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 

4 n o y t i n 

i 

o 0 ~) _ r. 

CONTAINS NO CB! 

3rYM 
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 Percutaneous Absorption and Cutaneous Disposition of [14C]-

Diacetone Alcohol In Vitro in Human Skin (123-42-2) 

A review of the 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 4 Test Rule (section 

799.5115(h)) . Skin discs 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 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 from 32 ± 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 why the 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 from the 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 NO CB!' ~51'3 ~ Gs 
integrity was evaluated by measuring the absorption of tritiated water before and after testing. It 

was reported that, in general, permeability of water through the skin was increased following 24 

hours of incubation with diacetone alcohol, but was still within the limits of acceptance (<0.3% 

penetration) . A steady state flux experiment determined that the permeability coefficient (Kp) 

was 0.000577 ± 0.000318 cm/hour. 

For determination of the short-term penetration rates, 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 why the 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 why the diacetone alcohol was 

diluted rather than applied neat. Therefore, the data that was 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 diacetone alcohol. A completed Study Report Review Form is 

attached . 
Review of 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 Report and Study Conduct 

Enter one of the following codes into each of the 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 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. 

REVIEW OF TSCA SECTION 4 FINAL STUDY REPORT 

March 2006 Version 
[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 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 transforrnations, 

statistical analyses, or modeling parameters used. 

Part 11. Conclusions 

Place a check mark beside the summaa statement(s) that apply to this review and add comments below as 

appropriate 

Part A. To be filIed 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 [ X ] 

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 temperature of the skin could not be maintained at 32°C for all skin disks. Most of 

the skin temperatures ranged from 32 ± I 'C. It was reported that these small differences 

did not appear to change the kinetics of absorption significantly. . 

The major problem with this study was 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 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 bv 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. 

[] 

[] 

REVIEW OF TSCA SECTION 4 FINAL STUDY REPORT 2 

March 2006 Version 
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 3 

March 2006 Version 
"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 how the 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 review of 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 review 101408 .doc 

E PA-H Q-0 PPT-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 4 Final Study Report diacetone alcohol. doc