Document e5Bdk038ROKvZyw8N9Vdpa4n4

from Tuxiuu \m* Appi-JLi* I'h ak M m,uL<*^ , \i*lmo< **. V-mltri l Vn it l>> r I`Mm r<.|iriuli| / I4#* !' A- hI l" PrtHh.l <> t S i ToxicoiiKiv a\i> Arri.im pu\k\i \< nn,v 9, SCI-504 Mfi it 197$ R N. WHiUM, JR, Chronic Oral Toxicity to Rats of a Vinyl Chloride-Vinyl Acetate Copolymer Hunky F. Smyth. Jk., and Carrol S. Wkil Chemical Hygiene Fellow ship, Mellon Institute, Fitt.sburi;h, Prunsyliania !'-! ' Keerivetl July loots High molecular weight polymers are generally accepted as safe for food contact, although there is a dearth of published evidence. In particular, no reports of long time experimental feeding of polyvinyl resins, widely used in food packaging, appear in the literature. In order to till this gap. a study completed in 1947 is presented. MKTlloto Sample. The sample was then characterized as vinyl resin YYXU.1 It was a copolymer of 95'i vinx 1 chloride and 5'i vinyl acetate, with a molecular weight of 25.000 to 50.000 as determined by the Staudinger method, or 200,000 as measurer! by osmotic pressure. The resin was produced in the form of particles with a diameter of 0.1 ji that tended to agglomerate loosely. Animal management and observation. Each of the parental generation group con sisted of 12-15 Wistar-strain albino rats of each sex. approximately 6 weeks of age at the tirst dose. They were housed 4-6. half of each sex, in wire-bottom cages. Ten to 12 offspring of each sex. consisting of the first filial generation, were fed the diets until the end of the study and, as no differences were found from the parental generation rats, both generations were considered together. For the first 18 months the basic diet consisted of a mixtuie of 100 parts of ground whole wheat, 5 parts of dried whole milk, and 2 parts of iodized table salt. Wheat then became unavailable to the local miller, and during the last o months a commer cial ground laboratory chowJ was utilized. The growth curves of the rats showed no appreciable upset from the shift in basic diets. One group received the basic diet, one had 1.5' i VYNT added, the third had 12'/i YYNU added, with no attempt made to correct for high nonnutrient content. The respective intakes of YYNC averaged 0.61 and 5.75 g kg day. The observations made during the feeding were (1) tone and behavior of animals, (2) average food consumption, (3) body weight, (4) occurrence of death and infec tion, (5) red, white, and differential white blood cell counts, and (6) occurrence of pregnancy, number of pups born, and survival and growth of the pups. At death or sacrifice gross pathology was recorded, and neoplasms were sought. Body length was measured, and livers and kidneys were weighed. Organ weights were calculated as a percentage of body weight. Adrenal, small intestine, kidney, liver, lung, pancreas, spleen, testis, and neoplasms 1 Manufactured by a company known at that time as Union Carbide Plastics Division. - Purina Laborators Chow Meal, Ralston Purina Compan\. St. Louis, Missouri. 501 UCC 084627 502 HENKY F. SMYTH. JH., AND CAKKOL S. WKIL were fixed in formalin, stained with eusin ami hematoxylin, and examined hi*topathologically. All numerical results were evaluated for statistical significance by Student's t test (Fisher, 1938). RESULTS No abnormalities in body tone or behavior were observed, other than those resulting from chronic murine pneumonia. Table 1 summarizes the data on survival. The suggestion of a dose-related TABLE I Survival or Rats Receivuco Rlsin VYNl' in Tin Dict for Two Yt \ks Dietary level <7c> Katssluilicil Parental Filial Hats turvivint; to^65da>$ui ape Moan am* at fic3thu`#' (days) Rau .'urvivine to end of study 12 2S 22 Id 247 152 5 1.5 27 22 21 D9 * 156 10 0 2 7 -M ,4 a <44 it 176 s Excludes all rats sacrificed ior examination. *> Mean it Sli. shortening of life is weakened by the high dispersion of the mean ages at death. Seventy-five rats died of lung infection, and these deaths were distributed equally among the three groups. Seventeen were killed for middle-ear infection, and 4 for other reasons. During the period on the wheat-milk-salt diet the teeth of 6 of the rats, distributed among the three groups, grew continuously without the character istic rodent attrition, due to the absence of roughage. Three of these were killed when their inability to eat resulted in marked inanition. Table 2 summarizes the data on dosage, food consumption, and body weight of TABLE 2 Dot Conscmi.d, Diisaul, ami Boiiy Wlh-mt of Rais Rlieivim. Rlsin VYNL i\ Tin. Dot !ur Two Years Dietary Io\cl (7c) Mean diet eaten" (rat day) M ea n (Insane (it ku day ) Mean weilthl <>f males at 580 (lays of ace" let Maximum weight attained liy males alive at iso days of auc" let 12 11.6 OA 5.75 573 05 412 it 51 1.5 10.4 it 0.2 <* 0.61 414 it 88 459 it 116 0 11.2 it 0.5 0 364 69 417 it 79 * Mean it SD. P 0.04. males. The body weight of females fluctuated widely because of frequent pregnancy. The suggestion of a lower weight from the high level is weakened by the high standard deviation. Since rats on the low level of YYNU grew as much as did the controls, no importance is attached to their slightly lower diet consumption. Table 3 summarizes liver and kidney weights, expressed as percentages of body weight, of rats sacrificed after one or two years. At one year, the livers of rats on diets containing 12% YYNU were heavier than those of the controls. They were UCC 084628 CHRONIC TOXICITY OK A VINYL COPOLYMER 503 TABLE 5 Liver and Kidney Weight Ratio Data ox Rats Receiving Resin VYNl' in the Diet eor One and ior Two Years Period of feeding Dietary level O) Organ weight u, percentage o! body weight" Liter Kidney 1 Year 12 1.5 0 4,0S 3: 0.4.0' 5.05 0.57 5 12 2: 0 55 0.79 0.18 0.06 0 05 0,b4 0.17 -2 Years 12 1.5 0 5,00 0 51 3,05 2. 0.55 5.U 0,4 5. 0.59 - 0.17'' 0,6(1 it 0 00 0.70 :t 0.10 " Mean SD. <> P < 005. histologically normal, and at two years livers of rats in the same group were numeri cally but not significantly lighter. Similarly, a slieht, but statistically significant, de crease in mean relative kidney weight was seen at two years, but not at one year, with all sections histologically normal. Neither was considered to he a deleterious effect from the inclusion of YYNC in the diet. Table -1 summarizes the reproduction results and does not suggest any effect. TABLE 4 Reproduction or Rats" Receiving Resin VVNU is' the lw.i run Two Yearn Dietary level ' tf'e) Females of parental generation Total Infertile Females of Fj generation Total Infertile Total per female Litters born'' Pups born alive*' 12 5 1 6 1 6.5 5.5 47.8 28.7 1.5 5 1 4 0 5.5 *4.0 45.2 504 0 10 1 6 1 5,4 5.5 51.6 41.0 Alive at 565 days of age, * Mean SI). The tissues of the 3S rats sacrificed for examination alter one or two years were histopathologically normal. An infective or traumatic cause of deaLh was dear for all rats dying, and none of their tissues showed any histopathologv not directly related to this cause. Careful search of all rats dying or sacrificed revealed only 6 neoplasms, possibly because half of the rats did not survive the lung infection into the second year of feeding. At the 12'/o level of VYN'C there were two neoplasms in the mesentery, at the l.S^f level one uterine neoplasm, and the controls had one in the mesentery and two in the lung. DISCUSSION This study, completed 20 years ago, differs in many respects from the design one would expect in a current study of the safety of a food-packaging resin. In particular, it would be preferable to add to animal diets only that fraction of the resin which transfers to food jiackaged in a formulation. Furthermore, were reproduction considered of sufficient importance to be studied, a separate group of animals would be desirable, with opportunity for mating provided onlv at estrus. UCC 084629 504 HENRY F. SMYTH, JR., AND CARROL S. WEIL SUMMARY Starting in 1944. albino rats of both sexes cased together were maintained for two years upon diets containing 1.5% and 12% of a vinyl chloride-vinyl acetate copolymer. No effect attributable to the resin was found. REFERENCE Fisher, R. A. (19iS). Statistical Methods for Research Workers, 7th ed. Oliver & Boyd. Edinburgh and London. UCC 084630