Document k9axma6w7MZQVMKBE55RLkVeJ

LC1A / ' "i / ao Chemical Manufacturers Association VIA FEDERAL EXPRESS April 24,1998 Yee-Wan Stevens, M.S. Agency for Toxic Substances and Disease Registry Mail Stop E-29 1600 Clifton Road Atlanta, GA 30333 Re: Response to Reviewer Comments on the Vinvl Chloride Development Toxicity Study Dear Ms. Stevens: This letter is in response to the Agency for Toxic Substances and Disease Registry (ATSDR) peer reviewer comments on the final report of the developmental toxicity portion of the study "Vinyl Chloride Combined Inhalation Two-Generation Reproduction and Developmental Toxicity Study in CD Rats." The enclosed responses were prepared by David Penney, Senior Toxicologist, CONDEA Vista Company and study monitor for the Vinyl Chloride Health Committee (VCHC). as well as Ray Schroeder and Dean Rodwell, respectively the study monitor and Vice President or Toxicology for Huntingdon Life Sciences. Organ-to-body~weight ratios as evidence of maternal toxicity (Dr. R. Hood) - We agree that the apparent increase in organ-to*body-weight ratios for the kidney and liver that the reviewer refers to are slight in magnitude, and taken alone may not indicate toxicity. However, at least one other study, cited in the current ATSDR toxicological profile for vinyl chloride1, has also reported elevated liver-to-body-weight ratios following short-term exposure to VC at concentrations similar to those used in the present study. In this case, increased liver-to-body-weight ratios were observed in rats exposed to 1500 ppm vinyl chloride for 7-9 days during either the first or second trimester of pregnancy2. The ATSDR profile also cites a study that provides histological evidence of hepatic toxicity manifest as an increased incidence of hepatocellular ' Agency for Toxic Substances and Disease Registry, Toxicological Profile for Vinyl Chloride (Update). September 1997. Ungvary G et al. Effects of vinyl chloride exposure alone and in combination with trypan blue-applied Jgmically during all thirds of pregnancy on the fetuses of CFY rats. Toxicology 11:45-53, Innovation, Technology and Rfsponsihle Ca*ev Aj Work U00 Wilkon Bivc , Arljncton, VA 22209 Tu^h,-;^ 703-741-5000 Fm- 702-741 -fiOOD rf* BFG 01243 Responsible C. j % APublic CwmWn APR 24 '98 15:23 CMA PPGE. P.  * / 30 r^ Stevens, ATSDR April 24> 1998 Page 2 hypertrophy observed 18 months after a single 1-hour exposure of mice to 500, 5,000, or 50,000 ppm vinyl chloride3. In addition, preliminary microscopic results of the twogeneration reproduction study with vinyl chloride conducted at Huntingdon Life Sciences found hepatocellular hypertrophy in livers of all rats in the high dose group (1100 ppm) of both parental generations. In light of the findings reported in the studies cited above, we believe it is very likely that the slight increased organ-to-body-weight ratios observed in this study were due to toxicity. However, as the reviewer noted, even if the apparent statistically significant increased organ-to-body-weight ratios are not interpreted to be indicative or toxicity, a limit dose of 1000 mg/kg/day was obtained in the study, making it valid for risk assessment purposes. ATSDR did review and comment on the draft study protocol which included the rationale for selecting (and example calculations) for deriving the dosing levels." Apparent exposure-related increase in pre-implantation loss or early resorption loss (Dr. J. Gerhart) - While these two studies were run simultaneously they utilized different animals. Due to the length of the reproductive toxicity study, the developmental toxicity study was completed and reported ahead of the reproductive study. However, having reviewed a portion of the preliminary results, we can now say that the reproductive toxicity study does provide further support for the interpretation of an absence of an exposure-related effect on early resorptions or pre-implantation loss. No effect of treatment on total litter size at birth (number of live plus dead pups during either the Fl or F2 litters) was indicated in the reproductive toxicity study. Litter size data (FI and F2) for the control and treated groups in the reproduction study in comparison to the number of live fetuses in the developmental toxicity study are summarized below: Group Exposure Level (ppm) Two-generation Reproduction study Mean number of pup (live plus dead) per litter at birth Developmental Toxicity Study 1(0) II (10) III (100) IV (1100) FI Litters 12.4 13.1 13.2 12.4 F2 Litters 14.0 13.9 13.3 12.3* Statistically different from control data: * p<0.051 Day 20 Gestation 13.5 12.4 12.9 12.7 1 Hehir, RM et al. Cancer induction following single and multiple exposures ro a constant amount of vinyl chloride monomer. Environ. Health Perspective 41:63-72, 1981. 4 See Lener from W. Cibulas to H. Shah of November 8, 1995. APR 24 '98 15:23 BFG 01244 cm FAGE.03 OMA 4 / *. 4 .< ad r'Ao C. ~x / ^ Stevens. A.TSDR April 24. 1998 Page 3 The similarity in these data between the control and treated groups and between the two studies confirms that the apparent slight increase in pre-implantation loss seen in the treated groups in the developmental toxicity study was not treatment-related. The data Huntingdon provided in the report had been reviewed by Huntingdon Life Sciences' Quality Assurance Department. Historical control data that was generated concurrently with the vinyl chloride study has not yet been audited and was therefore not included in the developmental study. However, the concurrent control data for mean post-implantation loss and early resorptions is 0.6; down slightly from the 1989 to 1994 historical control value of 0.9. However, the mean post-implantation loss and mean number of early resorptions for the vinyl chloride high dose group is 0.6. Therefore, we believe that this slight increase in the high dose group when compared to historical control data is not biologically meaningful. Dr. Gerhart also noted that there is an increase in mean pre-implantation loss in all three treated groups when compared to the control group. The historical control value for mean pre-implantation loss presented in the study was 1.3 and the concurrent unaudited historical control mean value is 1.5 for the years 1995 to 1997. Both of these mean historical control values are above the control group mean for this study (1.0). Since pre-implantation loss would have occurred prior to treatment, we believe the control group for this study is slightly below the treated groups due to biological variations and that the apparent increase does not reflect any biologically significant difference. Concern with statistical analysis offetal soft tissue and skeletal variations and malformations as subsectors (Dr. M. Christian) - It is true that the incidence of malformations using the Utter as an experimental unit was analyzed by subsectors, however, these findings were also analyzed by the total number of malformations in all categories as listed on page 24 of the report under "Statistical Analysis" 2.15.3 Incidence Data. Lack ofhistorical control datafor 2996 through 1997 (Dr. M. Christian) - It is true that EPA usually asks foT historical control data of a two-year period for studies which have been conducted in the same time frame as the reported study. Huntingdon has conducted ten rat teratology studies between the years 1996 and 1997, but the tabulated historical control data has not been audited by their Quality Assurance Department, and therefore was not included in the final developmental study report. We would be happy to provide a copy of the final audited 1996/1997 historical control data upon request. APR 24 '98 15:24 BFG 01245 CMA PAGE.04 LMA 4/ 2 4 j Stevens, ATSDR April 24, 1998 Page 4 f.-w We believe this letter fully responds to all the reviewers' comments on the developmental toxicity study report. Should you have any additional questions about that submission or the reproductive toxicity study, please feel free to call me at 703/7415639. Sincerely, Wendy K. Sherman Manager, Vinyl Chloride Health Committee cc: Vinyl Chloride Health Committee W. Caffey Norman, Esq, R. Schroeder. Huntingdon Life Sciences APR 24 '90 15=24 BFG 01246 total p. CMA PAGE.05