TOXICITY EVALUATION OF PETROLEUM BLENDING STREAMS: REPRODUCTIVE AND DEVELOPMENTAL EFFECTS OF LIGHT CATALYTIC CRACKED NAPHTHA DISTILLATE IN RATS

A distillate of light catalytic cracked naphtha (CAS number 64741-55-5, LCCN-D), administered by inhalation, was tested for reproductive and developmental toxicity in Sprague-Dawley rats, following a modified OECD Guideline 421, Reproductive/ Developmental Toxicity Screening Protocol. LCCN-D was administered as a vapor, 6 h/ d, 7 d/wk at target concentrations of 0, 750, 2500 or 7500 ppm to female rats for approximately 7 wk from 2 wk prior to mating, during mating through gestational d 19, and to males beginning 2 wk prior to mating for 8 consecutive weeks. Dams and litters were sacrificed on postnatal d 4, and males were sacrificed within the following week. Parental systemic effects observed at the 7500 ppm exposure level were increased kidney weights and relative liver weights in males and increased spleen weights in highdose females. Livers and spleens from rats in the high-dose group were normal in appearance at necropsy. Increased kidney weights in high-dose males were indicative of male-rat-specific light hydrocarbon nephropathy. No test-related m icroscopic changes were observed in the reproductive organs or nasal turbinate tissues of either sex. Reproductive performance was unaffected by treatment with LCCN-D. Fertility index was 90% in all dose groups. There were no exposure-related differences in implantation sites and live pups per litter, and no gross abnormalities were observed. Pups born from treated dams showed comparable body weights and weight gains to controls. The viability index on postpartum d 4 was 97% ; the high-dose group had more male than female pups at birth and at d 4 postpartum. Under the conditions of this study, the no-observable-adverse-effect level (NOAEL) for exposure to light catalytic cracked naphtha distillate for parental toxicity was 2500 ppm and the NOAEL for reproductive performance and developmental toxicity was 7500 ppm.     

TOXICITY EVALUATION OF PETROLEUM BLENDING STREAMS: REPRODUCTIVE AND DEVELOPMENTAL EFFECTS OF LIGHT CATALYTIC REFORMED NAPHTHA DISTILLATE IN RATS

A distillate of light catalytic reformed naphtha (CAS number 64741-63-5, LCRN-D) administered by inhalation was tested for reproductive and developmental toxicity in Sprague-Dawley rats, following a modified OECD Guideline 421, Reproductive/Developmental Toxicity Screening protocol. LCRN-D was administered as a vapor, 6 h/d, 7 d/ wk at target concentrations of 0, 750, 2500 or 7500 ppm to female rats for approximately 6 wk from 2 wk prior to mating, during mating through gestational d 19, and to males beginning 2 wk prior to mating for approximately 7 consecutive weeks. Dams and litters were sacrificed on postnatal d 4 and males were sacrificed within the week after the last litter was necropsied. Parental systemic effects observed at the 7500 ppm exposure level included slightly lower body weights for males throughout the study. Increased kidney to body weight and increased liver to body weight ratio in male rats exposed to 7500 ppm LCRN-D may be related to slightly lower final mean body weights. Body and organ weight data for female rats in all exposure groups were comparable to controls. No test-material-related microscopic changes were observed in the reproductive organs or nasal turbinate tissue of either sex. Reproductive performance was unaffected by exposure to LCRN-D. The mating and fertility indices were 100% in all groups. There were no significant exposure-related differences in implantation sites or live pups per litter, and no gross abnormalities were observed in pups from treated dams. Pups born from LCRN-D-exposed dams showed comparable body weights and weight gain to control pups. The viability index on postpartum d 4 was 97%. Under conditions of this study, the no-observed-adverse-effect level (NOAEL) for exposure to light catalytic reformed naphtha distillate for parental effects was 2500 ppm and the NOAEL for reproductive and developmental toxicity was 7500 ppm.     

Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of light catalytic reformed naphtha distillate in rats

A distillate of light catalytic reformed naphtha (CAS number 64741-63-5, LCRN-D) administered by inhalation was tested for reproductive and developmental toxicity in Sprague-Dawley rats, following a modified OECD Guideline 421, Reproductive/Developmental Toxicity Screening protocol. LCRN-D was administered as a vapor, 6 h/d, 7 d/wk at target concentrations of 0, 750, 2500 or 7500 ppm to female rats for approximately 6 wk from 2 wk prior to mating, during mating through gestational d 19, and to males beginning 2 wk prior to mating for approximately 7 consecutive weeks. Dams and litters were sacrificed on postnatal d 4 and males were sacrificed within the week after the last litter was necropsied. Parental systemic effects observed at the 7500 ppm exposure level included slightly lower body weights for males throughout the study. Increased kidney to body weight and increased liver to body weight ratio in male rats exposed to 7500 ppm LCRN-D may be related to slightly lower final mean body weights. Body and organ weight data for female rats in all exposure groups were comparable to controls. No test-material-related microscopic changes were observed in the reproductive organs or nasal turbinate tissue of either sex. Reproductive performance was unaffected by exposure to LCRN-D. The mating and fertility indices were 100% in all groups. There were no significant exposure-related differences in implantation sites or live pups per litter, and no gross abnormalities were observed in pups from treated dams. Pups born from LCRN-D-exposed dams showed comparable body weights and weight gain to control pups. The viability index on postpartum d 4 was > or =97%. Under conditions of this study, the no-observed-adverse-effect level (NOAEL) for exposure to light catalytic reformed naphtha distillate for parental effects was 2500 ppm and the NOAEL for reproductive and developmental toxicity was 7500 ppm.     

Toxicity evaluation of petroleum blending streams: inhalation subchronic toxicity/neurotoxicity study of a light catalytic reformed naphtha distillate in rats

A 13-wk whole-body inhalation study was conducted with Sprague-Dawley CD rats (16/sex/group) exposed to a light catalytic reformed naphtha distillate (LCRN-D, CAS number 64741-63-5) at target concentrations of 0, 750, 2500, and 7500 ppm for 6 h/d, 5 d/wk. Sixteen rats per sex in the control and high-dose groups were maintained after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, throughout exposure and after the recovery period. Neuropathology was evaluated at termination. No test-related mortality or effects on physical signs, body weight, food consumption, or clinical chemistry were observed. In males exposed to 7500-ppm LCRN-D, a statistically significant decrease in white blood cell counts and lymphocyte counts was observed at the termination of exposure that was not present in animals after the 4-wk recovery period. However, mean corpuscular volume was slightly decreased in high-dose males after the recovery period. Statistically significant increases in kidney weights relative to body weights in 7500-ppm male rats correlated with microscopically observed hyaline droplet formation and renal tubule dilation, indicative of light hydrocarbon nephropathy, a condition in male rats that is not toxicologically significant for humans. Statistically significant decrease in absolute and relative spleen weights in 7500-ppm male rats correlated with decreases in hematologic parameters but had no microscopic correlate and was not observed in animals after 4 wk of recovery. This mild, reversible effect in white blood cell populations may relate to the presence of aromatics in the distillate. The only effect of LCRN-D on neurobehavioral parameters was significantly higher motor activity counts among high-dose (7500 ppm) males after the 4-wk recovery period, suggesting a possible delayed effect of LCRN-D. However, there was no evidence of hyperactivity or abnormal behavior from the functional observational battery evaluations, and there were no microscopic changes in neural tissue to support this observation. The no-observed-adverse-effects level (NOAEL) for LCRN-D was 2500 ppm for both subchronic toxicity and neurotoxicity. The no-observed-effects level (NOEL) was 750 ppm.     

TOXICITY EVALUATION OF PETROLEUM BLENDING STREAMS: INHALATION SUBCHRONIC TOXICITY/NEUROTOXICITY STUDY OF A LIGHT CATALYTIC REFORMED NAPHTHA DISTILLATE IN RATS

A 13-wk whole-body inhalation study was conducted with Sprague-Dawley CD rats (16/sex/group) exposed to a light catalytic reformed naphtha distillate (LCRN-D, CAS number 64741-63-5) at target concentrations of 0, 750, 2500, and 7500 ppm for 6 h/d, 5 d/wk. Sixteen rats per sex in the control and high-dose groups were maintained after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, throughout exposure and after the recovery period. Neuropathology was evaluated at termination. No test-related mortality or effects on physical signs, body weight, food consumption, or clinical chemistry were observed. In males exposed to 7500-ppm LCRN-D, a statistically significant decrease in white blood cell counts and lymphocyte counts was observed at the termination of exposure that was not present in animals after the 4-wk recovery period. However, mean corpuscular volume was slightly decreased in high-dose males after the recovery period. Statistically significant increases in kidney weights relative to body weights in 7500-ppm male rats correlated with microscopically observed hyaline droplet formation and renal tubule dilation, indicative of light hydrocarbon nephropathy, a condition in male rats that is not toxicologically significant for humans. Statistically significant decrease in absolute and relative spleen weights in 7500-ppm male rats correlated with decreases in hematologic parameters but had no microscopic correlate and was not observed in animals after 4 wk of recovery. This mild, reversible effect in white blood cell populations may relate to the presence of aromatics in the distillate. The only effect of LCRN-D on neurobehavioral parameters was significantly higher motor activity counts among high-dose (7500 ppm) males after the 4-wk recovery period, suggesting a possible delayed effect of LCRN-D. However, there was no evidence of hyperactivity or abnormal behavior from the functional observational battery evaluations, and there were no microscopic changes in neural tissue to support this observation. The no-observed-adverse-effects level (NOAEL) for LCRN-D was 2500 ppm for both subchronic toxicity and neurotoxicity. The no-observed-effects level (NOEL) was 750 ppm.     

TOXICITY EVALUATION OF PETROLEUM BLENDING STREAMS: REPRODUCTIVE AND DEVELOPMENTAL EFFECTS OF A DISTILLATE FROM LIGHT ALKYLATE NAPHTHA

A distillate of light alkylate naphtha ( CAS number 64741-66-8; LAN distillate) was administered via inhalation, 6 h/ d, 7 d/wk to 4 groups of Sprague-Dawley rats (10/sex/ dose) at target concentrations of 0 (filtered air control), 5, 12.5, or 25g/m 3 with the highest dose exceeding 60% of the lower explosive limit of LAND. Exposure began 2 wk prior to mating and continued throughout gestation until postnatal d 4 for females or for 8 consecutive weeks for males. No apparent clinical signs indicative of systemic toxicity were observed in the F and F animals of either sex. Inhalation exposure to 0 1 LAND up to and including the 25 g/ m 3 dose level had no effect on parental food consumption, body weights, absolute and relative organ weights, and reproductive indices. All groups had comparable delivery data and a fertility index 80% . Pups in all groups showed comparable birth weights, weight gain, a viability index ( postnatal d 4) for all groups of 97% , and no histopathological changes. In the dams, there were no significant differences in the mean numbers of corpora lutea, implantation sites, and resorptions recorded at necropsy. In the males, the only remarkable findings at necropsy were a small right epididymis and testis seen in one mid-dose male and an abscess on the right epididymis of a high-dose male. In both cases, the dams that had been bred to these males produced normal litters. There were no test material-related microscopic changes observed in the testes and epididymis of the F male rats or ovaries of the F0 0 female rats exposed to LAND. Under the conditions of this experiment, the noobserved-adverse-effect level (NOAEL) for LAND via inhalation in rats is established at greater than 24.7 g/ m 3 (analytical concentration) .     

Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats.

Bisphenol A (BPA) was evaluated at concentrations of 0, 0.015, 0.3, 4.5, 75, 750, and 7500 ppm ( approximately 0.001, 0.02, 0.3, 5, 50, and 500 mg/kg/day of BPA) administered in the diet ad libitum to 30 CD((R)) Sprague-Dawley rats/sex/dose for 3 offspring generations, 1 litter/generation, through F3 adults. Adult systemic toxicity at 750 and 7500 ppm in all generations included: reduced body weights and body weight gains, reduced absolute and increased relative weanling and adult organ weights (liver, kidneys, adrenals, spleen, pituitary, and brain), and female slight/mild renal and hepatic pathology at 7500 ppm. Reproductive organ histopathology and function were unaffected. Ovarian weights as well as total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD). Mating, fertility, gestational indices; ovarian primordial follicle counts; estrous cyclicity; precoital interval; gestational length; offspring sex ratios; postnatal survival; nipple/areolae retention in preweanling males; epididymal sperm number, motility, morphology; daily sperm production (DSP), and efficiency of DSP were all unaffected. At 7500 ppm, vaginal patency (VP) and preputial separation (PPS) were delayed in F1, F2, and F3 offspring, associated with reduced body weights. Anogenital distance (AGD) on PND 0 was unaffected for F2 and F3 males and F3 females (F2 female AGD was increased at some doses, not at 7500 ppm, and was considered not biologically or toxicologically relevant). Adult systemic no observed adverse effect level (NOAEL) = 75 ppm (5 mg/kg/day); reproductive and postnatal NOAELs = 750 ppm (50 mg/kg/day). There were no treatment-related effects in the low-dose region (0.001-5 mg/kg/day) on any parameters and no evidence of nonmonotonic dose-response curves across generations for either sex. BPA should not be considered a selective reproductive toxicant, based on the results of this study.     

Tetrahydrofuran: two-generation reproduction toxicity in Wistar rats by continuous administration in the drinking water.

In a two-generation reproduction toxicity study, 25 male and 25 female Wistar rats per dose group and generation were exposed continuously to tetrahydrofuran in the drinking water for at least 70 days prior to and during mating, gestation, parturition and lactation to weaning, at concentrations of 0, 1000, 3000 or 9000 ppm (approximately 100, 300 and 700 mg/kg/day in males and females premating, 100, 300 and 800 mg/kg/day in females during gestation, and 200, 500 and 1300 mg/kg/day in females during lactation) through two successive generations. In both generations and sexes, water consumption was dose-relatedly reduced at all doses; food consumption and body weight were reduced at 9000 ppm. Necropsy kidney weights were increased in 9000 ppm F0 males. Pup body weight gain during lactation was reduced in both generations (F1 and F2 pups) and eye opening delayed in the first generation (F1 pups) at 9000 ppm; there were no treatment-related malformations. The NOAEL of tetrahydrofuran in drinking water is 9000 ppm for parental fertility and reproductive performance, and 3000 ppm for systemic parental and developmental toxicity.     

Evaluation of the subchronic and reproductive effects of a series of chlorinated propanes in the rat. II. Toxicity of 1,2,2,3-tetrachloropropane and 1,1,2,2,3-pentachloropropane

Comparative subchronic and reproductive toxicity studies by inhalation exposure were conducted with 1,2,2,3-tetrachloropropane (TECP) and 1,1,2,2,3-pentachloropropane (PCP). Groups of 5 male and 5 female CD rats were exposed 6 h/d, 5 d/wk for 4 wk to either TECP or PCP at target concentrations of 0, 100, 300, 600, or 900 ppm (single exposure only). Deaths occurred at and above 300 ppm PCP and 600 ppm TECP. Significant irritation of mucosal tissue was attributed to vapors of TECP and PCP. Lower group mean body weights of surviving male rats of all groups were observed after 4 wk of exposure to TECP. Liver, kidney, and ovary weights were affected by PCP treatment. Groups of 15 male and 15 female CD rats were exposed to target vapors of 0-50 ppm TECP or PCP for 6 h/d, 5 d/wk for 13 wk. Irritation about the nose and eyes was observed at all TECP, but not with PCP, test levels. Liver weights were increased at and above 5 ppm in all groups of TECP-treated males. Kidney weights were also elevated in male rats at 15 and 50 ppm PCP and females from the 50 ppm PCP group. Degenerative changes in these two corresponding tissues were seen at and above 5 ppm TECP and PCP. A treatment level of 1.5 ppm TECP or PCP was without systemic effect clinically or pathologically. Groups of 10 male and 20 female CD rats were exposed 6 h/d, 5 d/wk for a premating, mating, or gestation (F only) period to target levels of 0, 5, or 15 ppm TECP or PCP. No treatment-related effects were seen in the PCP study. While mating performance overall was poor in the TECP study, female mating performance of the 15 ppm TECP-exposed group appeared lower than control. In a follow-up study with TECP using the same study design, no effects on female or male fertility or fecundity or on offspring were seen up to 1.5 ppm TECP.     

An oral two-generation reproductive toxicity study of S-111-S-WB in rats

S-111-S-WB (CAS No. 72968-38-8), a mixture of perfluoro fatty acid ammonium salts, was administered daily via oral gavage to 30 Crl:CD(SD) rats/sex/group at 0.025, 0.125 and 0.6mg/(kgday) over two generations to assess potential reproductive toxicity. Reproductive performance, mean litter size, pup survival and pup weights were unaffected. Lower mean body weights were observed in 0.6mg/(kgday) group F(0) and F(1) males. Higher liver weights, correlating to hepatocellular hypertrophy in the 0.6mg/kg group, were noted for parental males in the 0.125 and 0.6mg/(kgday) groups, parental females in the 0.6mg/(kgday) group and F(1) pups in the 0.125 and 0.6mg/(kgday) groups. Higher kidney weights, correlating to renal tubule hypertrophy in the 0.6mg/kg group, were observed for parental males and females in the 0.125 and 0.6mg/(kgday) groups. Systemic exposure (measured only in females) to total S-111-S-WB was proportional to dose following 9 weeks of daily administration on the gestation day 19. Total S-111-S-WB concentration in the serum of male and female pups was 1.2-1.4-fold higher than in the dams 2h following administration to the dams on lactation day 13. A dosage level of 0.6mg/(kgday) was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive function. A dosage level of less than 0.025mg/(kgday) was considered to be the NOAEL for F(0) and F(1) parental systemic toxicity based on microscopic hepatic findings in the males of all test article groups, and a dosage level of 0.025mg/(kgday) was considered to be the NOAEL for neonatal toxicity based on higher liver weights in the F(1) and F(2) pups at 0.125mg/(kgday) and higher.     

Reproductive toxicity screen of trifluoroiodomethane (CF(3)I) in Sprague-Dawley rats

CF(3)I is being considered by the U.S. Air Force as a replacement for Halon 1301 for fire-extinguishing requirements in unoccupied spaces. The purpose of this study was to determine and evaluate the potential for CF(3)I to produce reproductive toxicity and to provide additional information on the effect of CF(3)I exposure on the thyroid. Groups of 16 male and 16 female rats were exposed (6 h/day) to CF(3)I vapor at concentrations of 0 (control), 0.2, 0.7, and 2.0% using whole-body inhalation chambers. Prior to mating, rats were exposed to CF(3)I for 4 wk (5 days/wk). Exposures were 7 days/wk during the periods of mating (2 wk), gestation (3 wk), and lactation (3 wk). First-generation pups were not exposed to CF(3)I vapor. In parental animals, there were no clinical signs of toxicity except for a minimal decrease in mean body weight in female rats at 2.0% CF(3)I. At necropsy, gross findings, mean serum chemistry levels, mean hematology values, mean bone marrow micronuclei scores, and mean organ weights were similar for all exposure groups, including the air control group. Statistically significant differences did not show a pattern and/or were considered incidental. There were no treatment-related microscopic tissue findings, including the thyroid organ. Analysis of reproductive indices and parameters indicates CF(3)I is not a reproductive toxicant. Results of serum thyroid hormone levels (e.g., T(3), T(4), rT(3), and TSH), showed concentration-related increases in TSH, T(4), and rT(3). T(3) levels were decreased. First-generation pup survival and mean body weights were similar in all exposure groups, including the control. Exposure of 2.0% CF(3)I vapor for approximately 14 wk produced minimal general toxicity and no reproductive toxicity in Sprague-Dawley rats. On the basis of reproductive indices and parameters, the NOAEL for this study is 2.0% CF(3)I.     

A two-generation reproductive toxicity study of decamethylcyclopentasiloxane (D5) in rats exposed by whole-body vapor inhalation

This two-generation reproduction study assessed the reproductive hazard potential of decamethylcyclopentasiloxane (D(5)). Sprague-Dawley rats (30/sex/group) were exposed by whole-body vapor inhalation to a target concentration of 30, 70, or 160 ppm D(5) or filtered air for 6h/day. Exposures for the F(0) and F(1) generations started at least 70 days prior to mating and lasted through weaning of the respective pups on postnatal day (PND) 21. Female exposures were interrupted from gestation day (GD) 21 through PND 4 to allow for parturition and to permit continuous maternal care for the early neonates. F(2) pups were not directly exposed to D(5). There were no exposure-related mortalities, clinical signs of toxicity, or effects on body weight or food consumption. There were no treatment-related gross findings or organ weight effects at the F(0) and F(1) necropsies. Other than minimal alveolar histiocytosis in all exposed groups, there were no noteworthy microscopic findings. Reproductive parameters (number of days between pairing and mating, mating and fertility indices, gestation length, and parturition), spermatogenic parameters and ovarian primordial follicle counts and numbers of corpora lutea in the F(0) and F(1) parental animals were not significantly changed between treated and control groups. Mean live litter sizes, number of pups born, sex ratios, pup body weights, postnatal pup survival and general physical condition of offspring in each generation were not affected. The slight, but statistically significant, increase in the mean F(1) male pup AGD in the 160 ppm group was not considered to be related to treatment. Vaginal patency and balanopreputial separation were unchanged compared to controls. Thus, the No-Observed-Adverse-Effect-Level (NOAEL) for parental and reproductive toxicity was determined to be 160 ppm D(5).     

Developmental and reproductive toxicity evaluation of toluene vapor in the rat. I. Reproductive toxicity

The reproductive toxicity of toluene was evaluated in a 2-generation test in which male and female Sprague–Dawley rats, parental (F0) and first generation (F1), were exposed to toluene via whole body inhalation, 6 h/day, 7 days/week for 80 days premating and 15 days of mating at concentrations of 0, 100, 500 and 2000 ppm (0, 375, 1875 and 7500 mg/m³). Toluene was administered at 2000 ppm to both sexes, or to females or males only to be mated with untreated partners. Pregnant females at all dose levels were exposed from gestation day (GD) 1–20 and lactation day (LD) 5–21. At LD5, females were removed from their litters for daily exposure and returned when 6 h of exposure was completed. F1 pups selected to produce the F2 generation were treated for 80 days beginning immediately after weaning (LD21) and initially mated at a minimum of 100 days of age. F2 pups were not exposed to toluene by inhalation.

Toluene exposure did not induce adverse effects on fertility, reproductive performance, or maternal/pup behaviors during the lactation period in males and females of the parental or first generation, but did inhibit growth in F1 and F2 offspring in the 2000 ppm (both sexes treated) and 2000 ppm (females only treated) groups. Caesarean section of selected 2000 ppm (both sexes treated) dams at GD20 showed reduced fetal body weight and skeletal variations. Exposure to toluene caused decreased pup weights throughout lactation in F1 and F2 2000 ppm (both sexes treated), and 2000 ppm (females only treated) groups. Exposure at 2000 ppm to male parents only did not induce similar weight inhibition in offspring. The toluene offspring NOAEL is 500 ppm in groups in which maternal animals were exposed, and 2000 ppm for male only treated groups.     

Two-generation reproductive toxicity study of inhaled toluene diisocyanate vapor in CD rats.

Twenty-eight 42-day-old pups/sex/group (F0) were exposed to toluene diisocyanate vapor (TDI; 80% 2,4-TDI, 20% 2,6-TDI) by inhalation at 0.0, 0.02, 0.08, or 0.3 ppm, 6 h/day, 5 days/week, for 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapor, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.     

Two-generation reproduction and developmental neurotoxicity study with sodium chlorite in the rat

The potential for sodium chlorite to produce reproductive toxicity, developmental neurotoxicity and alterations in hematology and thyroid hormones was evaluated in Sprague-Dawley rats administered sodium chlorite in the drinking water continuously for two generations. The F(0) generation animals (30 of each gender per group) and F(1) generation animals (25 of each gender per group) selected to rear the F(2) generation were allowed free access to drinking water containing 0, 35, 70 or 300 ppm sodium chlorite for a 10-week prebreed period, through mating for males and through mating, gestation and lactation for females. These drinking water concentrations corresponded to sodium chlorite doses of approximately 4, 8 and 30 mg kg(-1) day(-1) for males and 5, 10 and 39 mg kg(-1) day(-1) for females, respectively. Evaluations included standard reproductive and postnatal indices, sperm morphology and motility, estrous cyclicity, a functional observational battery, motor activity, auditory startle, swim maze, hematology, serum thyroid hormone analyses and histopathology of reproductive and nervous system tissues. Sodium chlorite resulted in a decrease in water consumption in all groups and a decrease in food consumption and body weights in the 70 and 300 ppm groups. There was no evidence of reproductive toxicity. Pup body weight was decreased in the 300 ppm group and small delays were observed in the time to preputial separation and vaginal opening. Mild anemia and mild methemoglobinemia were observed for animals in the 300 ppm group. Thyroid hormone levels were not affected by treatment. Changes to the nervous system were limited to small decreases in amplitude of auditory startle response for postnatal day (PND) 25 pups in the 70 and 300 ppm groups and a small decrease in absolute brain weight for PND 11 pups in the 300 ppm group. These effects were considered to be of questionable neurotoxicological significance. Based on the results of this study, the no-observed-effect level (NOEL) for effects on reproduction and thyroid hormones is 300 ppm. The no-observed-adverse-effect levels (NOAEL) for hematological toxicity and neurotoxicity are considered to be 70 and 300 ppm, respectively.     

Oral (drinking water) two-generation reproductive toxicity study of bromodichloromethane (BDCM) in rats

Bromodichloromethane (BDCM) was tested for reproductive toxicity in a two-generation study in CRL SD rats. Thirty rats/sex/ group/generation were continuously provided BDCM in drinking water at 0 (control carrier, reverse osmosis membrane-processed water), 50,150, and 450 ppm (0, 4.1 to 12.6, 11.6 to 40.2, and 29.5 to 109.0 mg/kg/day, respectively). Adult human intake approximates 0.8 microg/kg/day (0.0008 mg/kg/day). P and F1 rats were observed for general toxicity (viability, clinical signs, water and feed consumption, body weights, organ weights [also three weanling Fl and F2 pups/sex/litter], histopathology [10/sex, 0- and 450-ppm exposure groups]) and reproduction (mating, fertility, abortions, premature deliveries, durations of gestation, litter sizes, sex ratios, viabilities, maternal behaviors, reproductive organ weights [also three weanling Fl and F2 pups/sex/ litter], sperm parameters, and implantations. F1 rats were evaluated for age at vaginal patency or preputial separation. Ten P and F1 rats/sex from the 0- and 450-ppm exposure groups and rats at 50 and 150 ppm with reduced fertility were evaluated for histopathology (gross lesions, testes, intact epididymis, all F1 dams for number of primordial follicles). Developmental parameters in offspring included implantation and pup numbers, sexes, viabilities, body weights, gross external alterations, and reproductive parameters (Fl adults). Toxicologically important, statistically significant effects at 150 and/or 450 ppm included mortality and clinical signs associated with reduced absolute and relative water consumption, reduced body weights and weight gains, and reduced absolute and relative feed consumption (P and F1 rats). Significantly reduced body weights at 150 and 450 ppm were associated with reduced organ weights and increased organ weight ratios (% body and/or brain weight). Histopathology did not identify abnormalities. Small delays in sexual maturation (preputial separation, vaginal patency) and more Fl rats with prolonged diestrus were also attributable to severely reduced pup body weights. Mating, fertility, sperm parameters, and primordial ovarian follicular counts were unaffected. The no-observable-adverse-effect level (NOAEL) and the reproductive and developmental NOAELs for BDCM were at least 50 ppm (4.1 to 12.6 mg/kg/day), 5125 to 15,750 times the human adult exposure level, if delayed sexual maturational associated with severely reduced body weights is considered reproductive toxicity. If considered general toxicity, reproductive and developmental NOAELs for BDCM are greater than 450 ppm (29.5 to 109.0 mg/kg/day), or 36,875 to 136,250 times the human adult exposure level. Regardless, these data indicate that BDCM should not be identified as a risk to human reproductive performance or development of human conceptuses.     

Two-generation reproductive toxicity study of inhaled acrylonitrile vapors in Crl:CD(SD) rats

To assess the effects of acrylonitrile (AN) exposure on reproduction, Sprague-Dawley rats (25/sex/group) were exposed to vapor atmospheres of AN via whole-body inhalation at concentrations of 0, 5, 15, 45 (two offspring generations) and 90 ppm (one offspring generation), 6 h daily, 1 litter/generation, through F2 weanlings on postnatal day 28. After approximately 3 weeks of direct exposure following weaning, exposure of the F1 animals at 90 ppm was terminated due to excessive systemic toxicity in the males. There were no exposure-related mortalities in adult animals, no functional effects on reproduction or effects on reproductive organs, and no evidence of cumulative toxicity or of enhanced toxicity in pregnant and lactating dams or in developing animals. Adult systemic toxicity was limited to body weight and/or food consumption deficits in both sexes and generations (greater in males) at 45 and 90 ppm and increased liver weights in the 90 ppm F0 males and females and 45 ppm F1 males. Neonatal toxicity was expressed by F1 offspring weight decrements at 90 ppm. Clinical signs of local irritation during and immediately following exposure were observed at 90 ppm. Microscopic lesions of the rostral nasal epithelium, representing local site-of-contact irritation, were observed in some animals at 5 to 45 ppm. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity over two generations and neonatal toxicity of AN administered to rats via whole-body inhalation was 45 ppm. The NOAEL for reproduction was 90 ppm for the first generation. The NOAEL for parental systemic toxicity was 15 ppm.     

Comparative reprotoxicity of three oximes

One-generation reproductive toxicity studies have been conducted on the following three oximes: acetaldehyde oxime (AAO), aldecarb oxime (ADO), and methyl isobutyl ketoxime (MIBKO). The studies followed the OECD 415 guideline (One-Generation Reproduction Toxicity Study), with a few modifications. Rats were exposed to the test material for 10 weeks prior to mating and 2 weeks of mating. Males were killed following mating, and females were continuously exposed through gestation and lactation. For MIBKO, the F1 generation was exposed from weaning until approximately 7 weeks of age to include when the vaginal opening occurred in females or when balanopreputial separation occurred in males. With the exception of an increased number of stillbirths in the ADO high-dose-group animals, no adverse effects were observed in any of the reproductive or litter parameters or in the F1 pups. Toxicity to the F0 animals included signs of hemolytic anemia, along with compensatory extramedullary hematopoiesis and hemosiderosis of the spleen. This occurred for all three test materials. For AAO, the no-observed-adverse-effect level (NOAEL) for the F0 generation was considered to be less than 5?mg/kg/day, based on decreased mean corpuscular hemoglobin concentration values and histological changes in the spleen. The NOAEL for the F1 generation and reproductive toxicity was considered to be 50?mg/kg/day, the highest dose tested. For ADO, the NOAEL for parental toxicity was considered to be less than 5?mg/kg/day, based on the histological changes observed in the livers of females in all groups. The NOAEL for reproductive toxicity and the F1 generation was considered to be 25?mg/kg/day, based on the higher number of stillborn pups in the high-dose group. For MIBKO, the NOAEL for parental toxicity was considered to be 30?mg/kg/day, based on the histological effects on the spleen. The NOAEL for the F1 generation and reproductive toxicity was 100?mg/kg/day, the highest dose tested.     

TOXICITY EVALUATION OF PETROLEUM BLENDING STREAMS: INHALATION SUBCHRONIC TOXICITY/NEUROTOXICITY STUDY OF A LIGHT ALKYLATE NAPHTHA DISTILLATE IN RATS

A 13-wk inhalation study was conducted with Sprague-Dawley CD rats ( 12/sex/ group) were exposed by inhalation for 13 weeks to a light alkylate naphtha distillate (LAND-2, C-C ; average molecular weight 89.2) at actual average concentrations of 0 (room 4 10 air), 668, 2220, or 6646 ppm, 6 h/d, 5 d/wk; 12 additional rats/sex in the control and high dose groups were held after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, during 5, 9, and 14 wk of the study, and after the 4-wk recovery period. Wholebody perfusion and microscopic examination of selected organs and nervous tissue from the control and high dose rats were conducted at the end of exposure. No testrelated mortality or effects on physical signs, body weight, or food consumption were observed. Statistically significant increases in absolute and relative kidney weights in high-exposure males correlated with microscopically observed hyaline droplet formation and renal nephropathy, effects in male rats that are not toxicologically significant for humans. Increased liver weights in both sexes at the highest dose had no microscopic correlate and appeared reversible after the 4-wk recovery period. Exposure to LAND-2 at any dose did not produce neurotoxicity measured by MA, FOB, or neuropathology. The no-observed-effects level (NOEL) for LAND-2 was 2220 ppm for subchronic toxicity and 6646 ppm for neurotoxicity.     

Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats

Butyl benzyl phthalate (BBP) was administered in the diet at 0, 750, 3750, and 11,250 ppm ad libitum to 30 rats per sex per dose for two offspring generations, one litter/breeding pair/generation, through weaning of F2 litters. Adult F0 systemic toxicity and adult F1 systemic and reproductive toxicity were present at 11,250 ppm (750 mg/kg per day). At 11,250 ppm, there were reduced F1 and F2 male anogenital distance (AGD) and body weights/litter during lactation, delayed acquisition of puberty in F1 males and females, retention of nipples and areolae in F1 and F2 males, and male reproductive system malformations. At 3750 ppm (250 mg/kg per day), only reduced F1 and F2 offspring male AGD was present. There were no effects on parents or offspring at 750 ppm (50 mg/kg per day). The F1 parental systemic and reproductive toxicity no observable adverse effect level (NOAEL) was 3750 ppm. The offspring toxicity NOAEL was 3750 ppm. The offspring toxicity no observable effect level (NOEL) was 750 ppm, based on the presence of reduced AGD in F1 and F2 males at birth at 3750 ppm, but no effects on reproductive development, structures, or functions.