### 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 . Reviewof 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

4 n o y t i n i

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# CONTAINS NOCB! 

# 3rYMOCCUPATIONAL SAFETY AND HEALTHADMINISTRATION 200 CONSTITUTIONAVENUE, 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 Percutaneous Absorption and Cutaneous Disposition of [14C]- Diacetone Alcohol In Vitro in Human Skin (123-42-2) Areviewofthe study report entitled "Percutaneous Absorption and Cutaneous Disposition of [14C]-Diacetone Alcohol In Vitro in Human Skin" is provided below . The report was submitted by the American Chemistry Council, 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 Suinmary In vitro dermal absorption testing of diacetone alcohol was undertaken at hi Vitro Technologies, Inc. using a test standard specified in the TSCA Section 4Test Rule (section 799 .5115(h)) . Skin discs that had been obtained by cutting human cadaver abdominal skin with a dermatome to a thickness of200to 500 ~Lm were mounted in a static diffusion cell using 0 .9 % saline as receptor fluid. The temperature of the skin could not be maintained at 32°C for all skin disks. Most of the skin temperatures ranged from32 ± 1°C. It was reported that these small differences did not appear to change the kinetics of absorption significantly. Radiolabeled [14C] diacetone alcohol at a concentration of 80.3 mg/mL in aqueous solution was applied over the epidermal surface under infinite dose and occluded conditions. There was no explanation provided as to whythe diacetone alcohol was diluted rather than applied neat . It was reported that the amount of diacetone alcohol dosed onto the skin discs appeared to simulate an infinite dose under the experimental conditions used. This was inferred fromthe observation that the total amount absorbed was less than 6%even after exposure for 24 hours and that the amount of diacetone alcohol absorbed into the receptor fluid reached a steady state . Skin membrane 

## AINS NOCB!' 

# ~51'3 ~ Gs

### integrity was evaluated by measuringthe absorption oftritiated water before and after testing. It

was reported that, in general, permeability ofwater through the skin was increased following 24 hours ofincubation with diacetone alcohol, but was still within the limits ofacceptance (<0 .3% penetration) . Asteady state flux experiment determined that the permeability coefficient (Kp) was 0 .000577 ± 0

.000318 cm/hour. For determination of the short-termpenetrationrates, radiolabeled [14C] diacetone alcohol at a concentration of 80.3 mg/mL in aqueous solution was applied over the epidermal surface under occluded conditions. As with the steady state flux experiment, there was no explanation provided as to whythe diacetone alcohol was diluted rather than applied neat . The short-term penetration rates were estimated to be 56.6 ± 15.4 and 37.3 f 18.0 ~tg/cm2/h for the 10- and 60- minute time periods, respectively under this experimental protocol . This study does not completely comply with the test standard required by the TSCA Section 4 Test Rule. There was no explanation provided as to whythe diacetone alcohol was diluted rather than applied neat. Therefore, the data that was presented in the study report may not be reliable and maynot be useful for estimating the amount of chemical absorbed across the skin from

dermal contact with diacetone alcohol . A completed Study Report Review Formis attached.

### Reviewof TSCA Section 4 Final Study Report

CITB Project Manager : Catherine Roman Chemical Name: Diacetone alcohol CAS Registry Number : 123-42-2 

### Report Title: Percutaneous Absorption and Cutaneous Disposition of [14C]-Diacetone Alcohol In Vitro in Human Skin Test Sponsor: American Chemistry Council Testing Lab: In Vitro Technologies, Inc 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 I . Test R

eport and Study Conduct Enter one ofthe following codes into each ofthe checkboxes 1 through 13: Aeree lAl Disagree fDl . Not Applicable rNA] or Cannot Determine Cl, 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 of deviations fromthe "should" statements in the study protocol that may have a bearing on thestudyconclusions. 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, andfindings were missing or not signed. There is evidence that QA procedures may be inadequate. [ D] 6 . There is evidence that Good LaboratoryPractice Standards (GLPS) were inadequately followed. [ D ] 7. The test, control, or reference substances are different from that specified in the section 4test 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. REVIEW

OF TSCA SECTION4FINAL STUDY REPORT March 2006Version[D] 10 . The study report inadequately describes the test system . [ 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 ofstudyconducted), or individual data were not provided. [ D] 13. The study report inadequately describes the calculations, interpolations, data transforrnations, statistical analyses, or modeling parameters used. 

### Part 11 . Conclusions Place a check mark beside the summaa statement(s) that apply to this reviewand add comments below as appropriate Part A . To be filIed out by Reviewer Study Conduct 1 . The studywas well-conducted. [ ] 2 . The studywas generally well-conducted, with some minor [ ] deficiencies (list in notes below) . 3. The study conductwas 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 [ X] statistical significance. 6 . Ifrepeated, 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, ifneeded) : 

### The temperature of the skin could not be maintained at 32°C for all skin disks. Most of the skin temperatures ranged from32 ± I 'C . It was reported that these small differences did not appear to change the kinetics of absorption significantly. . The major problem

with this studywas that there was no explanation of why the diacetone alcohol was diluted in deionized 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 shoul ave een 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 bv CITB_PM Tiered Testing Decision 1 . Thetiered testing trigger was met, additional testing is indicated. (whenapplicable) 2 . Thetrigger for additional (tiered) testing was not met . [] []

REVIEW

OF TSCA SECTION4FINAL STUDY REPORT 2 March 2006 VersionStudy Acceptability 3. The study is acceptable . 4 . Thestudy may not be acceptable (provide rationale in memo to CITB chief) .

REVIEW

OF TSCA SECTION4 FINAL STUDY REPORT 3 March 2006Version"Gulledge, William" To Catherine Roman/DC/USEPA/US@EPA <William Gulledge@america cc nchemistry .com

> 12/17/2008 10:17 PM

Catherine: bcc Subject RE: Dermal absorption test of Diacetone Alcohol (123-42-2)

The information on the DAA study was retrieved, and it certainly refreshed my memory of howthe study was conducted . In order to achieve steady state absorption, DAA was diluted with water . The neat solution DAA, when applied to the skin, did not sufficiently penetrate the skin membrane, and a steady state absorption rate could not be obtained . I trust this information is helpful . Have a wonderful Holiday season . Bill -----Original Message----- 

### Dermal absorption test of Diacetone Alcohol Catherine Roman to: william_gulledge 11/13/2008 02:27 PM Cc: Mike Mattheisen On August 25, 2006, you submitted a final report for the dermal absorption rate testing of diacetone alcohol (CAS # 123-42-2) on behalf of the Ketones Panel in response to a TSCA section 4 test rule. The rule was "/n 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 reviewof that study and the reviewer had a concern that I hope you can address . The reviewer asked "why was the test substance, diacetone alcohol, diluted with water instead of applied neat to the skin samples in the experiment?" Although the test standard may allow for what was done per 799.5115(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.catherineQa epa.gov. 

# nlii~ diacetone alcohol test review101408.doc

EPA-HQ-0PPT-2003-0006-0001 . pdf Catherine Roman USEPA 1200 Pennsylvania Ave., NW, 7405M Washington, DC 20460 (202) 564-8172 (202) 564-4765 (Fax) Review of TSC4 Section 4Final Study Report diacetone alcohol . doc