Re: Fw: Declassified reviews of studies on Pigment Blue (1324-76-1) Notes Link

Ryan Wallace to

: Jeffrey Santacroce 

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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1200 Pennsylvania Ave. NW 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON D.C., 20460 

VIA FACSIMILE: 201-437-4801 

April 19,2012 

Attention: Glenn Merritt (201-437-4000) 

OFFICE OF 

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES 

Subject: Follow-up to fax transmission of 4/13/12 (ePMA removal ofCBI claims regarding 

identified studies) 

Dear Mr. Merritt: 

This is sent to you pursuant our conversation of several minutes ago. In Larry Robinson's fax of 

April 13th while there is a waiver of confidential business information (CBI) claims in the 

identified studies there is a an assertion of copyright protections and some additional text that 

provides in part ... "Reproduction, reference, summarization, retransmission or other use of this 

copyrighted document. .. including electronic transmission, using the internet or email .... 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 per the 

TSCA activity are not to be made available in an Agency e-docket (electronic docket) or be 

included in EPA websites among the collection of TSCA health 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 of non-CBI materials submitted by entities subject to TSCA 

regulations (including the posting of such materials on government websites) and submitted by 

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 of the studies. 

Can you please confirm CPMA's intent? Many thanks. 

Scott M. Sherlock, Attorney Advisor 

Environmental Assistance Division 

Office of Pollution Prevention and Toxics 


SRC TR-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

Task FGOO7.0.009.004 j ili 11 I I

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 ~ ~ IETA

oo -ION S30oa DOES NOT CONTAi""

8ECURITv 5Me~~ n '
HPV1 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

March 2010

Submitted to:

High Production Volume Chemicals Branch

Risk Assessment Division

Office of Pollution 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 of a 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 professional judgment 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. If the study

was determined to be inadequate, a basis for that conclusion is supplied. For studies already

assigned Klimisch codes, an explanation is provided if the reviewer's assessment of data

adequacy differed from the pre-assigned Klimisch code.

A detailed evaluation of the test report and study conduct is provided at the end of the

summary document in a section entitled "Review of TSCA 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 of appropriate controls and test substances.

Any deficiencies in the descriptions of the 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 of the 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 of C.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% of the sex mean

Number of animals/sex/dose: 1 0/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 of lactation)

Animals were dosed once daily for 7 days per week, approximately the same time each day (max

of 6 hours 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/day
Statistical methods used: If the 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 of the treated groups and the control groups for each sex. The Steeltest (Miller, 198 1) (many-to-one rank test) was applied if the 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 of organ 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 of pregnancy, and

delivery date), observations of offspring (sex determination, mortality/viability and clinical signs

daily, and body weights on lactation day 1 and 4), clinical pathology at the end of treatment,

hematology, clinical chemistry, macroscopy, organ weights (adrenal glands, brain, epididymides,

heart, kidneys, liver, spleen, testes, and thymus), and histopathology that included specific

examination of testes for staging of spermatogenesis. Reproductive organs assessed included

cervix, clitoral gland, coagulation gland, epididymides, ovaries, preputial gland, prostate gland,

seminal vesicles, testes, uterus, and vagina. The numbers of implantation sites and corpora lutea

were counted. Chemical analyses of formulations were conducted once during the study to assess

accuracy, homogeneity and stability.

RESULTS

Endpoint value(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 of feces, 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 or bluish discoloration of the mesenteric lymph nodes,

increased relative spleen weight in 1000 mg/kg-bw/day males, small amounts of blue material in

the lumen of the intestines (duodenum, ileum, jejunum, colon, or rectum), and blue material in

the superficial skin of the tail; these effects were not considered to be toxicologically relevant.

The submitter considered the following effects (in the absence of correlated microscopic

findings) to be common in caged rats of the 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 of the epididymides, reduced seminal vesicles size, dark red or reddish discoloration of
the mandibular lymph nodes, reddish discoloration of the pancreas, and red brown discoloration

of the adrenal glands.

Reproductive parameters, breeding parameters, and development of pups 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 of gestation, numbers of live and dead pups, numbers of

implantation sites and corpora lutea, and pup body weights on lactation day 1 and 4. Incidental

clinical symptoms, as indicated by the submitter, consisted of small pup size, red spot on the

nose or head, and pale appearance of pups. At macroscopic examination, autolysis and absence

of milk 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 of this 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 of C.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 of the 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 4 Final 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 in rats 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 of the following codes into each of the checkboxes 1 through 13: Aaree FAl. Disagree [DI. Not

Applicable fNA]. or Cannot Determine f Cl. and add comment, below, as needed

[D] 1. The final 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.

[D] 2. The final 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.

[D] 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).

[D] 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 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 of other discrete

observations pertinent to the type of study 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

Part A. To be filled out by Reviewer

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 dhtW a1rQg6fil 1or ~e~fi4eedon etd 1 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). I

Reviewer Comments (continue on separate page, if needed):

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

Reviewer Signature: j

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 IlAiV
SRC 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) - tA L-\O

Document count: 3