Reproductive and neurobehavioural toxicity study of tartrazine administered to mice in the diet.

Tartrazine was given in the diet to provide levels of 0% (control), 0.05%, 0.15%, and 0.45% (approximately 83, 259, 773 mg/kg/day, respectively) from five weeks of age of the F0 generation to nine weeks of age of the F1 generation in mice, and selected reproductive and neurobehavioural parameters were measured. In movement activity of exploratory behaviour in the F0 generation, number of vertical activity was significantly increased in the middle-dose group in males. There were no adverse effects of tartrazine on either litter size, litter weight and sex ratio at birth. The average body weight of male offspring was significantly increased in the high-dose group and that of female offspring was significantly increased in the middle-dose group at birth. In behavioural developmental parameters, surface righting at PND 4 was significantly accelerated in the high-dose group in male offspring, and those effects were significantly dose-related in a trend test (P<0.01). Cliff avoidance at PND 7 was significantly accelerated in the middle-dose group in male offspring. Negative geotaxis at PND 4 was significantly delayed in the high-dose group in female offspring. Other variables measured showed no significant adverse effects in either sex in the lactation period. In movement activity of exploratory behaviour in the F1 generation, number of movement showed a significant tendency to be affected in the treatment groups in male offspring in a trend test (P<0.05). The dose level of tartrazine in the present study produced a few adverse effects in neurobehavioural parameters during the lactation period in mice. Nevertheless, the high-dose level were in excess of the ADI of tartrazine (0-7.5 mg/kgbw), and the actual dietary intake of tartrazine is presumed to be much lower. It would therefore appear that the levels of actual dietary intake of tartrazine is unlikely to produce any adverse effects in humans.     

Reproductive and neurobehavioural toxicity study of bis(2-ethylhexyl) phthalate (DEHP) administered to mice in the diet.

Bis(2-ethylhexyl) phthalate (DEHP) was given in the diet to provide levels of 0 (control), 0.01, 0.03, and 0.09% from 5 weeks of age of the F0 generation to 9 weeks of age of the F1 generation in mice, and selected reproductive and neurobehavioural parameters were measured. There were no adverse effects of DEHP on either litter size, litter weight or sex ratio at birth. The average body weight of male offspring was significantly decreased in the low-dose group at birth. In behavioural developmental parameters, surface righting at PND 4 was significantly delayed in the low- and middle-dose group in female offspring, and those effects were slightly dose related (P < 0.05). Surface righting at PND 7 was significantly depressed in the high-dose group of male offspring, and those effects were significantly dose related (P < 0.001). That of female offspring was significantly depressed in the low-dose group. The dose level of DEHP in the present study produced few adverse effects in reproductive and neurobehavioural parameters in mice.     

Reproductive and neurobehavioural toxicity study of Ponceau 4R administered to mice in the diet.

Ponceau 4R was given to mice in the diet at levels of 0 (control), 0.12%, 0.24%, and 0.48% from 5 weeks of age of the F(0) generation to 9 weeks of age of the F(1) generation, and selected reproductive and neurobehavioural parameters were measured. There was no adverse effect of Ponceau 4R on litter size, litter weight or sex ratio at birth. The average body weight of male and female offspring was increased significantly in the high-dose group at postnatal days (PNDs) 0, 4 and 21. In behavioural developmental parameters, surface righting at PND 4 was affected significantly in the high-dose group in male offspring. Other variables measured showed no consistently significant adverse effect on either sex in the lactation period. In multiple water T-maze performance in the F(1) generation, the time taken was significantly longer than the control in the middle-dose and high-dose groups in males, and those effects were significantly dose-related (P<0.01). The dose level of Ponceau 4R in the present study produced no adverse effect on reproduction, and a few adverse effects on neurobehavioural parameters in mice. The non-observed adverse effect level (NOAEL) was presumed to be 0.12% in the diet (approximately 205mg/kg per day) for maze learning by males in the F(1) generation. Nevertheless, the middle-dose and high-dose levels were in excess of the acceptable daily intake (ADI) of Ponceau 4R (0-4.0mg/kg body weight), and the actual dietary intake of Ponceau 4R in humans is presumed to be much lower. It would appear, therefore, that the level of dietary intake of Ponceau 4R is unlikely to produce any adverse reproductive or neurobehavioural effect in humans.     

Reproductive and neurobehavioural effects of bis(2-ethylhexyl) phthalate (DEHP) in a cross-mating toxicity study of mice.

Bis(2-ethylhexyl) phthalate (DEHP) was given in the diet to provide levels of 0% (C) or 0.03% (T) from 5 weeks of age of the F0 generation to 9 weeks of age of the F1 generation in mice. At 9 weeks of age, each female was paired with one male from the same or another treatment groups (cross-mating: C/C, T/C, C/T, T/T), for a period of 5 days. The selected reproductive and neurobehavioural parameters were measured. There were no adverse effects of DEHP on either litter size, litter weight and sex ratio at birth. The average body weight of female offspring was significantly affected in group IV (T/T) at PND 14. In behavioural developmental parameters, swimming direction at PND 4 was significantly accelerated in group III (C/T) in female offspring. In movement activity of exploratory behaviour at 3 weeks of age, number of movement of male offspring was significantly affected in group IV (T/T). The dose level of DEHP in the present cross-mating study produced few adverse effects in reproductive and neurobehavioural parameters in mice.     

Reproductive and neurobehavioural effects of phloxine administered to mice

The colour additive phloxine was given in the diet to provide dietary levels of 0 (control), 0.1, 0.3 and 0.9%, from 5 wk of age of the F₀ generation to 8 wk of age of the F₁ generation in mice, and selected reproductive and neurobehavioural parameters were measured. There was little effect of phloxine on either litter size or weight, or sex ratio, whereas the body weight of the pups in the lactation period was significantly increased in all treatment groups. Among the neurobehavioural parameters measured, surface righting at postnatal day 4 of male pups was significantly reduced in all treatment groups. Some parameters of the motor activity of pups at 3 wk of age differed from those of the controls; in particular, the average speed of movement male pups was significantly reduced in all treatment groups. The dose levels of phloxine in this study produced a few adverse effects in reproductive and neurobehavioural parameters in mice.     

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.     

Effects of bis(2-ethylhexyl) phthalate (DEHP) on secondary sex ratio of mice in a cross-mating study.

Bis(2-ethylhexyl) phthalate (DEHP) was given in the diet to provide levels of 0 (C) or 0.03% (T) from 5 weeks of age of the F(0) generation to birth of the F(1) generation in mice. At 9 weeks of age, each female was paired with one male from the same or another treatment groups (cross-mating: C/C, T/C, C/T, T/T), for a period of 5 days. The males were removed from females after 5 days, and the females were allowed to carry their litters to term and deliver. There were no adverse effects of DEHP on either litter size, litter weight and sex ratio at birth. The average body weight of male offspring was significantly increased in all treatment groups at birth. There were no adverse effects of DEHP on female offspring weight at birth. The dose level of DEHP in the present study produced no adverse effects on secondary sex ratio, which meant sex ratio at birth, in mice.     

Two-generation reproductive toxicity evaluation of dietary 17beta-estradiol (E2; CAS No. 50-28-2) in CD-1 (Swiss) mice.

No information exists on reproductive/developmental effects in mice exposed to dietary 17beta-estradiol (E2) over multiple generations. Therefore, under OECD Test Guideline 416 with enhancements, CD-1 mice (F0 generation, 25 mice/sex/group) were exposed to dietary E2 at 0, 0.001, 0.005, 0.05, 0.15, or 0.5 ppm ( approximately 0, 0.2, 1, 10, 30, or 100 mug E2/kg body weight/day) for 8 weeks prebreed, 2 weeks mating, approximately 3 weeks gestation, and 3 weeks lactation. At weaning, selected F1 offspring (F1 parents; 25/sex/group) and extra retained F1 males (one per litter) were exposed to the same dietary concentrations and durations as the F0 generation; study termination occurred at F2 weaning; F1/F2 weanlings (up to three per sex per litter) were necropsied with organs weighed. At 0.5 ppm, effects were increased F1/F2 perinatal loss, prolonged F0/F1 gestational length, reduced numbers of F2 (but not F1) litters/group, reduced F1/F2 litter sizes, accelerated vaginal patency (VP) and delayed preputial separation (PPS), increased uterus + cervix + vagina weights (UCVW) in F0/F1 adults and F1/F2 weanlings, and decreased testes and epididymides weights (TEW) in F1/F2 weanlings. At 0.15 ppm, effects were increased UCVW in F0/F1 adults and F1/F2 weanlings, accelerated VP, delayed PPS, and reduced TEW in F1/F2 weanlings. At 0.05 ppm, UCVW were increased in F1/F2 weanlings, and PPS was delayed only in extra retained F1 males. There were no biologically significant or treatment-related effects on F0/F1 parental body weights, feed consumption, or clinical observations, or on F0/F1 estrous cyclicity, F0/F1 andrology, or F1/F2 anogenital distance at any dose. The no observable effect level was 0.005 ppm E2 ( approximately 1 mug/kg/day). Therefore, the mouse model is sensitive to E2 by oral administration, with effects on reproductive development at doses of 10- 100 mug/kg/day.     

Reproductive and neurobehavioural effects in three-generation toxicity study of piperonyl butoxide administered to mice

Piperonyl butoxide (PB) was administered continuously to mice from 5 weeks of age in the F₀ generation to weaning of the F₂ generation. PB was administered in the diet at levels of 0 (control), 0.1, 0.2, 0.4 and 0.8%. Selected reproductive, developmental and behavioural parameters were measured. Litter size and litter weight were reduced in higher-dosed groups, and the body weight of the pups in the lactation period was reduced in dosed pups in each generation. The survival index at postnatal day 21 of the group receiving 0.8% PB was reduced in each generation. The developmental and behavioural parameters in the lactation period were little different from those of the controls, apart from olfactory orientation in the F₁ generation. However, in the F₂ generation mice, surface righting, cliff avoidance and olfactory orientation were adversely affected in treatment groups. The results suggest that PB had adverse effects on reproductive, developmental and behavioural parameters of mice, with increasing effects in subsequent generations of offspring.     

Effects of amaranth on F1 generation mice.

The color additive, amaranth, was given in the diet to provide dietary levels of 0 (control), 0.03, 0.09 and 0.27%, from 5 weeks of age in F₀ generation mice to 9 weeks of age in F₁ generation mice, and some reproductive, developmental and behavioral parameters were measured. There was no effect on the parameters of litters, litter size, pup weight and litter weight. The body weight of pups during the lactation period in the treatment groups increased less significantly, and the survival index at postnatal day (PND) 21 of the amaranth 0.27% group was reduced. Developmental parameters, direction of swimming on PND 4 in male pups and olfactory orientation in each sex were significantly reduced in the treatment groups. The dose levels of amaranth in this study influenced some reproductive, developmental and behavioral parameters in mice.     

Effects of piperonyl butoxide on F1 generation mice.

Piperonyl butoxide (PB), used in Japan as a pesticide synergist and food additive, was administered to mice from 5 weeks of age in the F0 generation to 9 weeks of age in the F1 generation, in the diet at levels of 0 (control), 0.15, 0.30 and 0.60%, and some reproductive, developmental and behavioral parameters were measured. Some parameters of open field activity were reduced in the treatment groups; in particular, ambulation and rearing were significantly reduced in F0 generation male mice and in 3-week-old F1 generation male mice. The weight of the pups was significantly reduced and litter weight tended to be reduced in the treatment groups. Body weight of dosed pups was reduced in the lactation period. Of the developmental parameters, olfactory orientation was significantly reduced as compared to controls. The dose levels of PB in this study, therefore, had an effect on some reproductive, developmental and behavioral parameters in mice.     

Effects of tartrazine on exploratory behavior in a three-generation toxicity study in mice

Tartrazine was given to mice in the diet at levels of 0 (control), 0.05%, 0.15%, and 0.45% from 5 weeks of age of the F(0) generation to 9 weeks of age of the F(2) generation, and selected reproductive and neurobehavioral parameters were measured. In the F(1) generation, the development of swimming direction at postnatal day (PND) 7 was accelerated significantly in male offspring in a dose-related manner. Surface righting at PND 7 was affected significantly in female offspring in dose-related manner. Several variables in exploratory behavior showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age. In the F(2) generation, the development of swimming direction at PND 7 was accelerated significantly in the high-dosed group in male offspring. Time taken of olfactory orientation at PND 14 was accelerated significantly in male offspring in a dose-related manner. Several variables in exploratory behavior showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age, and in males at 8 weeks of age. The dose levels of tartrazine in the present study produced a few adverse effects on neurobehavioral parameters throughout generations in mice.     

Reproductive toxicity of MCPA (4-chloro-2-methylphenoxyacetic acid) in the rat

The reproductive effects of the administration of 4-chloro-2-methylphenoxyacetic acid (MCPA) to rats were evaluated through two generations, from prior to mating, throughout mating, to gestation and lactation. MCPA was administered in the diet at doses of 0, 50, 150, or 450 ppm to 25 male and female immature rats (F0 parents) for 10 weeks. F0 parents were then mated to produce a first litter (F1a), retained only until weaning, and were subsequently remated to produce a second litter, F1b. Groups of male and female F1b animals were then dosed as were their parents for 10 weeks postweaning, and the breeding was repeated to produce F2a and F2b animals. The study concluded with the F2b weanlings. MCPA was administered continuously throughout the study. Only minimal, non-treatment-related observations were noted, which included rhinorrhea (in both treated and control animals in the F0 generation) and malocclusion and alopecia (in both the F0 and F1b generations). There were no consistent dose-related effects on reproductive function for parental animals of either sex in either generation. Statistically significant differences were noted in body weights and body weight gains in the 450-ppm dose group for both male and female pups in F2a and F2b. There were no treatment-related macroscopic or microscopic observations noted for any animal in this study. The no-observable-effect level (NOEL) for reproductive function in rats administered MCPA continuously for two successive generations was determined to be 450 ppm (approximately 22 mg/kg/day). The NOEL for general systemic toxicity, based on body weight effects in adult animals in the F1b generation was 150 ppm. The NOEL for effects on the offspring of the F1b generation, manifested as reduced pup weights and pup weight gains was also 150 ppm (approximately 8 mg/kg/day). Based upon the results of this study, MCPA, administered for two generations to Crl:CD(SD)BR Albino rats, is considered not to be a reproductive toxicant.     

Absence of reproductive and developmental toxicity in rats following oral dosing with nelfinavir

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested.     

Two-generation reproduction study by dosing with glutaraldehyde in the drinking water of CD rats

Adult male and female CD rats (F0) were dosed with glutaraldehyde (GA; CAS number 111-30-8) in drinking water at concentrations of 0 (controls), 50, 250, or 1000 ppm for a 10-wk prebreed period and through mating, gestation, and lactation. Resultant F1 offspring, selected to be parents of the next generation, were continued on the same regime from prebreed through lactation. Twenty-eight parental animals per sex per generation for each dose group were evaluated for clinical signs, body weight (absolute and gain), and water and food consumption. The offspring were evaluated for survival and body weight to weaning. Necropsy and light microscopic examination of removed tissues were conducted in all F0 and F1 parents and in 10 offspring/sex/group/generation. Average daily consumptions of GA (as mean +/- SD) for the low, intermediate, and high concentrations were respectively 4.25 +/- 0.87, 17.50 +/- 4.16, and 69.07 +/- 14.58 mg/kg/d for F0 parental males, and 6.68 +/- 0.78, 28.28 +/- 4.09, and 98.37 +/- 11.71 mg/kg/d for F0 parental females. The corresponding values for the F1 parents were 4.53 +/- 1.02, 21.95 +/- 4.88, and 71.08 +/- 16.21 mg/kg/d for males and 6.72 +/- 0.84, 29.57 +/- 5.41, and 99.56 +/- 16.72 mg/kg/d for females. There were no effects on parental fertility and mating performance or on pup viability and litter size in any generation. No apparent treatment-related histopathology was seen in parents or offspring. Parental body weights and body weight gains were significantly reduced at 1000 ppm at a few isolated time periods, particularly during prebreed. Food consumption was significantly reduced at 1000 ppm for F0 and F1 parents during the prebreed and gestation periods, and at 250 ppm for F0 males during prebreed and gestation and F1 females during gestation and lactation. Water consumption by the F0 and F1 parents of the 250 at 1000 ppm groups was reduced throughout the prebreed period. At 1000 ppm, average litter weights were reduced over lactation d 21-28 for the F1 and F2 offspring. The no-observed-effect level (NOEL) for adult toxicity was 50 ppm and for offspring 250 ppm. There were no indications of reproductive toxicity, and the NOEL for this study was therefore > 1000 ppm.     

Evaluation of the reproductive and developmental toxicity of a fluoroalkylethanol mixture

The objective of these studies was to evaluate the reproductive and developmental toxicity of a commercial fluoroalkylethanol mixture, which is an intermediate in the production of fluorotelomers. The test substance was administered daily by gavage to Sprague-Dawley rats as a suspension in 0.5% aqueous methylcellulose. In a one-generation reproductive toxicity study, rats (20 per sex per group) were given dosages of 0, 25, 100, or 250 mg kg(-1) day(-1) for a period of 74 days prior to cohabitation, and during mating, gestation, and lactation. Body weights, feed consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity, and reproductive performance were evaluated for the P1 generation. The F1 offspring were.evaluated during the lactation period for growth and survival and given a gross pathology examination at weaning. A subset of the offspring were retained; body weights, feed consumption, clinical signs, and age at onset of vaginal opening and preputial separation were evaluated, and gross pathology was performed on postnatal day 60. In the developmental toxicity study, groups of time-mated Sprague-Dawley female rats were given the test substance as a suspension in 0.5% aqueous methylcellulose at daily dosages of 0, 50, 200, or 500 mg kg(-1) day(-1) by gavage on gestation days 6-20. During the in-life portion of the study, growth parameters and clinical observations were made. On gestation day 21, dams were euthanized, and the thoracic and abdominal viscera were examined. The uterine contents were removed and examined, and fetuses were evaluated for any alterations. In the reproduction study, litter size at birth, number of live pups per litter on day 0 and 4 of lactation, and pup weights during lactation were reduced in groups administered > or =100 mg kg(-1) day(-1). No other reproductive parameters were affected. There were no adverse reproductive effects observed at 25 mg kg(-1) day(-1). In the developmental toxicity study, reduced maternal body weight parameters, increased perineal fur staining, and increased fetal skeletal alterations were observed at 500 mg kg(-1) day(-1). There was no maternal or developmental toxicity at 50 or 200 mg kg(-1) day(-1). Under the conditions of the studies, the no-observed adverse effect levels for this mixture were 25 mg kg(-1) day(-1) for subchronic toxicity and reproductive parameters and 200 mg kg(-1) day(-1) for developmental toxicity end points. No functional reproductive or developmental effects were observed at dose levels that did not adversely affect adult animals.     

Developmental toxicity of the dopamine agonist pergolide mesylate in CD-1 mice. II: Perinatal and postnatal exposure

Pergolide mesylate is a dopamine agonist and, therefore, reduces prolactin secretion. In Experiment I, pregnant mice were given oral doses of 0, 0.1, 0.3, 1.0 or 3.0 mg/kg/day pergolide on GD 15 through PD 10 or 20 to identify a tolerated dose which would not markedly reduce offspring survival during late gestational and lactational exposure. Offspring survival was not affected at any dose, but dose-related decreases in progeny body weights occurred at weaning. On PD 10, suckling-induced increases in maternal serum prolactin concentrations did not occur in dams treated with 3.0 mg/kg/day. In Experiment II, pregnant mice were given oral doses of 0, 0.002, 0.1 or 3.0 mg/kg/day pergolide on GD 15 through PD 20. Dams were allowed to deliver and maintain their offspring throughout a 21-day lactation period. Growth and behavioral performance of one F1 male and one F1 female per litter were monitored, followed by a reproduction trial and terminal organ weight measurements. There were no treatment-related effects on maternal body weights, food consumption, or terminal organ weights and pathology. Three dams showed overt signs of mammary inflammation and lactational insufficiency and mean progeny survival was decreased slightly in the 3.0 mg/kg/day group. There were no adverse effects on growth, development or reproductive performance in the F1 treatment-derived generation. Neonatal negative geotaxis, 1-h activity levels at 30 and 60 days of age, auditory startle habituation at 55 days of age, and two-way active avoidance performance at 65 days of age were not affected significantly by treatment. Thus doses of pergolide that did not inhibit lactation completely in the F0 dams were found to have no enduring effects on offspring development.     

Evaluation of spinosad in a two-generation dietary reproduction study using Sprague-Dawley rats.

Spinosad, an insecticide derived from a naturally occurring bacterium via fermentation, represents a new class of insecticides acting by a novel mode of action. A dietary study was conducted in Sprague-Dawley rats in which groups of 30 rats/sex/dosage level were given diets that provided 0, 3, 10, or 100 mg spinosad/kg body weight/day, 7 days/week, for 2 successive generations. Following 10 weeks of dietary exposure, the P1 generation was mated twice to produce F1a and F1b litters. After weaning, groups of 30 rats/sex/dosage level were selected from the F1a litters, given diets containing spinosad for 12 weeks, and mated to produce the F2 generation. Dietary administration of spinosad to rats at a dosage of 100 mg/kg/day over 2 generations produced parental toxicity and effects on the offspring. Among adult males, body weights and weight gains were decreased 2-9% relative to controls, with P1 males more affected than P2. Absolute and relative liver, kidney, heart, spleen, and thyroid weights were increased by from 12% to as much as 240% of control values. Histologic changes consistent with cationic amphiphilic compounds were noted in the kidneys, lungs, mesenteric lymph nodes, spleen, and thyroid of P1 and P2 males and females. In females given 100 mg/kg/day, though premating body weights were not affected, weight gains during the F1a and F1b gestation periods were depressed 15-16%. Increased incidences of dystocia, and vaginal bleeding and mortality occurred during parturition and lactation at 100 mg/kg/day. Effects on the offspring (decreased litter size and survival through day 4 of lactation) were limited to the high-dosage group. Signs indicative of poor maternal care noted in the pups (stomachs void of milk, cold, thin, etc.) were observed at 100 mg/kg/day. Early postnatal effects on the offspring were considered likely secondary to the effects in maternal animals around the time of parturition. At 100 mg/kg/day, weight gain in pups was depressed throughout lactation, with statistically significantly decreased weights noted toward the latter half of the lactation period. There were no treatment-related effects on adults or their offspring at 3 or 10 mg/kg/day in either generation. Based on these results, spinosad is not considered a selective reproductive toxicant, (i.e., no effects on reproductive parameters were noted below a level that produced toxicity in the adults) and the no observed effect level (NOEL) for both parental and reproductive/perinatal toxicity was 10 mg/kg/day.     

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.     

Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats

Perfluorooctanesulfonate (PFOS) is a persistent acid found widely distributed in wildlife and humans. To understand the potential reproductive and developmental effects of PFOS, a two-generation reproduction study was conducted in rats. Male and female rats were dosed via oral gavage at dose levels of 0, 0.1, 0.4, 1.6, and 3.2 mg/(kg day) for 6 weeks prior to mating, during mating, and, for females, through gestation and lactation, across two generations. Due to substantial F1 neonatal toxicity observed in the 1.6 and 3.2 mg/(kg day) groups, continuation into the second generation was limited to F1 pups from the 0, 0.1, and 0.4 mg/(kg day) groups. No adverse effects were observed in F0 females or their fetuses upon caesarean sectioning at gestation day 10. Statistically significant reductions in body-weight gain and feed consumption were observed in F0 generation males and females at dose levels of 0.4 mg/(kg day) and higher, but not in F1 adults. PFOS did not affect reproductive performance (mating, estrous cycling, and fertility); however, reproductive outcome, as demonstrated by decreased length of gestation, number of implantation sites, and increased numbers of dams with stillborn pups or with all pups dying on lactation days 1-4, was affected at 3.2 mg/(kg day) in F0 dams. These effects were not observed in F1 dams at the highest dose tested, 0.4 mg/(kg day). Neonatal toxicity in F1 pups, as demonstrated by reduced survival and body-weight gain through the end of lactation, occurred at a maternal dose of 1.6 mg/(kg day) and higher while not at dose levels of 0.1 or 0.4 mg/(kg day) or in F2 pups at the 0.1 or 0.4 mg/(kg day) dose levels tested. In addition to these adverse effects, slight yet statistically significant developmental delays occurred at 0.4 (eye opening) and 1.6 mg/(kg day) (eye opening, air righting, surface righting, and pinna unfolding) in F1 pups. Based on these data, the NOAELs were as follows: reproductive function: F0> or =3.2 and F1> or =0.4 mg/(kg day); reproductive outcome: F0=1.6 and F1> or =0.4 mg/(kg day); overall parental effects: F0=0.1 and F1> or =0.4 mg/(kg day); offspring effects: F0=0.4 and F1> or =0.4 mg/(kg day). To distinguish between maternal and pup influences contributing to the perinatal mortality observed in the two-generation study, a follow-up cross-foster study was performed. Results of this study indicated that in utero exposure to PFOS causally contributed to post-natal pup mortality, and that pre-natal and post-natal exposure to PFOS was additive with respect to the toxic effects observed in pups.