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_10-24-2013F INAL (2).pdf

Deborah,

Yes, I did get a copy of the study (unofficially) b ut 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 Ma rcia’ s email,
I would say a copy was sent, but don’t know for sur e – If you would check at your end, I will check wi th 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 toxicit y screening) testing requirement for CASRN 98-09-9 promulgated in the final HPV3 tes t 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/k g-bw/day, based on histopathological effects in the kidneys, including minimal to mild foci of baso philic (regenerating) tubules, minimal to mild granular cast formation, mild to moderate intra-epi thelial hyaline droplets, and minimal single cell d eath. [1] The NOAEL for systemic toxicity in males was not established.

The LOAEL for systemic toxicity in females was 60 m g/kg-bw/day, based on increased mean cholesterol levels and effects on the stomach, incl uding increased incidence of thickening of the nonglandular region of the stomach and histopathologic al changes in the stomach, consisting of minimal to moderate spongiosis (epithelial vacuolation), minim al to moderate focal or diffuse epithelial hyperpla sia 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 fe males 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-b w/day, based on no effects at the highest dose

tested.

Best regards,

John

John Schaeffer Senior Biologist
USEPA/OPPT/CCD/CITB Page 1 of 2

1/13/2014 file://G:\HPV Test Rules Orphans\Records for FDMS\R E Question on FR notice listing stu

...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 wit h regards to several Section 4 Test Rules between Jun e 29, 2011 and July 31, 2013.

One of the studies we submitted for BSC is not show ing in Table 3 of the FR Notice----the Oral (gavage ) Combined Repeat Dose Toxicity Study with Reproducti on/Developmental Toxicity Screening in the Rat. I know this study for BSC (CAS# 98-09-9) was not sent unti l July 29, 2013 but that is within the time frame l isted. I also know that you received it since you sent an email t o my colleague, Marcia Croce, about the study and s he resent it since you had difficulty opening the first versi on.

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 th e hyaline droplet accumulation in male rats suggest s that the nephropathy in the males is occurring by an alpha 2u -globulin-mediated mechanism, which appears to be u nique to male rats

and the response is probably not relevant to humans for purposes of risk assessment. EPA’s Risk Asses sment Forum has outlined the key events and the data that are neces sary to demonstrate this mode of action (Alpha 2u -Globulin: Association

with Chemically Induced Renal Toxicity and Neoplasi a in the Rat, EPA/625/3-91/019F). One of the key e vents, alpha 2u globulin accumulation, has not been demonstrated. Therefore, the nephropathy is assumed to be relevan t to human health and it is concluded that a NOAEL for nephropathy in male rats was not established. Page 2 of 2

1/13/2014 file://G:\HPV Test Rules Orphans\Records for FDMS\R E Question on FR notice listing stu

...