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 4 test rule. Please add each review as a separate document to the docket 

for that rule, EPA-HQ-OPPT-2003-0006. Following is a description of each review: 

1 . Review of In 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 NO CC! 

3r~6~~ 
OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION 

200 CONSTITUTION AVENUE, NW 

WASHINGTON D.C. 20210 

October 14, 2008 

TO: Catherine Roman 

Chemical Information and Testing Branch (7405M) 

Office of Pollution, Prevention and Toxics 

US EPA 

FROM: Loretta Schuman 

Directorate of Standards and Guidance 

OSHA 

SUBJECT: Review of Determination of the In Vitro Absorption Rate of Diphenylamine (122-

39-4) 

A review of the 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 EPA concerns 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 a test standard specified in the TSCA Section 4 Test Rule (section 

799.5115(h)). Skin membranes that had been obtained by cutting human cadaver abdominal skin 

with a dermatome to a thickness of 200 to 500 [Lm were mounted in a static diffusion cell 

maintained at 32° C using 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 of between 1 and 

2 hours was observed before the absorption of radioactivity 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 from the 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 of percutaneous absorption, the membrane 

CONTAINS NO CBl 
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 of the six preparations over the course of the 

testing. The ratios of post-ER values to pre-ER values for the six samples were 1 .49, 1 .10, 1 .72, 

0.79, 1 .12, and 1 .56. 

Short-term dermal penetration experiments with [14C] diphenylamine in aqueous solution 

using the 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-term penetration 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 may not be reliable and 

may not be useful for estimating the amount of chemical absorbed across the skin from dermal 

contact with diphenylamine. A completed Study Report Review Form is attached . 
Review of 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 of the checkboxes 1 through 13 : Agree [A]Disagree (Dl Not 

Applicable jNAIor Cannot Determine [C] and add comment, below, as needed 

[ D ] 1 . The study report indicates evidence of gross, unauthorized or undocumented deviation from 

the EPA test 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 of deviations 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 of test 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 of Quality Assurance (QA) inspections, their dates, and findings were missing or 

not signed. There is evidence that QA procedures 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 of unhealthy animals or other factors (e.g ., 

deviations from temperature, 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 of other discrete 

observations pertinent to the type of study 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. To be filled out by Reviewer 

Study Conduct 1 . The study was well-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. The data are useful for risk assessment for the endpoint tested . 

8 . The data are useful for some other purpose (e.g ., dose-setting). 

9. The data 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 why the 

diphenylamine was diluted in water rather than applied neat. If there is a good 

explanation, then the data are useful . If there is no explanation, or no reason, and the 

substance should have been applied neat, then the data from this 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) testing was not met. 

Study Acceptability 3. The study is acceptable . 

4. The study may not be acceptable 

(provide rationale in memo to CITB chief) . 

REVIEW OF TSCA SECTION 4 FINAL STUDY REPORT 

March 2006 Version 

[] 

[] 

[~I' 

[] 

2 
p. 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 review and 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> 

11/14/2008 08:21 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 room temperature. The EPA Final Test Rule states that if the test substance cannot be applied 

neat because it is a solid at room temperature 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 maximum solubility) 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 behalf of Chemtura 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 FR 22402, April 26, 2004). 

Recently I received a review of 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 pdf copy 

of the 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 of TSCA 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)