Document YZOEdrp0KrRZLKnBadVBJJNk

AR226-3384 Evaluation o f the Subchronic, Reproductive, and Developmental Toxicity of a Fluoroalkylethyl Surfactant S.A. MacKenzie. E. Mvlchreest. S.M. Munley, J.C. Stadler. J.F. Hansen, and N.E. Everds DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, DE, USA. Ijjjj Abstract The objective of these studies was to evaluate the subchronic, reproductive, and developmental toxicity of a fluoroalkylethyl ethoxylate surfactant in rats. Test substance was administered by gavage at 0, 25, 100, or 500 mg/kg/day (90-day subchronic toxicity and one-generation reproduction), and at 0, 50, 100, or 400 mg/kg/day on gestation days 6-20 (developmental toxicity). The NOEL for subchronic toxicity was 25 mg/kg/day based on clinical signs, reduced body weight and nutritional parameters, thyroid follicular hypertrophy, and chronic progressive nephropathy at >100 mg/kg/day. Other adverse effects at 500 mg/kg/day were reduced red blood cell mass, increased liver enzyme activity, and reduced grip strength. Non-adverse liver hypertrophy and splenic effects were observed at >25 and >100 mg/kg/day, respectively. Except for effects on the thyroid at 500 mg/kg/day and kidney at >100 mg/kg/day, other effects were reversible after a 1- or 3-month recovery. No NOEL was determined for reproductive toxicity, based on reduced fertility in P2rats at >25 mg/kg/day, which was of similar magnitude at all dose levels. Body weights, food efficiency, and number of implantation sites were reduced in rats at 500 mg/kg/day, and viability and weights were reduced in Fj pups at >100 mg/kg/day. The reduced pup viability was relatively less severe and required much higher doses than the structurally related perfluorooctane sulfonate. Red blood cell and spleen effects were similar to those observed with ethylene glycol ethers, but there were no developmental or testicular effects as seen with glycol ethers. The mechanism for reduced fertility is not known. In the developmental toxicity study, the NOELs were 50 and 100 mg/kg/day for maternal and fetal toxicity, respectively, bgsed on reduced maternal body weight and nutritional parameters, and clinical signs at >100 mg/kg/day and reduced fetal weight and increased fetal variations at 400 mg/kg/day. No fetal malformations were observed. Ij Ih Introduction The objective of these studies was to evaluate the subchronic, reproductive, and developmental toxicity of a fluoroalkylethyl ethoxylate surfactant in rats. The test substance was administered by gavage, the route selected as the most efficient way to administer an accurate dose. In a two-month rangefinder study, rats demonstrated body weight loss when exposed to 1000 mg/kg/day and male rats demonstrated reduced body weight gain when exposed to 500 mg/kg/day. Blood fluorine levels plateaued within 2-3 weeks of dosing. The high dose of 500 mg/kg/day for the 90-day study was expected to produce toxicity without excessive mortality. The low dose of 25 mg/kg/day was expected to be the no-observed-effect level, while the 100 mg/kg/day dose was expected to induce minimal or no toxicity. The doses for the developmental toxicity study of 0, 50, 100, and 400 mg/kg/day were selected based on a pilot study in which maternal and fetal toxicity were observed at >400 mg/kg/day but no maternal or fetal toxicity were observed at <100 mg/kg/day. - t LMIf Study Design 90-Day and One-Generation Reproduction Study m Body weights, detailed clinical signs, and food consumption were determined weekly throughout the 90-day exposure and 1-month recovery periods. Clinical pathology, gross and microscopic pathology, and biochemical evaluations were performed at the end o f the 90-day exposure, 1-month recovery, and 3-month recovery periods. Reproductive evaluations were performed prior to mating and during the mating, gestation, and lactation periods. Developmental landmarks and gross pathology was also assessed on F t adults. Developmental Toxicity Study Groups of tifne-mated rats (22/dose) received oral gavage dose once daily over gestation days 6-20. Body weight, food consumption, and clinical observations data were collected. Dams were euthanized on gestation day 21 and examined for gross external and visceral alterations. Uteri were weighed and dissected and uterine contents were examined. Fetuses were removed, weighed, sexed, and examined for external, visceral, head, and skeletal alterations. I III Figure 1: Mean Body Weights o f Male Rats 0 mg/kg/day *- "25 mg/kg/day 100 mg/kg/day 500 mg/kg/day fefilf F8ure Mean Body Weights o f Female Rats a 0 mg/kg/day 25 mg/kg/day --100 mg/kg/day 500 mg/kg/day TABLE 1 CLINICAL PATHOLOGY DATA Dose (mg/kg/day): RBC (xl06/gL) end-of-dosing 1-month recovery 3-month recovery HGB (g/dL) end-of-dosing 1-month recovery 3-month recovery HCT (%) end-of-dosing 1-month recovery 3-month recovery SDH (U/L) end-of-dosing 1-month recovery 3-month recovery ALT (U/L) end-of-dosing 1-month recovery 3-month recovery Plasma F (jig/mL) end-of-dosing 1-month recovery 3-month recovery Urine F (gg) end-of-dosing 1-month recovery 3-month recovery Urine Vol. (mL) end-of-dosing 1-month recovery 3-month recovery Males 25 100 500 100% 98% ND ND 99% 98% 103% 97% 97% 99% 95% ND ND 101% 98% 92% 95% 99% 99% 96% ND ND 100% 99% 94% 96% 100% 113% 124% ND ND 157% 160% 130% 219% 221% 109% 112% ND ND 156% 147% 152% 129% 194% 200% 200% ND ND 100% 100% 500% 100% 100% 418% 1164% 5228% ND ND 1214% 132% 211% 459% 134% 85% 368% ND ND 123% 77% 78% 111% Females 25 100 500 97% 91% ND ND 100% 99% 89% 98% 101% 97% 90% ND ND 101% 94% 85% 97% 97% 98% 97% ND ND 104% 96% 96% 97% 100% 89% 68% ND ND 86% 120% 75% 112% 131% 76% 61% ND ND 83% 94% 73% 55% 109% 100% 200% 500% ND ND NC 100% 100% 100% 431% 1080% 5295% ND ND 714% 146% 168% 266% 194% 166% 351% ND ND 63% 139% 135% 131% Values are percent of control. Those in green bold italics are statistically significant. ND = No data NC = Not calculable as control value was zero. tEe i CLINICAL PATHOLOGY DATA Dose (mg/kg/day): Males 25 100 500 RBC (xl06/|iL) end-of-dosing 1-month recovery 3-month recovery HGB (g/dL) end-of-dosing 1-month recovery 3-month recovery HCT (%) end-of-dosing 1-month recovery 3-month recovery SDH (U/L) end-of-dosing 1-month recovery 3-month recovery ALT (U/L) end-of-dosing 1-month recovery 3-month recovery Plasma F (pg/mL) end-of-dosing 1-month recovery 3-month recovery Urine F (jig) end-of-dosing 1-month recovery 3-month recovery Urine Vol. (mL) end-of-dosing 1-month recovery 3-month recovery 100 98 103 ND ND 97 99 98 97 99 95 ND ND 101 98 92 95 99 99 96 94 ND ND 96 100 99 100 113 124 130 ND ND 219 157 160 221 109 112 152 ND ND 129 156 147 194 200 200 500 ND ND 100 100 100 100 418 1164 5228 ND ND 1214 132 211 459 134 85 368 ND ND 123 77 78 111 Females 25 100 500 97 91 89 ND ND 98 100 99 101 97 90 ND ND 101 94 85 97 97 98 97 96 ND ND 97 104 96 100 89 68 75 ND ND 112 86 120 131 76 61 73 ND ND 55 83 94 109 100 200 500 ND ND NC 100 100 100 431 1080 5295 ND ND 714 146 168 266 194 166 351 ND ND 63 139 135 131 Values are percent of control. Those in green bold italics are statistically significant. ND = No data NC = Not calculable as control value was zero. Dose (mg/kg/day): 0 Males 25 100 500 End-of-Dosine Thyroid Hypertrophy, Follicular Alteration, Colloid Kidney Nephropathy, Chronic Progressive 0/11 1/10 9/11 11/12 6/11 10/10 10/11 11/12 5/11 2/10 5/11 7/12 Liver Hypertrophy, Centrilobular Spleen Hematopoiesis Pigment 1/11 5/10 10/11 12/12 0/11 1/10 8/11 10/12 0/11 0/10 4/11 6/12 1-Month Recovery Thyroid Hypertrophy, Follicular Alteration, Colloid Kidney Nephropathy, Chronic Progressive Liver Hypertrophy, Centrilobular Spleen Hematopoiesis Pigment 0/10 ND 6/10 ND ND 8/10 ND 10/10 3/10 ND ND 8/10 0/10 ND ND 7/10 0/10 . ND ND 8/10 0/10 ND ND 7/10 3-Month Recovery Thyroid Hypertrophy, Follicular Alteration, Colloid Kidney Nephropathy, Chronic Progressive Liver Hypertrophy, Centrilobular Spleen Hematopoiesis Pigment 0/4 0/5 0/4 4/5 1/4 5/5 4/4 5/5 4/4 4/5 3/4 2/5 0/4 0/5 0/4 0/5 0/4 1/5 1/4 0/5 0/4 0/5 0/4 0/5 Values in green bold italics are statistically significant. Females 0 25 100 500 0/10 0/10 2/10 9/10 3/10 6/10 10/10 10/10 2/10 2/10 5/10 5/10 0/10 0/10 9/10 10/10 0/10 1/10 6/10 7/10 1/10 0/10 0/10 10/10 0/10 ND ND 6/10 1/10 ND ND 10/10 0/10 ND ND 8/10 0/10 ND ND 1/10 0/10 ND ND 1/10 0/10 ND ND 0/10 0/4 0/5 0/4 0/4 1/4 3/5 4/4 3/4 2/4 2/5 4/5 4/5 0/4 0/5 0/5 0/5 0/4 0/5 0/5 0/5 0/4 0/5 2/5 2/5 Neurotoxicology ^Effects Reduced forelimb and hindlimb grip strength in male rats at 500 mg/kg/day, attributed to reduced body weight. No effects considered to represent neurotoxicity. IJill Reproduction Evaluation Reduced body weight parameters at 500 mg/kg/day - Pxmales and females Reduced food efficiency at 500 mg/kg/day - females No effect on P1generation sperm parameters Increased Pj female estrous cycle length at all dose levels Reduced Pj fertility at all dose levels No effect on Pj generation mating or gestation length Reduced l uterine implantation sites and litter size at 500 mg/kg/day Reduced 1lactation pup survival parameters and body weights at 100 and 500 mg/kg/day ? TA IS3 P, GENERATION REPRODUCTIVE PARAMETERS ____ Dose (mg/kg/day): 0______25_____ 100 500 Percent of Days in Estrus 32 31 34 29 Percent of Days in Diestrus 60 59 60 60 Percent of Days in Proestrus 7 10 6 10 Mean Cycle Length (days) 4.3 4.7 4.9 4.8 Mean Precoital Interval (days) 3.4 3.3 2.8 3.1 Mating Index (%) 100.0 100.0 95.0 100.0 (number copulated/cohoused) Fertility Index (%) 85.0 55.0 57.9 65.0 (number delivered/copulated) Gestation Length (days) 22.6 22.4 22.5 22.9 Number of Implantation Sites 15.3 14.1 14.8 10.7 Implantation Efficiency (%)a 90.0 93.2 88.6 86.0 Sperm Motility (% motile) 92.8 91.7 93.4 91.1 Sperm Morphology (% normal) 98.3 98.3 98.9 97.7 Epididymal Sperm (millions) Per cauda Per gram Cauda 318.4 278.8 291.1 279.4 1180.2 979.2 969.0 1062.1 Testicular Spermatids (millions) Per Testis Per gram Testis 126.5 128.8 128.2 137.0 83.3 93.7 87.4 83.4 a Number of pups bom/number of implantation sites X 100. Values in green bold italics are statistically significant. Values in blue bold are not statistically significant but considered test substancerelated. TA^JLE 4 F, GENERATION LITTERS Dose (mg/kg/day) N 0 17 25 11 100 11 500 13 Mean Number of Pups/Litter Bom 14.3 13.7 13.4 103 Bom Alive 14.3 13.5 13.1 9.4 Day 4 Preculling 14.1 12.8 12.9 7.5 Day 4 Postculling 8.0 7.9 8.0 63 Day 7 8.0 7.9 7.7 4.8 Day 14 8.0 7.9 63 1.1 Day 21 8.0 7.9 6.1 0.8 Survival (%) Sex Ratio (males) Gestation Indexa Mean % Bom Alive 0-4 Day Viability Lactation Indexb Litter Survival0 0.48 100.0 100.0 97.6 100.0 100.0 0.58 100.0 98.8 98.5 98.2 100.0 0.50 100.0 98.1 98.9 76.1 90.9 0.46 92.3 86.7 82.8 11.4 25.0 Mean Pup Weights (grams) Day 0 6.9 6.8 6.7 6.2 Day 4 Preculling 11.5 12.2 10.8 8.2 Day 4 Postculling 11.5 12.3 10.8 8.2 Day 7 18.4 18.9 15.9 9.9 Day 14 38.0 37.7 35.7 213 Day 21 62.6 59.9 58.6 35.9 a Percent litters delivered having at least one live pup. b Mean percent survival from Day 4 Postculling to Day 21. c Percent litters bom with at least one pup alive on Day 21. Values in green bold italics are statistically significant. m TABLE 5 DEVELOPMENTAL TOXICITY STUDY RESULTS Dose (mg/kg/day): 0 25 100 500 Maternal BWG (g) (GD 6-21) 153.1(20.3) 144.5(21.4) 133.3(19.8) 85.2(19. 7) Fetal weight (g) 5.50(0.28) 5.49(0.26) 5.40(0.39) 4. 76(0.29) Supernumerary ribs 6/22 (litters affected/examined) 6/21 10/22 12/21 Skull, retarded ossification 10/22 (litters affected/examined) 9/21 12/22 16/21 Values in green bold italics are statistically significant. I / // Discussion Exposure to the test substance produced reversible decrements in body weight and nutritional parameters and non-specific clinical signs of toxicity. No evidence of neurotoxicity was observed. Reductions in grip strength were attributed to lower body weight. Liver, thyroid, kidney, and red blood cells were identified as target organs, based on clinical and anatomic pathology evaluations. Effects were generally mild and all adverse effects demonstrated reversibility, except chronic progressive nephropathy in females. The reduction in fertility index and mean number of implantation sites, in the absence a reduction in implantation efficiency (an indicator of in utero post-implantation loss) suggests pre implantation embryonic loss. The reduction in pup viability and survival may be due to the postnatal manifestation of a developmental effect due to in utero exposure, maternal factors (insufficient milk supply, neglect), or result from postnatal toxicity from lactational transfer to the nursing pups. In the developmental toxicity study, the test substance did not produce fetal malformations. There was no evidence of increased sensitivity of the fetus to the test substance. JJJJJ Conclusions NOEL for Subchronic Toxicity: The no-observed-effect level (NOEL) for males and females was 25 mg/kg/day, based on decrements in body weight and nutritional parameters, clinical signs of toxicity, and thyroid and kidney histopathology, all observed at 100 mg/kg/day. NOEL for Reproductive Toxicity: There was no NOEL for the reproductive toxicity parameters evaluated under the conditions of this study; this was based on effects at all dose levels on the fertility index in the generation. NOEL for Developmental Toxicity: The maternal NOEL was 50 mg/kg/day, based on reduced maternal body weight and nutritional parameters. The fetal NOEL was 100 mg/kg/day, based on reduced fetal weight and increased fetal variations. No fetal malformations were observed. j ^ f Acknowledgments We wish to thank the following individuals for their technical assistance: Linda A. Malley for neuropathology evaluations Primary Technician: Nita B. Baker Poster Preparation: Maryanne M. Wilford Evaluation of the Subchronic, Reproductive, and Developmental Toxicity of a Fluoroalkylethyl Surfactant S.A. MacKenzie. E. Mvlchreest, S.M. Munley, J.C. Stadler, J.F. Hansen, and N.E. Everds The DuPont Company, Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware, USA I Abstract T he objective o f these studies was to evaluate the subchronic, reproductive, and developmental toxicity o f a fluoroalkylethyl ethoxylate surfactant in rats. Test substance was administered by gavage at 0 ,2 5 .1 0 0 , o r 500 mg/kg/day (90-day subchronic toxicity and one-generation reproduction), and at 0 . 5 0 , 1(X). or 400 mg/kg/day on gestation days 6-20 (developmental toxicity). The NOEL for subchronic toxicity was 25 mg/kg/day based on clinical signs, reduced body weight and nutritional parameters, thyroid follicular hypertrophy, and chronic progressive nephropathy at >100 mg/kg/day. Other adverse effects at 500 mg/kg/day were reduced red blood cell mass, increased liver enzyme activity, and reduced grip strength. Non-adverse liver hypertrophy and splenic effects were observed at >25 and >100 mg/kg/day, respectively. Except for effects on the thyroid at 500 mg/kg/day and kidney St >100 mg/kg/day, other effects were reversible after a 1- or 3-mcnth recovery. No NOEL was determined for reproductive toxicity, based on reduced fertility in Pt rats at >25 mg/kg/day, which was o f simitar magnitude at all dose levels. Body weights, food efficiency, and number o f implantation sites were reduced in P, rats at 500 mg/kg/day. and viability and weights were reduced in F, pups at >100 mg/kg/day. The reduced pup viability was relatively less severe and required much higher doses than the structurally related perfluorooctane sulfonate. Red blood cell and spleen effects were simitar to diose observed with ethylene glycol ethers, but (here were no developmental or testicular effects as seen with glycol ethers. The mechanism for reduced fertility is not known. In tire developmental toxicity study, the NOELs were 50 and 100 mg/kg/day for maternal and fetal toxicity, respectively, based on reduced maternal body weight and nutritional parameters, and clinical signs at >100 mg/kg/day and reduced fetal weight and increased fetal variations at 400 mg/kg/day. N o fetal malformations were observed. JIntroduction The objective o f these studies was to evaluate the subchronic. reproductive, and developmental toxicity o f a fluoroalkylethyl ethoxylate surfactant in rats. T he test substance was administered by gavage. the route selected as the most efficient way to administer an accurate dose, in a two-month rangefinder study, rats demonstrated body weight loss when exposed to 1000 mg/kg/day and male rats demonstrated reduced body weight gain when exposed to 500 mg/kg/day. Blood fluorine levels plateoucd within 2-3 weeks o f dosing. The high dose o f 500 mg/kg/day for the 90-day study was expected to produce toxicity without excessive mortality. The low dose o f 25 mg/kg/day was expected to be the no-observedeffect level, while the 100 mg/kg/day dose was expected to induce minimal o r no toxicity. The doses for the developmental toxicity study of 0 .5 0 ,1 0 0 , and 400 mg/kg/day were selected based on a pilot study in which maternal and fetal toxicity were observed at >400 mg/kg/day but no maternal or fetal toxicity were observed at <100 mg/kg/day. Body weights, detailed clinical signs, and food consumption were determined weekly throughout the 90-day exposure and l-roonth recovery periods. Clinical pathology, gross and microscopic pathology, and biochemical evaluations were perform ed at the end o f the 90-day exposure. 1-momh recovery, and 3-month recovery periods. Reproductive evaluations were performed prior to mating and during the mating, gestation, and lactation periods. Developmental landmarks and gross pathology were also assessed on F, adults. Developmental Toxicity Study Groups o f time-mated rats (22/dose) received oral gavage dose once daily over gestation days 6-20. Body weight, food consumption, and clinical observations data were collected. Dams were euthanized on gestation day 21 and examined for gross external and visceral alterations. Uteri were weighed and dissected and uterine contents were examined. Fetuses were removed, weighed, sexed, and examined for external, visceral, head, and skeletal alterations. Results Fluire 1-MeanBedyWeightssf Mele Rate Figure2- MeanBodyWeightsofFerait Bats Table 1 Clinical Patiiology Data Females IViw /mv/kc/davl: 75 100 .500 25 1M 500 RBC (xlOtyL) end-of-doslng 100 98 103 ND ND 3-montli recovery 99 98 97 97 91 89 100 HGB (g/dL) end-of-dosing 99 95 92 ND ND 3.month recovery 101 98 99 97 90 85 101 HCT<*) 99 96 94 ND ND 96 3-moMJi recovery 100 99 100 98 97 96 104 SDH(U/L) 113 124 130 ND ND 219 3-monlh recovery 157 160 221 89 68 15 86 120 131 ALT (U/L) 109 112 152 76 61 73 1-nionlh recovery ND ND 129 ND 3-momh recovery 156 147 194 Plasma F(uo/mDend-of-dosing 200 200 500 1-mondi recovery ND ND 3-montli recovery 100 100 100 too 200 500 Urine F (ng) 418 164 5228 ND 1214 3-mondi recovery 132 211 459 431 1080 5295 146 266 Urine Voi. (mL) end-of-dosing 134 85 368 194 166 351 77 78 111 139 135 131 W.'.K.uU.UW.u, nets..ipIftcuL Table 2 Histopnthology Data AlUndioa.Colloid Ncurotoxicotogy Effects Reduced forclimb and hindlimb grip strength in male rats at 500 mg/kg/day, attributed to reduced body weight. No effects considered to represent neurotoxicity. Reproduction Evaluation Reduced body weight parameters at 500 mg/kg/day - P, males and females Reduced food efficiency at 500 mg/kg/day - P, females Noeffect onP, generation spermparameters Increased4?| female esuous cycle length at all dose levels Reduced P, fertility at all dose levels No effect on P, generation mating or gestation length Reduced P, uterine implantation sites and litter size at 500 mg/kg/day Reduced F, lactation pup survival parameters and body weights at 1O0 and 500 mg/kg/day Table 3 Pi Generation Reproductive Parameters Dose (mc/ke/dayl: 0 25 100 500 Percent of Daysin EsUus 32 31 34 29 Percent of Days in Diesmts 60 59 60 60 Percent ofDays in Proeslrus 7 10 6 10 Mean Cycle Length (clays) 4.3 - ' Mean Precoital Interval (days) 3.4 3.3 28 31 Mating Index (*) 100.0 100.0 95.0 100.0 (umber copulated/cohoused} Fertility Index {*) 85.0 55.0 57.9 65.0 Gestation Length (days) 22.6 224 225 22.9 Number oflmplantatlon Sites 15.3 14 1 14.8 ", > Implantation Efficiency W SpermMotilily (%motile) 90.0 93.2 880 86.0 92.8 91.7 934 91.1 SpermMorpliology (1 normal) 98.3 98.3 98.9 97.7 Epididyma] Sperm(millions) 318.4 Per gramCauda 11802 979.296901062 1 Tesciculur Spermatids (millions) 1265 128.8 128.2 Per gramTestis 83.3 93.7 87.4 Table 4 Fi Generation Litters Dose (mg/kg/day) 0 25 100 500 N_______________ 17 11 H 13 Mean Numberof Puns/Litter Bom 14.3 Bom Alive 143 Day 4 Preculling 14.1 Day 4 Postculling 8.0 Day 7 8.0 Day 14 tO Day 21 tO 13.7 13.5 12.8 7.9 7.9 7.9 7.9 13.4 13.1 129 Survival (%) Sex Ratio(males) 0.48 Gestation Index* 100.0 Mean Born Alive 100.0 0-4 Day Viability 97.6 Lactation Index* 100.0 UtterSurvival" 1000 0.58 100.0 98.8 98.5 98.2 100.0 0.50 I00O 98.1 98.9 '<,.! 90.9 0 . 913 SA.7 828 Ut ->*<) Mean Pup Weiebulgrams) DayO 6.9 Day 4 Preculling Day4Postcuiling 6.3 10.8 Day 21 38.0 62.6 59.9 S8.6 Tabic 5 - Developmental Toxicity Study Results Dose (mg/kg/day): 153.1(20.3) 144.501.4) /JjJ(7M) 85J9.7) 5.50(0.28) 5.49(0.26) 5.40(0.39) 4.76(0.29) 6/22 rs affected/examined) 6/21 10/22 12/21 nettled ossification Discussion Exposure to die test substance produced reversible decrements in body weight and nutritional parameters and non-specific clinical signs o f toxicity. No evidence of neurotoxicity was observed. Reductions in grip strengds were attributed to lower body weight. Liver, thyroid, kidney, and red blood cells were identified os target organs, based on clinical and anatotnic pathology evaluations. Effects were generally mild and all adverse effects denxtnstrated reversibility, except clironic progressive nephropathy in females. The reduction in fertility index and mean number of implantation sites, in the absence a reduction in implantation efficiency (an indicator of in ulero post-implantation loss) suggests pre-implantation embryonic loss. Tlie reduction in pup viability and survival may be due to die postnatal manifestation of a developmental effect due to in ulero exposure, maternal factors (insufficient milk supply, neglect), or result from postnatal toxicity from lactational transfer to the nursing pups. In the developmental toxicity study, the test substance did not produce fetal malformations. There was no evidence of increased sensitivity of die fetus to die test j Conclusions NOEL for Subchronic Toxicity: The no-observed-effect level (NOEL) for males and females was 25 mg/kg/day, based on decrements in body weight and nutritional parameters, clinical signs of toxicity, and thyroid and kidney lustopathology, all observed at 100 mg/kg/day. NOEL for Reproductive Toxicity: Tiiere was no NOEL for the reproductive toxicity, parameters evaluated under the conditions of this study; this was based on effects at all dose levels on die fertility index in die P, generation NOEL for DevelopmentalToxicity: The maternal NOEL was 50 mg/kg/day. based on reduced maternal body weight and nutritional parameters. The fetal NOEL was 100 mg/kg/day. based on reduced fetal weight and increased fetal variations. No fetal malformations were observed. %Acknowledgements We wish to tiiank tiie following individuals for tlietr technical assistance; Linda A. Malley for neuropathology evaluations Primary Technician: NitaB Baker Poster Preparation. Maryunnc M. Wilford