From:                              Schaeffer, John

Sent:                               Wednesday, November 20, 2013 3:22 PM

To:                                   deborah.vercek@lanxess.com

Cc:                                   Lewis, Paul; Njo, Heather; Calvo, Kathy; Mattheisen, Mike

Subject:                          RE: Question on FR notice listing studies received for Section 4 Test Rules

Attachments:                 98-09-9_HPV3_DA_Repeat-Dose_Repro_Devel_10-24-2013FINAL (2).pdf

 

Deborah, 

Yes, I did get a copy of the study (unofficially) but just looked in the docket and it’s not there – do you know if an 

official copy was sent to the docket at the address provided in the FR notice? Just guessing from Marcia’s email, 

I would say a copy was sent, but don’t know for sure – If you would check at your end, I will check with the 

docket folks and get back in touch with you.

On a more positive note concerning this study, EPA’s review of the study has been completed and I just received 

comments yesterday that the study was adequate (I’ve also attached the full review):

Data submitted by Lanxess Corporation and reviewed in this document are adequate to satisfy the F1 

(combined repeated-dose toxicity with reproduction/development toxicity screening) testing requirement 

for CASRN 98-09-9 promulgated in the final HPV3 test rule. A brief summary of effects is provided 

below. Please refer the attached DA for details. 

 

Systemic Toxicity: 

The LOAEL for systemic toxicity in males was 5 mg/kg-bw/day, based on histopathological effects in 

the kidneys, including minimal to mild foci of basophilic (regenerating) tubules, minimal to mild 

granular cast formation, mild to moderate intra-epithelial hyaline droplets, and minimal single cell death.

[1] The NOAEL for systemic toxicity in males was not established.

 

The LOAEL for systemic toxicity in females was 60 mg/kg-bw/day, based on increased mean 

cholesterol levels and effects on the stomach, including increased incidence of thickening of the nonglandular region of the stomach and histopathological changes in the stomach, consisting of minimal to

moderate spongiosis (epithelial vacuolation), minimal to moderate focal or diffuse epithelial hyperplasia 

of the squamous epithelium, and minimal to moderate submucosal inflammation. The NOAEL for 

systemic toxicity in females was 20 mg/kg-bw/day. 

 

Reproductive Toxicity: 

The NOAEL for reproductive toxicity in males and females was 60 mg/kg-bw/day, based on no effects 

at the highest dose tested. 

 

Developmental Toxicity: 

The NOAEL for developmental toxicity was 60 mg/kg-bw/day, based on no effects at the highest dose 

tested. 

Best regards, 

John

John Schaeffer 

Senior Biologist 

USEPA/OPPT/CCD/CITB 

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file://G:\HPV Test Rules Orphans\Records for FDMS\RE Question on FR notice listing stu... 1/13/2014
1201 Constitution Ave, NW 

Washington, DC 20460 

Mail Code: 7405M 

Phone: 202-564-8173

From: deborah.vercek@lanxess.com [mailto:deborah.vercek@lanxess.com] 

Sent: Wednesday, November 20, 2013 2:29 PM 

To: Schaeffer, John 

Subject: Question on FR notice listing studies received for Section 4 Test Rules

 

Hi John, 

I am a bit confused by the November 6, 2013 Federal Register Notice that lists the studies EPA has received with 

regards to several Section 4 Test Rules between June 29, 2011 and July 31, 2013. 

One of the studies we submitted for BSC is not showing in Table 3 of the FR Notice----the Oral (gavage) 

Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening in the Rat. I know 

this study for BSC (CAS# 98-09-9) was not sent until July 29, 2013 but that is within the time frame listed. I also 

know that you received it since you sent an email to my colleague, Marcia Croce, about the study and she resent 

it since you had difficulty opening the first version. 

Is there a reason it is not listed in the FR notice? Is this anything we need to be concerned about? 

Looking forward to your response. 

Kind regards, 

Debbie Vercek 

Best regards, 

Deborah Vercek 

LANXESS Corporation 

111 RIDC Park West Drive 

Pittsburgh, PA 15275-1112 

412-809-3709

[1] The presence of nephropathy in association with the hyaline droplet accumulation in male rats suggests that the 

nephropathy in the males is occurring by an alpha2u-globulin-mediated mechanism, which appears to be unique to male rats 

and the response is probably not relevant to humans for purposes of risk assessment. EPA’s Risk Assessment Forum has 

outlined the key events and the data that are necessary to demonstrate this mode of action (Alpha2u-Globulin: Association 

with Chemically Induced Renal Toxicity and Neoplasia in the Rat, EPA/625/3-91/019F). One of the key events, alpha2uglobulin accumulation, has not been demonstrated. Therefore, the nephropathy is assumed to be relevant to human health 

and it is concluded that a NOAEL for nephropathy in male rats was not established.

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