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## DEC 11 2008 GEN

OFFICE QP PREVENTION, PES'~I'~iDES AND TOXIC SUBST)6~iCES 

### Ms. Simone A

. Miller, Corporate Director Environmental,Health, Safety &Regulatory Affairs Aceto Corporation One Hollow

Lane, Suite 201 Lake Success, NY 11042 

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RE: Repeat of Study entitled "Human Percutaneous Absorption and Cutaneous Disposition of [r4C]-Nitroaniline In Vitro" Dear Ms. Miller : On January 24, 2005, Aceto Corporation notified EPA of its intent to conduct a test ofpnitroaniline (CAS No. 100-01-6) required by a TSCA section 4 test rule in part 799.5115 (69 FR 22402, April 26, 2004) . The test protocol and datawere submitted to EPA by Aceto on 

### December 22, 2005. In an e-mail on August 28, 2007 and again on December 4, 2007, EPA,__ informed Aceto that the study did not meet certain requirements of the test standard and thatit must be repeated (Attachment 1) . Your response on January 16, 2008, included a letter from _ Celsis In Vitro Technologies, which performed the study and said it was prepared to repeat the study (alsoAttachment 1) . In a phone conversation on August 7, 2008, you informed a member ofmy staff, Catherine Roman, that the laboratory expects to be paid again to repeat the study - with only a 10%discount (Attachment 2) . During that same conversation, you also relayed that Aceto Corporation no longer imports or handles p-nitroaniline and does not want to spend $70,000 to have the study repeated, especially becauseAceto is not confident that another Tier 1 company (which was not named) and customer will share in the test costs, although the unnamed Tier 1 company committed to pay 50% of the costs whenthe test was initially performed. I want to advise you that, per 40 CFR790 .59(a), Acetowill be in violation ofthe test rule if it fails to conduct the test in accordance with the test standard. EPAhas identified how the study did not meet the requirements of the test standard and the laboratory states that it can perform the test and that it successfully performed the test with another chemical in the same test rule. To avoid being found in violation ofthe test rule and subject to penalties, Aceto should move toward having the test repeated. Although Aceto submitted the letter of intent to test, it might not bear the full burden of the cost oftesting or repeat testing if there are companies from whom Aceto can seek 

## CONTAINS NOC0 Internet Address (URL) " http:l/www .epa.gov Recycled/Recyclable -Printed with Vegetable Oil Based Inks on Recycled Paper (Minimum50%Postconsumer content) 

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### reimbursement under 40 CFR791 . Per 799 .5115(b)(1), the persons subject to the rule include those who manufacture, import, or process p-nitroaniline during the reimbursement period, i .e., any time after the effective date of the rule (May 26, 2004) until the end of the reimbursement period (December 22, 2010) . Under 799 .5115(c)(3), Tier 2 companies are granted an automatic conditional exemption fromtesting . TSCA section 4(b)(3) provides for reimbursement by exemptionholders of persons whoperformthe required testing, ifthat testing is the basis for the exemption. Therefore, in addition to the other Tier 1 company and customer/processor thatyou have already identified, other companies that begin or began manufacturing, importing, or processing p-nitroaniline during the reimbursement period are subject to therule andmay ultimately have reimbursement obligations. Under 791 .50(a)(3), eligible costs include "[t]he cost ofrepeating or repairing tests where failure was demonstrablydue to some cause otherthan negligence of the tester ." EPAis not expressing an opinion regardingthe applicability of 791 .50(a)(3) in this case, a determination ofthis issue could be made under the hearing procedures in part 791, subpart B . 2006 TSCA Inventory Update Rule reporting, which is based on 2005 data, only includes one company, other than Aceto, as an importer ofp-nitroaniline. That company is Flexsys America L.P., whichreported importing 3.6 million pounds in 2005. Flexsys has not requested an exemption fromtesting. 2006TSCA Inventory Update reporting did not include any manufacturers inthe U

.S., and processors are not required to report . Under 40 CFR791 .40(b) and 791 .48, a company's fair share ofthe test costs is in proportion to that company's share of the total production/importvolume of the test chemical during the period that begins one calendar year before the publication ofthe final test rule in the Federal Register [i .e. 2003] and continues up to the latest data available upon resolution ofa dispute. IfAceto has identified companies from

whom it seeks reimbursement and with whom Aceto has been unable to agree on reimbursement, Aceto may initiate reimbursement hearings byfollowing theprocedures in 40 CFR791 .20

. It is unfortunate that Aceto will be bearing the cost of testing a second time. In the future, I suggest stipulating in the laboratory contract that a test must meet the requirements of the test standard, or be repeated at no additional charge. I would appreciate aresponse indicating your intentions byJanuary 15, 2009. If additional testing is conducted, a new report should be prepared. Copies ofthe new report should be provided to Catherine Roman and the EPAdocket indicating that theyare a revision of the original submission. 0 

### illis, Director mical Control Division Attachments (2)

### cc Catherine Roman (7405M)

Renee Kearney/Docket No. EPA-HQ-OPPT-2003-0006 Ms. Jennifer Fleischer, Celsis In Vitro Technologies, 1450 South Rolling Road, Baltimore, MD 21277 Ms. Sharen Breyer, Flexsys America L.P., Americas Headquarters, Akron Marketing & Technical Center, 260Springside Drive, Akron, OH44333-2433"Simone A . Miller" <SMiller@aceto .com> 01/16/2008 10:51 AM Happy New

Year! To Catherine Roman/DC/USEPA/US@EPA cc "Fred Trudwig" <FTrudwigQa aceto.com> bcc Subject RE: In Vitro Dermal Absorption Rate study of p-nitroaniline

I just wanted to give you an update about Aceto's status with the below request . Aceto has been in contact with the testing lab which informed us that the study director that originally performed the test is no longer with the company. Thus, Aceto has been assigned a new study director who has provided a response (see below in red) . In response to our phone conversation of December 18, 2007, 1 amproviding the following response to ~the questions raised by the EPA in regard to the skin permeability testing of p-nitroaniline. Based on the results fromour initial studywith this compound, we have determined that follow-up studies are necessary in order to address adequately the EPA's concerns and to ensure regulatory compliance, particularly as specified in 40 CFR Part 799.5115. We therefore plan to conduct two studies . We will first conduct a pilot studyfor two purposes: 1 . to determine the solubility of p-nitroaniline in isopropyl myristate (IPM) and 2. to determine the time required to achieve steady state absorption of p-nitroaniline when dissolved in IPMand applied to cadaver skin. Conduct of this short pilot study will enable us to select the appropriate concentration of p-nitroaniline required to maintain receptorfluid p-nitroaniline levels at less than 10%of the initial level applied to the donor side of the skin. Results fromthe pilot studywill also allow for appropriate selection of 4 steady state timepoints fromwhich the permeability coefficient (Kp) can be correctly calculated in a statistically sound manner. Afull studywill then be conducted to follow40 CFR Part 799.5115, including GLP compliance. We will use the protocol generated for our study of isophorone as a guide in developing the protocol for the full study of p-nitroaniline. We are formulating a Statement ofWork for these two studies, which will be available to you shortly. Please don't hesitate to contact me if the EPA requires further details of our plan or has additional questions or concerns. Of course I amalways available to you for discussion of study plans and protocols as well . Sincerely, Jennifer Fleischer Study Director, ADMEITox Celsis In Vitro Technologies jfleischer@celsis .com Best regards, Simone A

. Miller Corporate Director, EHS & RegulatoryAffairs Aceto Corporation One HollowLane, Suite 201Lake Success, NY 11042

Tel : (516) 627-6000 ext. 515 Fax: (516) 627-6093 -----Original Message----- From : Roman.Catherine@epamail .epa.gov fmailto: Roman.Catherine(cr~epamail .epa.ctovl Sent : Tuesday, December 04, 2007 3:34 PM To: Simone A. Miller Subject : Fw

: In Vitro Dermal Absorption Rate studyof p-nitroaniline Sending again. Catherine Roman USEPA 1200 Pennsylvania Ave., NW, 7405M Washington, DC20460 (202) 564-8172 (202)564-4765(Fax) ----- Forwarded by Catherine Roman/DC/USEPA/US on 12/04/2007 03:33 PM Catherine Roman/DC/USEPA/U S To

smiller@aceto.com 08/28/2007 02:59 cc PM Greg Schweer/DC/USEPA/US@EPA,

Ward Penberthy/DC/USEPA/US@EPA

Subject In Vitro Dermal Absorption Rate study of p-nitroaniline

Simone Miller: On December 22, 2005, you submitted subject study (attached) on behalf ofAceto Corp. to comply with a TSCAsection 4 test rule (69 FR 22402, April 26, 2004) . A recent review of the study (attached) and an e-mail message (attached) by Dr. Val Schaeffer of the Occupational Safety and Health Administration identified some concerns which you should forward to the laboratory that conducted the study, In Vitro Technologies, Inc., for resolution/explanation. Following are Dr.Schaeffer's concerns:

The technical data sheets were not provided that verify that the source of radiolabeled test compound used in the studywas the purified para isomer of nitroaniline as specified in the final rule. In several instances, EPA's test standard (799.5115(h)) for measuring the permeabilityconstant (Kp) was not followed: 1 . Paragraph 799.5115 (h)(iii) of the test standard states the testing laboratory must verify that the concentration of test substance in the receptorfluid is less than 10 percent of the initial concentration in the donor chamber . This specification ensures that there is an undepletable , reservoir of test compound at the surface of the skin and that a strong concentration gradient is maintained across the epidermal membrane (i .e. infinite dosing conditions) during the course of the experiments. However, the study data show

that p-nitroaniline concentration in the receptor fluid for all six skin experiments exceeded the 10 percent value (range from25 to 68 percent of the initial concentration by the end of the 24 hour study period - table 6) . Since appropriate dosing conditions may not have occurred, it is conceivable that a maximumsteady state flux was not achieved in any of these experiments and the true Kp underestimated. 2. Paragraph 799.5115 (h)(viii) of the test standard states that the in vitro dermal absorption must be performed until at least four absorption measurements per diffusion cell experiment are obtained during the steady state absorption portion of the experiment. Two of the samples achieved a marginallysteadyflux for a roughlyfour-hour period (4 to 8 hours) covering only two absorption measurements per diffusion cell experiment . For the sake of consistency across all the experiments, the testing laboratory chose to calculate the permeabilitycoefficient (Kp) froma single eight-hour absorption measurement per diffusion cell experiment rather than froma larger and more statistically robust number of measurements. 3. Paragraph 799.5115 (h)(vi) of the test standard states that if the concentration of a hydrophobic test substance in water is not high enough so that a steadystate absorption can be obtained, the test substance must be dissolved inisopropyl myristate (IPM) . Based on the problems with consistently achieving infinite dosing conditions due to the limited p-nitroaniline solubility in water, In Vitro Laboratories should have carried out the permeability experiments using IPMas the vehicle. Dr. Schaeffer also added that it is useful to compare the rather questionable infinite dosing studydata used to determine the Kp for p-nitroaniline with the more rigorous and more acceptable (in my view) study data generated for isophorone by the same testing laboratory. In the case of isophorone, a 30-fold higher concentration (25 mg/ml) of radiolabeled test substance in IPM was applied to the skin that generated receptorfluid concentrations following the 24-hour exposure period thatwere less than 5 percent of the initial concentration in the donor chamber . In all experiments steady state fluxwas achieved and maintained for over 16 hours (8 to 24 hours) . This data allowed the Kp to be determined froman average of six absorption measurements for each of the six diffusion cell experiments. Failing to conduct a test in accordance with the test standard adopted in the test rule is considered a violation of the test rule under 40CFR 790.59(a) . To avoid possibly being found in violation of the test rule, you should address the concerns identified by Dr. Schaeffer . Please provide awritten response to me that addresses these concerns by September 30, 2007. Catherine Roman USEPA 1200 Pennsylvania Ave., NW, 7405M Washington, DC 20460 (202) 564-8172 (202) 564-4765 (Fax) (See attached file: p-Nitroaniline.pdf) (See attached file: nitroaniline test review

.doc) (See attached file: VaISchaefferE-mail .pdf)p. 9 DATE TIME GENERAL CONTACT REPORT ~~ ~-( ~ ~ ,o~ NAME OF EPA REP. CHECK IF CONTACT INITI~ ATOR NAME OF MFR70RG REP. CHECK IF CONTACT INITIATORC7 ~1t~-r .c~-u_- ~/L SUMMARY OF ISSUES DISCUSSED AND COMMENTS RECEIVED MANUFACTURER/ORGANIZATION TYPE OF CONTACT j MELEPHONE 13 MEETING C3 OTHER

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