Document MMw287zD9ov5XJjD5NedMJydL

R&S 036198 SUBJECT: PROTOCOL FOR A STUDY OF THE EFFECTS OF MATERNALLY INHALED VINYL CHLORIDE CM RAT AND RABBIT EMBRYONAL AND FETA_. DEVELOPMENT. FIF.ST supplement: SECOND ST.'vGE ST-JDTES SUBMITTED BY: B. A. Schwetz and B.K.J.' Leong DATE: September 18, 1974 (original was dated December, 1973) ; FILE NUMBER: NB T3.4-16-10 \ K-NUMBER: K-1711 PROBLEM NUMBER: 998-0060100 COPY: Preliminary ________ DISTRIBUTION: BRAUN DITTEN3ER F1AUSCN GEHRING mefnss HCCVHR HUM'STCN ^ JERSEY KSElER XOCiEA L-sSEAU LEONG LISCVvE ! MURPHY i --i Vatanabe | Bibbs Kalnins Lichy |nit<ch<h ! NORRIS j | CL SON, K. j 1 QJAST l Rampy i ramsey ! j i ROSE I1 - j 1 ; >AUEf?nO - -* ! SCN.aETZ j 'H j( wage | j" *. i ! '.vGL= ! ii YAXEL ; | i yCUNG, J. . i j jBalraer | Heeg Karbowski Winieckie .i - DOW CONFIDENTIAL SUPPLEMENTAL PROTOCOL (1), VINYL CHLORIDE TERATOLOGY STUDIES INTRODUCTION This supplemental protocol describes the'second part of a multi-stage teratology study on vinyl chloride. In the first stage, pregnant mice, rats and rabbits were exposed to 500 ppm vinyl chloride 7 hours daily throughout organo genesis (see NB T3.4-16-10 issued on Dec. 11, 1973). A summary of the results of this first stage is included in this protocol. The examination of the skeletons of some of the mice and rabbits remains to be completed, but enough of the study has been completed to design the second stage of this experiment. As noted in the summary, maternal toxicity was not observed in either rats or rabbits. Deaths were observed among the mice, however. No teratogenic effects were observed in any species, based on the external and soft tissue examinations. One group of nice exposed to vinyl chloride was allowed 15% ethanol as their source of liquids. This experimental group was included to determine whether or not simultaneous ingestion of ethanol would enhance the 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. EXPERIMENTAL PROCEDURES Based on the above observations, it is recommended that in the second stage of this experiment an additional group of mice be exposed to vinyl chloride at a concentration of 50 ppm 7 hr/day on days 6-15 of gestation. Half of the group of mice will receive 15% ethanol while the others will' receive tap water and no ethanol. The purpose of this study is to determine if the teratogenic potential of vinyl chloride at 50 ppm is also enhanced by simultaneous inges tion of ethanol. In addition to this 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 will receive ethanol in the 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 or 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 examination of the fetuses for evidence of a teratogenic effect will be the 0 3 6 199 a? fib co 2- - snme as those described in the original protocol. A summary of the completed studies and the - proposed- second..stage is indicated below. The estimated cost of this second stage of experiments is $17,900. STAGE 1 TERATOLOGY STUDIES mice mice mice rats rabbits mice,rats, rabbits Vinvl Chloride 500 ppm 500 ppm 0 , 500 ppm 500 ppm 0 Ethanol done STAGE 2 rats rats rats rabbits rabbits .rabbits mica mice 2500 ppm -------------- -- 0 ? (^2500 ppm 157^ . --------- 0--r------------------ L5% .(done), 50 ppm 50 ppm 15% 0 R&S 036200 SUMMARY - VINYL CHLORIDE TERATOLOGY STUDIES Vinyl chloride, 500 ppm, 7 hr/day Ethanol - 15% in drinking water Gestation days of treatment Rats yes no 6-15 Rabbits yes no 6-18 yes no 6-15 Mice yes yes 6-15 No. maternal deaths/No. treated % Pregnancy No. litters examined Maternal weight gain Maternal food consumption Maternal liver weight - absolute - relative Implantation sites/dam % Resorptions Litters totally resorbed Litter size Fetal body weight Fetal crown-rump length External malformations Visceral malformations Skeletal malformations 0/3.3 94 (control - 96) 31 a -- -- -- -- -- 0/31 -- dec. inc. . -- NC 0/19 95 (control ** 100%) 18 -- dec. .-- -- si. dec. '-- 1/19 si. dec. -- -- -- -- NC 6/30 (20%) 72 (control 88) 19 si. dec. -- si. dec. -- si. Inc.` ^ 0/19 si. dec. si. dec. -- NC 4/30 (13%) 31 (control 5 dec'. dec. dec. dec. . . dec. 2/7 dec. dec. dec i -- inc. NC 3-- no change, dec. = decrease, inc. Increase, si. slight, NC = exam not completed ^cieft palate , t *. V 102900 S$y -4- VINYL CHLORIDE - ESTIMATED COSTS OF STAGE 2 Hours Salaried Fetal exam (60 rats + 36 rabbits + 40 mice 0 2 hr) . 272 Exposure 150 Data Evaluation 30 Report ' 30 482 X $24 $11568 Animals SUBTOTAL $14368 4 40 rabbits 0 $15.00 50 mice 0 $0.50 75 rats 0 $7,00 600 25 525 Chambers 2 chambers, 2 weeks each 305 Space % room for 1 mo. 262 Cage Wash $18/rack X 9 racks + 10% 162 $16247 1625 TOTAL ' $17872 Hourly 50 150 a? Ho CO 036202 200 X $14 .$2800 R&S 036203 % t-WT iyf so? CD i-sw 1-6Z5 tw' '-717 <5 c) Z.