Document 85Vjkb7Z1NnEOVRyjv986DGZZ

W /V DEC 2 6 19/* PROTOCOL FOR CONTINUED STUDY OF THE EFFECTS OF MATERNALLY INHALED VINYL CHLORIDE ' ON MOUSE, RAT AND RABBIT EMBRYONAL AND FETAL DEVELOPMENT Prepared for the companies sponsoring The Manufacturing Chemists' Association Technical Task Group on Vinyl Chloride Research December 16, 1974 Toxicology Research Laboratory Health and Envrionmental Research Dow Chemical U.S.A. Midland, Michigan AS I 000017232 I. INTRODUCTION This protocol describes the second part of a multi-stage teratological study on Vinyl Chloride. In the first stage described in a protocol distributed January 29, 1974 pregnant mice, rabbits and rats were exposed to 500 ppm Vinyl Chloride 7 hours daily throughout the period of organogenesis. A summary of the results of this part is attached to this protocol and complete reports have been previously distributed to the sponsors and submitted as part of the testimony of The Dow Chemical Company at the OSHA hearings in July 1974. As noted in the summary maternal toxicity was not observed in either rats or rabbits but deaths were observed in the mice. No teratogenic effects were observed in any species exposed to Vinyl Chloride alone, based on the external and soft tissue examinations. One group of mice exposed to Vinyl Chloride was given 15% ethanol in their drinking water as their only source of liquid. This experimental group was included to determine whether or not simultaneous ingestion of ethanol might enhance any teratogenic potential of Vinyl Chloride. This treatment combination did result in an increase in the maternal toxicity as well'as an increase in the incidence of cleft palate, a teratogenic response. ASI 000017233 -2- II, EXPERIMENTAL PROCEDURES Based on the above observations, it is recommended that in the second part of this experiment an additional group of mice (large enough to yield at least 40 litters) be exposed to Vinyl Chloride at a concentration of 50 ppm 7 hours/day on days 6-15 of gestation. Half the group of mice will receive 15% ethanol in water while the others will receive tap water and no ethanol. In addition to the study in mice, additional groups of rats and rabbits will be exposed to 2500 ppm Vinyl Chloride on the same treatment schedule as in the first experiment. In each species, half of the group (enough to produce 15 rabbit or 20 rat litters) will receive 15% ethanol in their drinking water and the remaining half will receive no ethanol. In addition to these groups of rats and rabbits receiving 2500 ppm Vinyl Chloride with and without ethanol, an additional group of rats and rabbits will be given 15% ethanol alone. These groups will serve as controls for the Vinyl Chloride exposed animals that also receive ethanol. The methods of exposure of the animals and examinations of the fetuses for evidence of teratogenic effect will be the same as those described in the original protocol. AS I 000017234 TABLE I GENERAL DESIGN OF TERATOLOGY STUDIES "Species Vinyl Chloride Exposure PART I -- COMPLETED Mice Mice Mice Rats Rabbits Mice,rats,rabbits 500 ppm 500 ppm 0 500 ppm 500 ppm 0 Percent Ethanol in Water 0 15% 15% 0 0 0 PART II -- PROPOSED Rats Rats Rats Rabbits Rabbits Rabbits Mice Mice 2500 ppm 2500 ppm 0 2500 ppm 2500 ppm 0 50 ppm 50 ppm 0 15% 15% 0 15% 15% 15% 0 000011235 AS I TABLE II SUMMARY - VINYL CHLORIDE TERATOLOGY STUDIES Rats Vinyl chloride, 500 ppm, 7 hr/day Ethanol - 15% in drinking water Gestation days of treatment yes no 6-15 Rabbits yes no 6-18 yes no 6-15 No. maternal deaths/No. treated % Pregnancy No. litters examined Maternal weight gain Maternal food consumption Maternal liver weight - absolute - relative Implantation sites/dam % Resorptions Litters totally resorbed > Litter size Fetal body weight Fetal crown-rump length ^ % External malformations Visceral malformations ^ 03 Skeletal malformations 0/33 94 (control = 96) 31 a -- -- -- -- -- 0/31 -- dec. inc. -- -- <* C/19 95 (control = 100%) 18 -- dec. -- -- si. dec. -- 1/19 si. dec. -- i -- -- a-- *s no change, dec. ** decrease, inc. *> increase, si. = slight ^cleft palate 6/30 (20%) 12 control 19 si. dec. -- si. dec. -- -- si. inc. 0/19 si. dec. si. dec. -- -- -- 00 OO n Mice yes yes 6-15 4/30 (13%) 31 (control 83) 5 dec. dec. dec. dec. dec. -- 2/7' dec. dec. dec. -- i^nc. b