. The short-termpenetration rate was calculated to be 0

.005925±0

.00496 Rg/cm2 for 60-minute time period. There was no quantifiable absorption in the 10-minute experiment . It was noted that it was not possible to measure the electrical resistance (skin barrier fiznction) of the skin membranes following the 10 and 60 minute exposure times as it was important to collect the receptor fluid from beneath the skin membranes at study termination in order to obtain a mass-balance. This study does not completely comply with the test standard required by the TSCA Section 4 Test Rule. Therefore, the data presented in the study report maynot be reliable and may not be useful for estimating the amount of chemical absorbed across the skin fromdermal contact with diphenylamine. Acompleted Study Report ReviewFormis attached.

### Reviewof TSCA Section 4 Final Study Report

CITB Project Manager : Catherine Roman Chemical Name: Diphenylamine CAS Registry Number : 122-39-4 

### Report Title: Determination of the In Vitro Absorption Rate of Diphenylamine Test Sponsor : Chemtura Corporation Testing Lab: SafePharm Test Standard: 799

.5115(h) Date Study Received by EPA : Date Study Due to EPA : NA Special Instructions (e.g., regarding approved protocol modifications, etc.) : 

### Part 1 . Test Report and Study Conduct Enter one of the following codes into each ofthe checkboxes 1 through 13: Agree [A]Disagree ( D l Not Applicable jNAIor Cannot Determine [C] and add comment, below, as needed [ D] 1 . The study report indicates evidence ofgross, unauthorized or undocumented deviation from the EPAtest standard requirements, including "shall," "must," or "will" violations. List significant test standard deviations and "shall," "must," or "will" violations in comments below . [A] 2. The study report indicates evidence ofdeviations from the "should" statements in the study protocol that may have a bearing on the study conclusions. List these in comments below . [NA ] 3. Approved modifications oftest standard or testing protocol (CITB PM describe or attach) were not followed or are inadequately documented. [ D] 4 . There is evidence that laboratory Standard Operating Procedures (SOPs) were inadequately followed. [D] 5 . The Statement ofQuality Assurance (QA) inspections, their dates, and findings were missing or not signed. There is evidence that QAprocedures may be inadequate. [ D] 6 . There is evidence that Good Laboratory Practice Standards (GLPS) were inadequately followed. [ D] 7. The test, control, or reference substances are different from that specified in the section 4 test rule or Enforceable Consent Agreement (ECA) . [NA ] 8. Animal identification is inadequate or unclear ; use ofunhealthy animals or other factors (e.g., deviations fromtemperature, lighting, dosing) are apparent. [ D] 9

. The study report inadequately describes the study method. [D] 10 . The study report inadequately describes the test system . REVIEW

OF TSCA SECTION 4 FINAL STUDY REPORT March 2006 Version[ D] 11 . The study report inadequately describes the dosage information.

[ D] 12. The study report does not accurately reflect the individual animal data (or that ofother discrete observations pertinent to the type ofstudy conducted), or individual data were not provided. [ D] 13. The study report inadequately describes the calculations, interpolations, data transformations, statistical analyses, or modeling parameters used. 

### Part II . Conclusions Place a check mark beside the summary statement(s) that apply to this review and add comments below as appropriate Part A . T o be filled out by Reviewer Study Conduct 1 . The study waswell-conducted. 2 . The study was generally well-conducted, with some minor [ ] deficiencies (list in notes below) . 3. The study conduct was significantly deficient or questionable, (give [X] reasons in notes below) . Data Reliability 4 . The study results are precise and accurate. [ ] 5 . Appropriate methods were used to determine [X1 statistical significance. 6 . If repeated, the test results would be expected to be the [ X] same. Data Utility 7. Thedata are useful for risk assessment for the endpoint tested. 8. Thedata are useful for some other purpose (e.g., dose-setting) . 9 . Thedata are not useful for any purpose (describe in notes below) . [] [] [X ] Reviewer Comments (continue on separate page, if needed) : 

### The major problem

with this study was that there was no explanation of whythe diphenylamine was diluted in water rather than applied neat . If there is a good explanation, then the data are useful . Ifthere is no explanation, or no reason, and the substance should have been applied neat, then the data fromthis study are not useful . Reviewer Name/Title/Branch/Division/Office : Loretta Schuman, Directorate of Standards and Guidance, OSHA Reviewer Signature: Part B . To be filled out by CITB PM Tiered Testing Decision 1 . The tiered testing trigger was met, additional testing is indicated . (when applicable) . 2 . The trigger for additional (tiered) testingwas not met . StudyAcceptability 3 . The study is acceptable . 4 . The study may not be acceptable (provide rationale in memo to CITB chief) . REVIEW

OF TSCA SECTION4 FINAL STUDY REPORT March 2006 Version [] [] 

### [~I' [] 

### 2p. 6

To Mark.Thomson aQchemtura .com cc "Taylor, Alan - Middlebury, CT" <AIan.Taylor@chemtura .com>, "Campbell, Robert C ." <Robert .Campbell@chemtura .com>, "LoMenzo, Joe - bcc Subject Fw

: Diphenylamine (CAS # 122-39-4) in vitro percutaneous absorption Mr . Thomson, Thank you, you sent me exactly what I needed . acceptable. I will attach it to the reviewand indicate that the study is Catherine Roman USEPA 1200 Pennsylvania Ave ., NW, 7405M Washington, DC 20460 (202) 564-8172 (202) 564-4765 (Fax) ----- Forwarded by Catherine Roman/DC/USEPA/US on 11/14/2008 10:47 AM----

Catherine Roman/DC/USEPA/US 11/14/2008 10:54 AM

"Thomson, Mark - Middlebury, CT" <Mark .Thomson @chemtura .c om> 11/14/200808:21 AM



### Dear Catherine, To Catherine Roman/DC/USEPA/US@EPA cc "Taylor, Alan - Middlebury, CT" <AIan.Taylor@chemtura .com>, "Campbell, Robert C ." <Robert .Campbell@chemtura .com>, "LoMenzo, Joe - Middlebury, CT" <Joseph.LoMenzo@chemtura.com>, Mike Mattheisen/DC/USEPA/US@EPA Subject Diphenylamine (CAS # 122-39-4) in vitro percutaneous

absorption



### Per your request below, I have asked the study directors to review comments submitted by the agency regarding the aforementioned . Their response follows. 'The test material, Diphenylamine (CAS No. 122-39-4), has a melting point of 52.9 °C and therefore is a solid at roomtemperature. The EPA Final Test Rule states that if the test substance cannot be applied neat because it is a solid at roomtemperature or because it damages the skin when applied neat, it must be dissolved in water. As such, Diphenylamine was dissolved in water (at approximately 50%of its quoted maximumsolubility) and applied as an aqueous solution.' 

### Please let us know

if this explanation satisfactorily addresses the agency's concerns. 

## Mark Dr. Mark A. Thomson Manager, Toxicology & Risk Assessment Chemtura Corporation Middlebury, CT 06749 USA +1 .201 .954

.4445 (mobile) +1,203. 573

.3390 (office)From

: Roman .Catherine@epamail .epa .gov [ mailto~Roman Catherine~~epamail .e.pa.gov] Sent: Thursday, November 13, 2008 2:29 PM To: Taylor, Alan - Middlebury, CT Cc: Mattheisen.Mike@epamail .epa .gov Subject: Dermal absorption testing of Diphenylamine On March 22, 2006, you submitted a final report for the dermal absorption rate testing of diphenylaminc (CAS # 122-39-4) on behalfofChemtura Corporation in response to a TSCA sectio24 test rule. The rule was "!In Vitro Dermal Absorption Rate Testing of Certain Chemicals of Interest to the Occupational Safety and Health Administration" (60 FR22402, April 26, 2004) . Recently I received a reviewof that study and the reviewer had a concern that I hope you can address The reviewer asked "why was the test substance~ diphenylamine, diluted with water instead of applied neat to the skin samples in the experiment?" Although the test standard may allow for what was done per799.5115(h)(5)(vi), the report does not provide a reason. I have attached copies of the reviews and a pdfcopy ofthe rule which contains the test standard with the cited paragraph (799 .5115(h)(5)(vi)) on page 22439 . Please respond to me at roman.catherine@epa .gov. (See attached file: diphenylamine test review 101408.doc) (See attached file: Review

ofTSCA Section 4 Final Study Report diphenylamine.doc) (See attached file: EPA-HQ-OPPT-2003-0006-OOOl .pdf)

Catherine Roman USEPF. 1200 Pennsylvania Ave ., NW, 7405M Washington, DC 20460 (202) 564-8172 (202) 564-4765 (Fax)