Re: Fw: Declassified reviews of studies on Pigment Blue (1324-76-1) Notes Link Ryan Wallace to : Jeffrey Santacroce 05/31/2012 03:45 PM

Cc : Catherine Roman, Scott Sherlock

From: Ryan Wallace/DC/USEPA/US To: Jeffrey Santacroce/DC/USEPA/US@EPA Cc: Catherine Roman/DC/USEPA/US@EPA, Scott Sherlock/DC/USEPA/US@EPA
I reviewed the documents with DCNs 40100000011, 40100000012, and 40100000013. Each of these documents is a review of a study or studies provided by the Color Pigment Manufacturers Association, Inc. (CPMA). The confidential business information (CBI) claims in the studies which these reviews reference were declassified by CPMA in a 4/13/2012 letter from J. Lawrence Robinson, President of CPMA, to Scott Sherlock of EPA. Because the studies referenced in the documents with DCNs 40100000011, 40100000012, and 40100000013 are no longer considered as CBI, the reviews are also no longer considered to be CBI. Ryan P. Wallace, Attorney Advisor Environmental Assistance Division Office of Pollution Prevention and Toxics (202) 564
-8824 wallace.ryan@epa.gov

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## - ntUNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D

.C., 20460

VIA FACSIMILE: 201-437-4801 April 19,2012 Attention: Glenn Merritt (201-437-4000) OFFICE OF PREVE NTION, PESTICIDES AND TOXIC SUBSTANCES

Subject: Follow-up to fax transmission of4/13/12 (ePMAremoval ofCBI claimsregarding identified studies) 

### Dear Mr. Merritt: This is sent to you pursuant our conversation ofseveral minutes ago. In Larry Robinson's fax of April 13th while there is a waiver ofconfidential business information (CBI) claims in the identified studies there is a an assertion ofcopyright protections and some additional text that provides in part
... "Reproduction, reference, summarization, retransmission or other use ofthis copyrighted document.

..including electronic transmission, using the internet oremail

....is strictly prohibited

...." While we understand the basis for the copyright protections, we have a concern that the language in the fax might be interpreted to mean that ePMA is asserting that the studies submitted perthe TSCA activity are not to bemade available in an Agency e-docket (electronic docket) orbe included in EPA websites among the collection ofTSCAhealth and safety studies. We are thinking that the identified limitations noted in the fax are not intended to apply to EPA's normal procedures for the handling ofnon-CBI materials submitted by entities subject to TSCA regulations (including the posting ofsuch materials on government websites) and submittedby such entities in order to comply with a TSCA requirement, but are rather intended to limit entities outside the government from the unauthorized use or appropriation ofthe studies. Can you please confirm CPMA's intent? Many thanks.

Scott M. Sherlock, Attorney Advisor Environmental Assistance Division Office ofPollution Prevention and ToxicsSRCTR-10-075

HPVlI TEST RULE
- DATA ADEQUACY ASSESSMENT Benzenesulfonic acid,[[4-[[4-(phenylamino)phenyl] [4-(phenylimino)-2,5-cyclohexadien- 1 - ylidene]methyl]phenyl]amino]-, CAS No. 1324-76-1 Combined Repeated-Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test Prepared by: Kendra Moran, Teresa Manyin, and Joan D. Garey Environmental Science Center SRC, Inc. 7502 Round Pond Road North Syracuse, NY 13212
Contract No. EP-W-09-027



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Submitted to: OPPT/RAD/HPVCB (7403M) U.S. Environmental Protection Agency 1200 Pennsylvania Avenue Washington, D.C. 20460 Elizabeth Margosehes, Project Officer Meena Sonawane, Work Assignment Manager David Brooks, Alternate Work Assignment Manager 

## March 15, 2010 ~ ~ 

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- Data Adequacy Assessment

Benzenesulfonic acid, [[4-[[4-(phenylamino)phenyl] [4-(phenylimino)-2,5-cyclohexadien- 1 - ylidene]methyl]phenyl]amino] -, CAS No. 1324-76-1 Combined Repeated-Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test

March 2010

Submitted to: High Production Volume Chemicals Branch Risk Assessment Division Office ofPollution Prevention and Toxics Environmental Protection Agency WAM: Meena Sonawane Alternate WAM: David Brooks 1200 Pennsylvania Avenue, NW

Washington, DC 20460-0001

Prepared By:

SRC, Inc. Environmental Science Center 2451 Crystal Drive, Suite 804 Arlington, VA 22202

### PREPARATION OF THE DATA ADEQUACY ASSESSMENT This document contains the review ofa toxicity study conducted in response to the first HPV TSCA Section 4 Test Rule (71 FR 13708, March 16, 2006). Using the applicable test guideline and professionaljudgment as guides, the study was reviewed for adequacy and evaluated for compliance with the test guideline. (The applicable test guideline is not always the test guideline required by the test rule, because some test sponsors requested and received approval from EPA to use a different guideline.) The study was summarized according to a standard format, assessed for adequacy, and assigned a Klimisch reliability code. Ifthe study was determined to be inadequate, a basis for that conclusion is supplied. For studies already assigned Klimisch codes, an explanation is provided ifthe reviewer's assessment ofdata adequacy differed from the pre-assigned Klimisch code. A detailed evaluation ofthe test report and study conduct is provided atthe end ofthe summary document in a section entitled "Review ofTSCA Section 4 Final Study Report". Any deviations from the applicable test guideline are described. The study is also evaluated for compliance with Standard Operating Procedures, Good Laboratory Practice Standards, and Quality Assurance procedures, as well as the use ofappropriate controls and test substances. Any deficiencies in the descriptions ofthe study method, test system, animals studied, physical conditions, dosage information, individual animal data, calculations, and statistical analyses are described, and internal inconsistencies within the study report are identified. An overall assessment is provided for each ofthe following: study conduct, data reliability, and data utility.REPEATED-DOSE/REPRODUCTIVEIDEVELOPMENTAL TOXICITY Title: A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test ofC.L.Pigment Blue 61 in rats by oral gavage 

### The study is: Z Adequate 

## F- Not Adequate TEST SUBSTANCE Identity: C.1.Pigment Blue 61 (Benzenesulfonic acid,[[4-[[4-(phenylamino)phenyl] [4- (phenylimino)-2,5 -cyclohexadien- 1 -ylidene]methyl]phenyl] amino]-), CAS No. 1324-76-1 Remarks: 96.83% purity; dark blue powder with granules; pH = 4.3 at concentration > 1% METHOD Method/guideline followed: OECD TG 422 Test type: Combined repeated-dose toxicity study with reproductive/developmental toxicity screening test GLP compliant?: Yes Year study performed: 2008 Test species: Crl:WI(I-an) rats; supplier: Charles River Deutschland, Sulzfeld, Germany; untreated animals and virgin females; age: approximately 10 weeks old; mean weight: 302 g (males) or 193 g (females); individual weights within ± 20% ofthe sex mean Number of animals/sex/dose: 10/sex/dose Route of administration: Oral Gavage Vehicle: Propylene glycol Exposure duration: Males: 30 days (2 weeks prior to mating, during mating [up to 14 days], and up to termination) Females: 41-45 days (2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days oflactation) Animals were dosed once daily for 7 days per week, approximately the same time each day (max of6hours difference between earliest and latest dose). Animals were dosed up to the day prior to scheduled necropsy. Doses/concentrations tested: 0 (vehicle control), 50, 250 and 1000 mg/kg-bw/dayStatistical methods used: Ifthe variables could be assumed to follow a normal distribution, the Dunnett-test (Dunnett, 1955) (many-to-one t-test) based on a pooled variance estimate was applied for the comparison ofthe treated groups and the control groups for each sex. The Steeltest (Miller, 1981)(many-to-one rank test) was applied ifthe data could not be assumed to follow a normal distribution. The Fisher Exact-test (Fisher, 1950) was applied to frequency data. All tests were two-sided and in all cases p <0.05 was accepted as the lowest level of significance. No statistical analysis was performed on histopathology findings. Test method/conditions remarks: The first 5 mated males and first 5 females with live offspring were examined for functional observations, clinical laboratory investigations, macroscopic examination and determination oforgan weights. Evaluated parameters included clinical signs daily, functional observations at the end of treatment, body weights and food consumption weekly and during post-coitumn and lactation at appropriate intervals, reproduction processes (mating date, confirmation ofpregnancy, and delivery date), observations ofoffspring (sex determination, mortality/viability and clinical signs daily, and body weights on lactation day 1and 4), clinical pathology at the end oftreatment, hematology, clinical chemistry, macroscopy, organ weights (adrenal glands, brain, epididymides, heart, kidneys, liver, spleen, testes, and thymus), and histopathology that included specific examination oftestes for staging ofspermatogenesis. Reproductive organs assessed included cervix, clitoral gland, coagulation gland, epididymides, ovaries, preputial gland, prostate gland, seminal vesicles, testes, uterus, and vagina. The numbers ofimplantation sites and corpora lutea were counted. Chemical analyses offormulations were conducted once during the study to assess accuracy, homogeneity and stability. RESULTS Endpointvalue(s): Systemic NOAEL (male and female) = 1000 mg/kg-bw/day Reproductive NOAEL = 1000 mg/kg-bw/day Developmental NOAEL = 1000 mg/kg-bw/day Results remarks: No treatment-related toxicologically significant changes were noted in any of the parameters investigated in this study (i.e., mortality, clinical appearance, functional observations, body weight, food consumption, hematology, clinical chemistry, macroscopic examination, organ weights, microscopic examination, reproductive and breeding parameters, and pup development). Effects observed included blue discoloration offeces, slight salivation, and lower prothrombin time in 1000 mg/kg-bw/day exposed females, higher cholesterol in 1000 mg/kg-bw/day exposed males, greenish orbluish discoloration ofthe mesenteric lymph nodes, increased relative spleen weight in 1000 mg/kg-bw/day males, small amounts ofblue material in the lumen ofthe intestines (duodenum, ileum,jejunum, colon, or rectum), and blue material in the superficial skin ofthe tail; these effects were not considered to be toxicologically relevant. The submitter considered the following effects (in the absence ofcorrelated microscopic findings) to be common in caged rats ofthe age and strain used in this study: alopecia and scabbing on several body parts, rales, piloerection, a broken tail apex, hard yellowish nodule on the tail ofthe epididymides, reduced seminal vesicles size, dark red or reddish discoloration ofthe mandibular lymph nodes, reddish discoloration ofthe pancreas, and red brown discoloration ofthe adrenal glands. Reproductive parameters, breeding parameters, and development ofpups were unaffected by treatment up to 1000 mg/kg/day. Percentage mating, fertility index, conception rate, and gestation index were 90 or 100% for all treatment and control groups. No treatment-related findings were observed for duration ofgestation, numbers oflive and dead pups, numbers of implantation sites and corpora lutea, and pup body weights on lactation day 1and 4. Incidental clinical symptoms, as indicated by the submitter, consisted ofsmall pup size, red spot onthe nose or head, and pale appearance ofpups. At macroscopic examination, autolysis and absence ofmilk in the stomach was noted for a few dead pups. No relationship with treatment was established for these observations and they were considered to be within the normal biological variation for rats ofthis age and strain. CONCLUSIONS From the results presented in this report, the parental, reproductive, breeding, and developmental No Observed Adverse Effect Level (NOAEL) for C.I. PIGMENT BLUE 61 was 1000 mg/kgbw/day. STUDY RELIABILITY [I] Reliable without restrictions. REFERENCES Beekhuijzen M.E.W. 2008. A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test ofC.I. Pigment Blue 61 in rats by oral gavage. NOTOX B.V. Testing Facility, NOTOX Project # 488232, Study completed 08 December 2008. Dunnett, 

### C.W. 1955. A multiple comparison procedure for comparing several treatments with a control. Journal ofthe American Statistical Association, 50, 1096-1121. Fisher, R.A. 1950. Statistical methods for research workers, Oliver and Boyd, Edinburgh. Miller R.G. 1981. Simultaneous statistical inference, Springer Verlag, New York.Review of TSCA Section 4Final Study Report CITB Project Manager: Catherine Roman Chemical Name: Benzenesulfonic acid,Ij[4-[4-(phenylamino)phenylJ [4-(phenylimino)-2,5-cyclohexadien-I
- ylidenelmethyllphenyl] amino]- CAS Registry Number: 1324-76-1 Report Title: A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of C.I. Pigment Blue 61 inrats by oral gavage Test Sponsor: Color Pigments Manufacturers Association, Inc. Testing Lab: NOTOX B.V. Test Standard: 40 CFR 799.9365. Date Study Received by EPA: 12/18/08 (Preliminary study report received 11/18/08) Date Study Due to EPA: 5/17/07 Special Instructions (e.g., regarding approved protocol modifications, etc.):
Part 1. Test Report and Study Conduct Enter one ofthe following codes into each ofthe checkboxes 1through 13: Aaree FAl. Disagree [DI. Not Applicable fNA]. or Cannot Determine fCl. and add comment, below, as needed
[D] 1.The final study report indicates evidence ofgross, 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. [D] 2. The final 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. [D] 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 ornot 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 4test rule or Enforceable Consent Agreement (ECA). [D] 8. Animal identification is inadequate or unclear; use ofunhealthy animals or other factors (e.g., deviations from temperature, lighting, dosing) are apparent. [D] 9.The final study report inadequately describes the study method.[D] 10. The final study report inadequately describes the test system. [D] 11. The final study report inadequately describes the dosage information. [D] 12. The final 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 final study report inadequately describes the calculations, interpolations, data transformations, statistical analyses, or modeling parameters used. Part 11. Conclusions Place a check mark beside the summairy statement(s) that apply to this review and add comments below as appropriate PartA. To be filled out byReviewer Study Conduct 1.The study was well-conducted. [xI 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[

reasons in notes below). Data Reliability 4. The study results are precise and accurate. [xl 5.Appropriate methods were used to determine [x]

51sti~fical significance. 6. If4 ted, the test results would be expected to be the [x] Data Utility 7. The dhtWa1rQg6fil 1or 1 ~e~fi4eedon etd X] 8. The data are U fi~ik .pm in p~ s(e.g., dose-setting). I 9. The data are not use 1 or'hh- describe in notes below). 

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Reviewer Comments (continue on separate page, ifneeded):

Reviewer Name/Title/Branchfflivision/Office: Kendra Moran and Teresa Manyin, SRC Reviewer Signature: 

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Part B. To be filled out by CITH 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. 

### [ IA'TVGVOO Study Acceptability 3. The study is acceptable. ', ITAMROCI41[ 4. The study may not be acceptableTAi4 AiATI OC 

### [ (provide rationale in memo to IlAiVSRC Document Receipt Documents Logged Out to US EPA's CBIC on March 15, 2010 by J.Garey

CASE No. Document Description JGO3151Oa HPV1 Data Adequacy Review Document Referencing EPA DCN No. 40090000007 and 40090000009 (algae) ~ 3 JGO31S10b HPV1 Data Adequacy Review Document Referencing EPA DCN No. 40090000007 and 40090000009 (Daphnia) 3X5PV 3'\ JGO3151Oc HPV1 Data Adequacy Review Document Referencing EPA DCN No. 40090000007 and 40090000009 (combined repeated-dose)

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Document count: 3