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Chemical Manufacturers Association April 22,1997 William Cibulas, Ph.D. Chief, Research Implementation Branch Division of Toxicology Agency for Toxic Substances & Disease Registry 1600 Clifton Road, NfE Mailstop E29 Atlanta, GA 30333 Re: Vinvl Chloride MOU Dear Dr. Cibulas: Enclosed are interim progress reports on the two-generation reproductive and developmental toxicity studies of vinyl chloride in CD rats that the CMA Vinyl Chloride Health Committee Panel is sponsoring pursuant to our Memorandum of Understanding (MOU) with the Agency for Toxic Substances and Disease Registry (ATSDR). As you have discussed with our counsel, Caffey Norman, also enclosed is a revised study plan indicating that these reports will be submitted together in April 1997. The modified study plan also reflects that I am replacing Dr. Robert Venezia as Project Manager. We will assume that the modified study plan is acceptable unless we hear otherwise from you. On October 25,1996, we informed you that the combined reproductive and developmental study would be initiated within a few days. You will see from the progress reports that dosing of the animals did not actually begin until January 7,1997 for the reproductive study and March 19,1997 for the developmental study. The delay was attributed to the resolution of a number of technical issues including additional time for setting up the chamber generation system and monitoring for leaks. Good Laboratory Practices characterization of the test material, calibration of gas chromatographs for periodic monitoring of the exposure concentrations and for comparison with infrared spectrophotometer results, and extension of the mating period for six days to achieve additional matings. Please call me at 703/741-5639 if you have any questions or need additional information. Sincerely, Enclosures (3) cc: W. Caffey Norman, Esq. Wendy K. Sherman Manager, Vinyl Chloride Panel 1300 Wilson Boulevard, Arlington, VA 22209 Telephone 703-741-5000 * Fax 703-741-6000 SL 109807 STUDY PLAN (Revised April 22,1997) COMBINED INHALATION TWO-GENERATION REPRODUCTION AND DEVELOPMENTAL TOXICITY TESTING OF VINYL CHLORIDE I. Test Requirements Contained in Study Plan Inhalation Two-Generation Reproduction Study of Vinyl Chloride in Rats Inhalation Developmental Toxicity Study of Vinyl Chloride in CD Rats H. Administrative Official and Project Manager Wendy K. Sherman Manager, Vinyl Chloride Panel Chemical Manufacturers Association 1300 Wilson Boulevard Arlington, VA 22209 Phone: 703/741-5639 Fax: 703/741-6091 III. Testing Facility: Huntingdon Life Sciences, Inc. P.O. Box 2360 Mettlers Road East Millstone, NJ 08875 Study Director: Raymond E. Schroeder M.S. Phone: 908/873-2550 (ext. 2910) IV. Professional Qualifications Curriculum Vitae (C.V.) providing the training and experience of each professional involved in this study were provided as an attachment to the original study plan. Copies of those C.V.s are available upon request from Ms. Sherman. V. Identity of Test Substance An analysis of the material which is being used in the studies was conducted and the results are available from Huntingdon Life Sciences, Inc. SL 109808 VI. Study Protocol The protocol for the combined inhalation two-generation reproduction and developmental toxicity testing was included as an attachment to the original study plan. A copy of the protocol is available upon request from Ms. Sherman. VII. Test Schedule Developmental Toxicity Study In-life phase starts: In-life phase completed: Progress report: Progress report Final report: October, 1996 April, 1997 April, 1997 October 1997 December, 1997 Reproduction Study: In-life phase starts: In-life phase completed: Progress report: Progress report: Progress report: Final report: October, 1996 September, 1997 April, 1997 October, 1997 April, 1998 July, 1998 2 SL 109809 Vinyl Chloride Combined Inhalation Two-Generation Reproduction and Developmental Toxicity Study in CD Rats Progress Report Reproduction Phase In this study, parental (P1.P2) generation animals (30/sex/group) are being treated via whole-body inhalation to vinyl chloride at exposure levels of 0, 10, 100 and 1100 ppm. The study is currently in the gestation/lactation periods of the PI parental generation to produce the FI litters. These animals have completed a 10 week premating treatment period (exposures were 6 hrs/day, 5 days/week - January 7 March 18, 1997) and a 20 day mating period (exposure 6 hrs/day, 7 days/week - March 18 - April 6, 1997). Once mated, females were treated 6 hrs/day from Days 0-20 of gestation and females delivering litters will be treated from Days 4-2S of lactation). Following is a timetable for key events through the remainder of the study. Event Proposed Date P2 premating treatment period (6 hrs/day, 5 days/week): Initiate Complete May 20, 1997 July 29, 1997 Mating period P2 - F2 litters (6 hrs/day, 7 days/week): Initiate Complete July 29, 1997 August 12, 1997 Gestation/Lactation of F2 litters Initiate Complete July 30, 1997 September 23, 1997 Sacrifice Schedule: PI Males PI Females P2 Males P2 Females April 28 & 29, 1997 May 19 & 20, 1997 September 15 & 16, 1997 September 24 & 25, 1997 Submission of the audited draft report Week of March 23, 1998 Study Comments: The start of the study was delayed by approximately two months from the contract date (anticipated start October 28, 1996). Animals for the study (PI) arrived December 23, 1996. This delay was attributed to the following: additional time required to set up the chamber generation system (test material in a one ton cylinder arrived September 19, 1997) and monitor for leaks; GLP characterization of the lot of test material received; and calibration of the gas chromatograph for the periodic monitoring of the exposures concentrations for comparison with the infrared spectrophotometer (MIRAN) results. Mating period was extended by six days to achieve more matings. SL 109810  2 Vinyl Chloride Combined Inhalation Two-Generation Reproduction and Developmental Toxicity Study in CD Rats Progress Report Developmental Phase In this study, mated rats (24/group) were treated with vinyl chloride via whole-body exposure (6 hrs/day) over the Day 6-19 gestation period (day of mating evidence = Day 0 of gestation). Body weight, food consumption and clinical findings were recorded periodically throughout gestation. Animals were sacrificed on Day 20 of gestation and corpora lutea/uterine implantation data recorded. Fetuses were weighed, sexed and given a gross external examination. One-half of the fetuses in each litter were evaluated for visceral malformations/variadons (microdissection procedure) and the remaining fetuses are being stained with Alizarin Red S for skeletal examination: Females were given a gross postmortem examination and liver, kidney and gravid uterine weights recorded. Gross lesions, kidneys and liver tissue were taken and preserved. Exposures and the Day 20 gestation maternal sacrifices have been completed for the developmental phase. Dates for these events are as follows: Mating imitated: March 12, 1997 Treatment period (Days 6-19 of gestation, 6 hrs/day): March 19 - April 10, 1997 Maternal Day 20 gestation sacrifices: April 2 - 11, 1997 Submission of the audited draft final report: Week of August 25, 1997 Study comments: Animals in the developmental phase were exposed along with the animals in the reproduction phase of the study. The fetal evaluations are on-going. Submitted by: Title: For: Date:. Raymond E. Schroeder, M.S., DABT Study Director Huntingdon Life Science Inc. SL 109811