Evidence Of Developmental Toxicity Research Articles

Nitroguanidine (NQ) (2016).

1-Nitroguanine (NG), also known as picrate, guanidine nitro, and N'-nitroguanidine, is used by the military as a propellant. Oral rodent LD50 data are generally >5000 mg/kg. NG is neither an eye nor a skin irritant, and it is not a skin sensitizer. NG is not genotoxic. No inhalation data are available; however, there are data from both 14- and 90-day oral (feed) toxicity studies in male and female Sprague Dawley rats at dosages up to 1000 mg/kg/day. There were no deaths on these studies and the only effect considered possibly related to treatment was decreased weight in females at the high-dose level in the 90-day study. Mice at similar dosages were even less affected. The NOAEL for both rats and mice (oral) was 316 mg/kg/day. There was no evidence of developmental toxicity in Sprague-Dawley rats administered NG by oral gavage, and the free-standing NOAEL was 1000 mg/kg with material toxicity. In Wistar rats, there was high mortality (50%) at 500 mg/kg NG administered by oral gavage; there was decreased body weight, feed consumption, and notable clinical signs in the dams at this dose level. Fetal toxicity could not be determined in this group. NG demonstrated maternal toxicity at 1000 mg/kg in rabbits; however, there were no evident differences in the rate of fetal malformations across the test groups. A NOAEL of 316 mg/kg was identified for maternal and fetal toxicity in this study. In a two-generation study, it was concluded the NG did not cause reproductive or fertility effects at dosages up to 1000 mg/kg/day. Absorption was rapid, non-dose dependent, and resulted in an apparent volume of distribution (VD) of between 0.66 (IV) and 0.85-0.87 (oral) l/kg. Elimination was primarily through the urine as unchanged compound. Human experience with NG dates back 100 years; however, no actual studies on humans have been reported. Non-military uses include automotive airbags, anti-corrosive coatings, and pharmaceutical manufacturing. The point of departure for Workplace Environmental Exposure Level (WEEL) derivations was 316 mg/kg, and a WEEL of 7 mg/m3 as an 8-h time-weighted average (TWA) was recommended.

Evaluation of the reproductive and developmental toxicity of 6:2 fluorotelomer alcohol in rats

6:2 fluorotelomer alcohol (6:2 FTOH) was evaluated for potential developmental and reproductive toxicity. 6:2 FTOH was administered by oral gavage to Sprague-Dawley rats as a suspension in 0.5% aqueous methylcellulose at dosages of 5, 25, 125, or 250mg/kg/day. The developmental toxicity study was performed in accordance with the Organization for Economic Development (OECD) Test Guideline 414, and the one-generation reproductive toxicity study was performed in accordance with the OECD Test Guideline 415. For the developmental toxicity study, adverse maternal toxicity observed at 250mg/kg/day included reductions in body weight parameters and food consumption. Evidence of developmental toxicity was limited to increases in skeletal variations (ossification delays in the skull and rib alterations) at 250mg/kg/day. There were no adverse maternal or developmental effects observed at 5, 25, or 125mg/kg/day and there were no effects on reproductive outcome or quantitative litter data at any dose level. For the one-generation reproduction toxicity study, systemic parental and developmental toxicity were observed at 125 and 250mg/kg/day. At 250mg/kg/day, there was increased mortality among male and female parental rats, effects on body weight parameters, food consumption, and clinical signs, and there were effects on offspring survival indices and body weights. At 125mg/kg/day, there was an increase in mortality in parental males only, and parental toxicity was limited to effects on body weight gain, food consumption (lactation), and clinical signs. Uterine weights were decreased at 125 and 250mg/kg/day, although there were no corroborative histopathological changes. At 125mg/kg/day, pup mortality was increased on lactation day 1, and body weights of the offspring were decreased during the second half of lactation. There was no evidence of either parental or developmental toxicity at 5 or 25mg/kg/day, and there were no effects on reproductive outcome at any dose level. Based on these data, 6:2 FTOH is not a selective reproductive or developmental toxicant at dosages that induce clear maternal/parental toxicity. Therefore, 6:2 FTOH would not be classified for reproductive/developmental toxicity under the United Nations’ Globally Harmonized System of Classification and Labeling of Chemicals.

Toxicological Assessment of Heavy Straight Run Naphtha in a Repeated Dose/Reproductive Toxicity Screening Test

Gasoline blending stocks (naphthas) are comprised of normal, iso- and cycloparaffins and aromatic hydrocarbons with carbon numbers ranging from C4 to C12. Heavy straight run naphtha (HSRN, CAS number 64741-41-9) was selected for toxicity screening because substances of this type contain relatively high levels (28%) of cycloparaffins by comparison to other naphtha streams and the data complement toxicity information on other gasoline blending streams. Rats were exposed by inhalation to wholly vaporized material at levels of approximately 100, 500, or 3000 parts per million (ppm) daily to screen the potential for systemic toxicity, neurotoxicity, reproductive toxicity, and developmental effects to postnatal day 4. All animals survived the treatment period. Principal effects of repeated exposure included increased liver weights in males and females, increased kidney weights in males, and histological changes in the thyroid, secondary to liver enzyme induction. These changes were not considered to be toxicologically meaningful and are not relevant to humans. There were no treatment-related effects in functional observation tests or motor activity; no significant reductions in fertility or changes in other reproductive parameters; and no evidence of developmental toxicity in offspring. The overall no observed adverse effect concentration was 3000 ppm (approximately 13, 600 mg/m(3)). In conclusion the HSRN effects on liver and kidney are consistent with the results of other studies of volatile fractions or other naphthas or formulated gasoline, and there were no HSRN effects on neurological developmental or reproductive parameters.

부산 지역 임산부의 모체혈, 제대혈, 모유에서 PFOA, PFOS의 농도

Objectives: Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are man-made, persistent global pollutants widely diffused throughout the environment. They have been even found in the cord blood and breast milk of humans. Furthermore evidence of developmental toxicity in animals exists. To assess the distribution of maternal and fetal exposure to PFOS and PFOA, we analyzed paired maternal blood, cord blood and breast milk samples. Methods: Maternal blood, cord blood and breast milk were collected from 150 volunteers from the general population (aged 20-40, mean ) of the city of Busan in 2009-2010. The samples were extracted using the weak anion exchange and solid-phase extraction methods and quantified by high-performance liquid chromatograph (HPLC, Agilent 1200 Series) coupled with an Triple Quad LC-MS/MS system (Agilent 6410). Results: Median PFOA and PFOS concentrations in maternal blood were 2.18 and 3.32 ng/ml, in cord blood were 0.83 and 0.58 ng/ml, and in breast milk were 0.13 and 0.11 ng/ml, respectively. PFOS and PFOA concentrations were significantly correlated among matrices (Spearson's , p = 0.05 for maternal blood; , p p

The Potential Role for Corticosterone in the Induction of Cleft Palate in Mice After Treatment With a Selective NK‐1 Receptor Antagonist, Casopitant (GW679769B)

Casopitant is a potent and selective NK-1 receptor antagonist that has shown clinical efficacy in the prevention of chemotherapy-induced and postoperative-induced nausea and vomiting. In an embryo-fetal development study, pregnant mice were given vehicle (sterile water) or doses of 30, 100, or 300 mg/kg/day casopitant on Gestation Day (GD) 6 to 15. Fetuses were evaluated for external, visceral, and skeletal abnormalities on GD 18. In a follow-on study to investigate casopitant-induced hormonal changes during the developmental period for palate formation, pregnant mice were given vehicle (sterile water) or 300 mg/kg/day casopitant once daily on GD 6 to 13. Blood was collected on GD 13 at various time-points for measurement of plasma adrenocorticotropic hormone and corticosterone (CRT) concentrations. There was no evidence of developmental toxicity in mice at 30 or 100 mg/kg/day but 9% of fetuses at 300 mg/kg/day had cleft palate. Mice are sensitive to glucocorticoid-induced cleft palates, and NK-1 antagonists are known to modulate the hypothalamic-pituitary-adrenal axis leading to increases in corticosterone. On GD 13, mean plasma adrenocorticotropic hormone levels at 300 mg/kg/day were elevated by approximately twofold from vehicle-treated levels at 1 hr post-dose and mean plasma CRT levels were elevated by 3, 5, and 10-fold at 0.5, 1, and 2 hr post-dose, respectively. The increased level of CRT was in the range previously shown in the literature to cause cleft palates in mice and was likely the underlying mechanism behind casopitant-induced cleft palate in mice.

Determinants of Fetal Exposure to Polyfluoroalkyl Compounds in Baltimore, Maryland

Polyfluoroalkyl compounds (PFCs), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), are ubiquitous, man-made chemicals. Human data suggest that in utero exposures to these chemicals occur and some evidence of developmental toxicity in animals exists. To assess the distribution and determinants of fetal exposure to PFCs, we analyzed cord serum samples from 299 singleton newborns delivered between 2004 and 2005 in Baltimore, MD for 10 PFCs by employing on-line solid-phase extraction coupled with reversed-phase high-performance liquid chromatography-tandem mass spectrometry. PFOS and PFOA were detected in 99 and 100% of umbilical cord sera, with geometric mean concentrations of 4.9 and 1.6 ng/mL, respectively. PFOS and PFOA concentrations were highly correlated (Pearson's r = 0.64 after natural log transformation, p < 0.01). Eight other PFCs were detected less frequently and at lower concentrations than PFOS and PFOA. Geometric mean concentrations of PFOS for Asians (6.0 ng/mL) and Blacks (5.1 ng/mL) were higher than those for Whites (4.2 ng/mL), while PFOA levels were more evenly distributed by race. Other maternal demographic and socioeconomic characteristics, including age, education, marital status, and living in the city limits were not significantly associated with cord concentrations. Our findings suggest that in utero exposure to PFOS and PFOA is ubiquitous in a population of babies born in Baltimore, MD.

Developmental Toxicity Study of Dimethylpiperidone

The potential maternal and developmental toxicity of dimethylpiperidone (DMPD) was assessed in rats. Groups of 25 mated female Crl:CD® (SD)IGS BR rats were exposed by inhalation (whole‐body exposures) for approximately six hours per day over days 7–21 of gestation (G); day 1G was the day of copulation plug detection. The exposure levels were 0, 52, 260, or 340 (vapor plus aerosol) mg/m3 DMPD. During the in‐life portion, body weights, food consumption, and clinical observation data were collected. On day 22G, the dams were euthanized and examined for gross external and internal alterations. The uterine contents were described and the fetuses were weighed and examined for external, visceral, and skeletal alterations. Maternal toxicity was seen at both 260 and 340 mg/m3. At 340 mg/m3, evidence of maternal toxicity included mortality, increased clinical observations, and decreased body weight and food consumption. At 260 mg/m3, maternal toxicity was limited to increased clinical observations and decreased food consumption. Developmental toxicity was also produced at 260 and 340 mg/m3. At 340 mg/m3, evidence of developmental toxicity included decreased fetal weight, increased embryofetal lethality with concomitant reductions in litter size, and increased fetal malformations and variations. At 260 mg/m3, effects in fetuses were limited to slightly decreased fetal weight and increased fetal variations; additionally, one litter from this level consisted entirely of resorptions. There were no compound‐related effects in either dams or fetuses at 52 mg/m3. It was, therefore, concluded that DMPD was not selectively toxic to the rat conceptus.

Teratogenesis and immunosuppressive treatment

Despite the potential risks to the mother and fetus caused by immunosuppressive drugs, uneventful pregnancies are now frequent among transplant recipients. Although there is no apparent increase in the type or incidence of malformations in the newborns or evidence of graft dysfunction, pregnancy-related complications, including premature termination and low birth weight, may be more frequent. To prevent graft rejection due to the increased immunologic reactivity of the transplant recipient during pregnancy, it is reasonable to wait 2 years after transplantation before conception, to have stable graft function and to be on low drug doses for maintenance immunosuppression. Among the immunosuppressive agents, corticosteroids may induce a number of treatment-related complications, including diabetes and osteoporosis; however, the incidence of fetal malformations during corticosteroid treatment is about 3.5%, a value close to that of the general population. Among immunosuppressive antibodies, no evidence of developmental toxicity has been demonstrated with basiliximab. On the contrary, some concerns have been raised about azathioprine, since its use has been associated with fetal abnormalities in animals; however, clinical data so far have indicated only a small teratogenic risk. Therefore, immunosuppressive therapy with selected drugs and antibodies does not apparently increase the risk of birth defects and may be continued in pregnancy. Finally, although breast-feeding is not recommended, because of drug transfer into maternal milk, the available clinical data do not support this limitation because of the low amount of drug absorbed by the infant and the absence of clinical toxicity in published case reports.

Children's health and the environment: public health issues and challenges for risk assessment.

Infants and children are not little adults. They are uniquely vulnerable to environmental toxicants. To protect infants and children against toxicants, the National Research Council in 1993 called for development of an approach to risk assessment that considers children's unique patterns of exposure and their special vulnerabilities to pesticides. Many aspects of that call were codified into federal law in the Food Quality Protection Act (FQPA) of 1996. This report highlights the central elements needed for development of a child-protective approach to risk assessment: a) improved quantitative assessment of children's exposures at different life stages, from fetal life through adolescence, including acute and chronic exposures, exposures via multiple routes, and exposures to multiple agents; b) development of new approaches to toxicity testing of chemicals that can detect unanticipated and subtle outcomes and that evaluate experimental subjects over the entire life span from early exposure to natural death to replicate the human experience; c) development of new toxicodynamic and toxicokinetic models that account for the unique physiologic characteristics of infants and children; d) development of new approaches to assessment of outcomes, functional, organ, cellular and molecular, over the entire life span; these measures need to be incorporated into toxicity testing and into long-term prospective epidemiologic studies of children; and e) application of uncertainty and safety factors in risk assessment that specifically consider children's risks. Under FQPA, children are presumed more vulnerable to pesticides than adults unless evidence exists to the contrary. Uncertainty and safety factors that are protective of children must therefore be incorporated into risk assessment when data on developmental toxicity are lacking or when there is evidence of developmental toxicity. The adequate protection of children against toxic agents in the environment will require fundamental and far-reaching revisions of current approaches to toxicity testing and risk assessment.

Developmental toxicity of levo-alpha-acetylmethadol (LAAM) in tolerant rats.

Mated Crl:CD VAF/Plus female rats, in a range-finding study (n = 5-6 per dose) and a subsequent definitive study (n = 30 per dose) were used to determine the developmental toxicity, including the teratogenic potential of levo-alpha-acetylmethadol (LAAM) hydrochloride, in tolerant rats. Tolerance was induced by initially administering the drug by gavage (10 ml/kg) at 2 mg/kg/day and increasing the dose every 2 weeks for 12 weeks until the doses of 2, 6, 9, 12, and 15, or 2, 6, and 12 mg/kg/day were achieved in the range-finding or definitive study, respectively. Females were then mated to stock males and treated throughout mating and gestation. Controls received distilled water on a similar regimen. The range-finding experiment was used for initial clinical evaluations and to determine tissue concentrations of LAAM and metabolites. In plasma, liver, and brain collected from dams and fetuses pooled by litter on gestation day 20, LAAM and its two N-demethylated metabolites, norLAAM and dinorLAAM, showed dose-dependent increases in concentration and in tissue to plasma ratios. Tissue to dam plasma ratios were highest in dam liver (17-60), intermediate in fetal liver (3-16), and fetal brain (3-14), and lowest in dam brain (0.8-5.6) and fetal plasma (0.3-2.1). In the definitive study, caesarean section examinations were performed following euthanization on gestation day 20 on all surviving females followed by teratologic examination of the fetuses. Drug-related outcomes, including increased activity, secondary hair loss, scabbing, focal swelling, and material around the nose, were exhibited by all groups receiving LAAM. Maternal toxicity was evident as decreased body weights, with maximum reduction at the 6-mg/kg/day dose, and reduction in feed consumption. There was also evidence of developmental toxicity in the form of postimplantation losses at all doses of LAAM. There were no deaths attributable to LAAM. No grossly observable visceral or skeletal anomalies related to LAAM were observed in the fetuses. In conclusion, the no-observable-effect level when administered to tolerant rats was less than 2 mg/kg/day with regard to clinical signs, body weight, body weight gain, and feed consumption, and with regard to developmental toxicity as reflected by postimplantation losses. Despite maternal and developmental toxicity, there was no evidence of selective fetal toxicity or teratogenic activity attributable to LAAM.

Genetic and reproductive toxicity of butadiene and isoprene

Butadiene (BD) and its 2-methyl analogue, isoprene, have been extensively studied in animals and BD in population studies. Both chemicals are metabolised by liver cytochrome P450 dependent monogenases to monoepoxide and diepoxide intermediates. The diepoxide intermediates of both compounds were mutagenic in Salmonella typhimurium. However, unlike the monoepoxide of BD, the monoepoxides of isoprene were not mutagenic. It appears that they have no alkylating capacity. BD did not induce somatic cell mutation and recombination or sex-linked recessive lethal mutation in Drosophila melanogaster and isoprene produced no increase in chromosomal aberrations in CHO cells in vitro. Comparative concentrations of haemoglobin adducts in the blood of mice and rats after exposure to BD indicated that reaction with blood may decrease the levels of reactive intermediates available to tissues in rats, but not in mice contributing to greater potency of BD in the mouse. For isoprene, the adducts reach approximately the same concentrations in both species. DNA adducts have also been detected in testicular and lung cells of mice after BD exposure. The level of epoxybutene haemoglobin adducts was significantly elevated in BD-exposed workers, but lower than in rats and mice. In conjunction with the toxicology and carcinogenesis studies for BD and isoprene, additional mice were included for the evaluation of cytogenetic effects. Both chemicals produced increases in sister chromatid exchanges in bone marrow cells and in the frequency of micronuclei in normochromatic and polychromatic erythrocytes, but only BD produced an increase in the percent of bone marrow cells with chromosomal aberrations. At similar doses, the effects with BD were 2–3 times larger than with isoprene. There were also increased hprt mutation frequencies in rats and mice after BD exposure. Biomonitoring studies with hprt mutations in lymphocytes showed conflicting results, with both positive and negative findings. BD has been shown to be positive in one human cytogenetic biomonitoring study and not in three others, but chromosomal aberrations were increased in BD-exposed workers after challenge with gamma rays. Re-analysis of GSTTI null individuals showed positive results. There was an increase in spermatid micronuclei in mice by BD and its metabolites and in rats only by its metabolites. The cytotoxic response of germ cells in mice is greater than in rats. Dominant lethal mutations have been induced by BD and diepoxybutane, but not by epoxybutene. There was some evidence of congenital malformations in mice after BD exposure and there was a linear concentration-related induction of heritable translocations in mice. There was no induction of dominant lethal mutations or congenital malformations in rats. Using the heritable translocation data in mice, it has been determined that if a worker is continually exposed over 5 or 6 weeks to 20–25 ppm of BD, the risk of producing a child with a balanced reciprocal translocation is twice as high as the background risk. Since genetic damage cannot be measured directly in human germ cells, risk to such cells can also be estimated from germ cells and somatic cells of the mouse and human somatic cells using the parallelogram approach. Using doubling doses, the fourth corner of the parallelogram was calculated as a doubling dose for human germ cells of 4390 ppm/h. However, it is still questioned if man is more like rat than mouse in terms of sensitivity to exposure. Similar germ cell data do not exist for isoprene. In conventional developmental studies, where rats and mice were exposed to BD, maternal toxicity was shown in rats but there was no evidence of developmental toxicity or teratogenic effects and there was a small effect on sperm morphology. After exposure to isoprene, there was no adverse effect on rat dams or other reproductive indices. In mice, there was reduced foetal body weight and decreased maternal weight gain and isoprene also affected ovarian follicles. There was a reduction in testicular function parameters such as testicular weight and sperm motility.

DEVELOPMENTAL TOXICITY STUDY OF TETRAMETHYLUREA (TMU) IN RATS

The developmental toxicity of tetramethylurea (TMU) was assessed in rats by inhalation exposure of the test material over days 6–20 of gestation. Groups of 25 mated female Crl:CD®BR rats were exposed whole-body for 6 hours/day to concentrations of either 0, 2, 20 or 100 ppm TMU. The dams were euthanized on day 21 and the offspring were weighed, sexed, and examined for external, visceral, and skeletal alterations. Maternal toxicity was demonstrated at both 20 and 100 ppm. Maternal body weights, weight changes, and food consumption were statistically significantly reduced at these concentrations; effects were more pronounced at 100 ppm. There was evidence of developmental toxicity only at 100 ppm. The only finding was a decrease in mean fetal weight. No fetal malformations or variations occurred in fetuses derived from rats exposed to all 3 test concentrations (up to 100 ppm). The maternal no-observed-effect-level (NOEL) was 2 ppm, the fetal NOEL was 20 ppm. Thus, TMU was not considered to be uniquely toxic to the rat conceptus.

INHALATION DEVELOPMENTAL TOXICITY AND REPRODUCTION STUDIES WITH CYCLOHEXANE

The reproductive and developmental toxicity of cyclohexane was assessed in a two-generation reproduction study with Crl:CD® BR rats and in developmental toxicity studies with Crl:CD®BR rats and Hra:(NZW)SPF rabbits. The animals were exposed whole-body to atmospheric concentrations of 0, 500, 2000, or 7000 ppm cyclohexane. In the two-generation reproduction study, parental effects included statistically significantly lower mean body weight, overall mean body weight gain, and overall mean food efficiency for P1 and F1 females of the 7000 ppm level and statistically significantly lower mean body weight for F1 males of that level. Adult rats exposed to 2000 ppm cyclohexane and above exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Mean pup weight was statistically significantly lower than control from lactation day 7 throughout the remainder of the 25-day lactation period for both F1 and F2 7000 ppm litters. Changes observed at 500 ppm were either considered not to be compound related or not adverse. Therefore, the systemic-toxicity no-observed-effect level (NOEL) was 500 ppm and the reproductive NOEL was 2000 ppm. The reproductive NOEL was based solely on the decreased pup weights in both the F1 and F2 generations observed at 7000 ppm. In the developmental toxicity studies, only the rats showed evidence of maternal toxicity. For rats in the 7000 ppm group, statistically significant reductions were observed in overall maternal body weight gain and overall maternal food consumption for the treatment period. Rats exposed to 2000 ppm cyclohexane and above again exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Therefore, for rats, the maternal no-observed-effect level (NOEL) was 500 ppm. In the rabbit developmental toxicitystudy, no compound-related maternal effects were observed at concentration levels of 7000 ppm and below. Therefore, the maternal NOEL for rabbits was 7000 ppm. No compound-related evidence of developmental toxicity was observed at any test concentration in either species. Therefore, the developmental NOEL for both species was 7000 ppm, the highest concentration tested.

Developmental toxicity of diethanolamine applied cutaneously to CD rats and New Zealand White rabbits.

Diethanolamine (DEA) was administered cutaneously to pregnant CD rats and New Zealand White rabbits during the periods of major organogenesis, Gestation Days 6-15 for rats and 6-18 for rabbits. Doses employed were 0, 150, 500, and 1500 mg/kg/day for rats and 0, 35, 100, and 350 mg/kg/day for rabbits. Rat dams exhibited reduced body weight at 1500 mg/kg/day, skin irritation and increased kidney weights at 500 and 1500 mg/kg/day, and a slight microcytic anemia with abnormal red blood cell morphology at all dose levels. Rat fetuses had increased incidences of six skeletal variations at 1500 mg/kg/day. Lower doses were without effect on the fetuses. Rabbit dams administered 350 mg/kg/day exhibited various skin lesions, reduced food consumption, and color changes in the kidneys but no hematological changes. Body weight gain was reduced at >/=100 mg/kg/day. There was no evidence of maternal toxicity at 35 mg/kg/day and no evidence of developmental toxicity in rabbits at any dose level. Developmental toxicity was observed only in the rat and only at doses causing significant maternal toxicity, including hematological effects. Due to a dose discrepancy, the no observable effect level (NOEL) for DEA developmental toxicity in rats was adjusted to 380 mg/kg/day. In rabbits, the embryonal/fetal NOEL was 350 mg/kg/day.

Developmental Toxicity Study of Glycolic Acid in Rats

ABSTRACTThe developmental toxicity of glycolic acid was assessed in rats by orally administering solutions of the test material in water over days 7-21 of gestation (the day of copulation plug detection was defined as day 1 of gestation). Groups of 25 mated female Crl:CD®BR rats were gavaged at daily dose levels of 0, 75, 150, 300 or 600 mg/kg. The dams were euthanized on day 22 and the offspring were weighed, sexed, and examined for external, visceral, and skeletal alterations. Clear evidence of maternal toxicity was demonstrated at 600 mg/kg; adverse clinical observations were statistically significantly increased (wheezing/lung noise, abnormal gait/staggering, lethargy). in addition, maternal body weights, weight changes, and food consumption were statistically significantly reduced at this dose level. Marginal evidence of maternal toxicity was demonstrated at 300 mg/kg; wheezing/lung noise similar to that seen at 600 mg/kg was observed in 2 of 25 dams. This increase approached statistical significance (p=0.0553). There was marked evidence of developmental toxicity at 600 mg/kg. Mean fetal weight was statistically significantly reduced while the incidences of skeletal (ribs, vertebra, and sternebra) malformations and variations were statistically significantly increased. At 300 mg/kg/day, there was a slight (2 affected fetuses from 2 litters) increase in the incidence of two skeletal malformations: fused ribs and fused vertebra. Although these increases were not statistically significant (p=0.0555), they were consistent with findings seen at 600 mg/kg/day and thus were considered relevant. There was no other evidence of developmental toxicity at 300 mg/kg/day nor was any developmental toxicity seen at 150 or 75 mg/kg/day. Thus, the maternal and developmental no-observed-effect level (NOEL) was considered 150 mg/kg.

Final Report on the Safety Assessment of Peg-30,-33,-35,-36, ANd-40 Castor Oil and Peg-30 and-40 Hydrogenated Castor Oil

PEG Castor Oils and PEG Hydrogenated Castor Oils are a family of polyethylene glycol derivatives of castor oil and hydrogenated castor oil that are used in over 500 formulations representing a wide variety of cosmetic products. They are used as skin conditioning agents and as surfactants (emulsifying and or solubilizing agents). The PEG Castor Oils and PEG Hydrogenated Castor Oils include various chain lengths, depending on the quantity of ethylene oxide used in synthesis. Although not all polymer lengths have been studied, it is considered acceptable to extrapolate the results of the few that have been studied to allingredients in the family. Because a principal noncosmetic use of PEG Castor Oils is as solvents for intravenous drugs, clinical data are available that indicate intravenous exposure can result in cardiovascular changes. Results from animal studies indicate very high LD50 values, with some evidence of acute nephrotoxicity in rats but not in rabbits. Short-term studies with intravenous exposure produced some evidence of toxicity in dogs but not in rabbits. Intramusuclar injection produced no toxicity in several species, including dogs. Subchronic oral studies also were negative. No dermal or ocular irritation was observed in studies in rabbits. Irritation was seen during induction, but no sen-sitization was found on challenge in guinea-pig studies using up to 50% PEG-35 Castor Oil; however, thisingredient was found to be a potent adjuvant in guinea pigs and mice. No evidence of developmental toxicity was seen in mice and rat feeding studies. Theseingredients, tested as vehicle controls, produced no mutagenic or carcinogenic effect. Clinical data are generally negative for irritation and sensitization, although some anaphylactoid reactions have been seen in studies of intravenous drugs in which PEG-35 Castor Oil was used as the vehicle. Because the maximum concentration used in animal sensitization studies was 50% for PEG Castor Oils and 100% for PEG Hydrogenated Castor Oils, it was concluded that PEG Castor Oils are safe for use in cosmetic formulations up to a concentration of 50% and that PEG Hydrogenated Castor Oils are safe as used in cosmetic formulations.

Systemic and developmental toxicity of dermally applied syntower bottoms in rats.

Syntower bottoms (STB) was evaluated for subchronic and developmental toxicity. In the subchronic study, undiluted STB was applied on the shaved backs of male and female rats at dose levels of 0, 8, 30, 125, and 500 mg/kg for 13 weeks, 5 days per week. Exposure sites were not covered. In the developmental toxicity study, STB was similarly applied, but to pregnant rats at dose levels of 0, 8, 30, and 125 mg/kg on Gestation Days 0-19. In addition, 4 mg/kg was dosed as 8 mg/kg every other day, starting on Gestation Day 0, and 500 mg/kg was dosed on Gestation Days 10-12. Evidence of toxicity observed in the subchronic study included death, decreased body weights, aberrant serum chemistry and hematology values, altered organ weights, and histopathologic changes in a variety of organs. A no observed adverse effect level for systemic toxicity could not be established. Evidence of maternal toxicity was observed at all exposure levels in the development study. Regardless of the length of the exposure period, STB was toxic to the developing conceptus. Evidence of developmental toxicity observed included increased resorptions with a concomitant decrease in litter size and reduced fetal body weights. Cleft palate was observed in fetuses exposed in utero to STB during Gestation Days 10-12 at 500 mg/kg. No evidence of teratogenicity was observed when the exposure period was throughout gestation. Ossification delays were observed in fetuses exposed in utero to STB at doses in excess of 4 mg/kg. A no observed adverse effect level for maternal and developmental toxicity could not be established.

Nonclinical Toxicology Studies with Zidovudine: Reproductive Toxicity Studies in Rats and Rabbits

Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague–Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before, during, or after mating and drug levels in the plasma and milk of lactating rats were determined. Finally, drug exposure data including observed peak plasma concentrations (Cmax) and area under the concentration–time curve (AUC) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity to the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the parental animals with 75 or 225 mg ZDV/kg bid. A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been dosed for 85 days, and females had been dosed for 26 days. To further evaluate the effects of ZDV on reproduction, dosing of male rats was continued to 149 days when they were mated a second time to virgin, untreated females. All reproductive parameters were normal in the untreated females from this second mating, indicating that the embryotoxic effect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CD rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic effect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratology) studies; however, pregnant New Zealand white rabbits given 250 mg/kg bid during gestation Days 6–18 showed reduced weight gain, anemia, and an increase in late fetal deaths. No other evidence of developmental toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose,Cmaxvalues in rats and rabbits were approximately 234 and 150 times higher, respectively, than the mean steady-state serum concentration in adults following chronic oral administration of 250 mg every 4 hr. In both the reproduction/fertility study and a peri- and postnatal study in rats, liveborn offspring showed no adverse effects on survival, growth, or developmental measurements.

Nonclinical Toxicology Studies with Zidovudine: Reproductive Toxicity Studies in Rats and Rabbits

Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague-Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before, during, or after mating and drug levels in the plasma and milk of lactating rats were determined. Finally, drug exposure data including observed peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity to the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the parental animals with 75 or 225 mg ZDV/kg bid. A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been dosed for 85 days, and females had been dosed for 26 days. To further evaluate the effects of ZDV on reproduction, dosing of male rats was continued to 149 days when they were mated a second time to virgin, untreated females. All reproductive parameters were normal in the untreated females from this second mating, indicating that the embryotoxic effect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CD rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic effect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratology) studies; however, pregnant New Zealand white rabbits given 250 mg/kg bid during gestation Days 6–18 showed reduced weight gain, anemia, and an increase in late fetal deaths. No other evidence of developmental toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose, Cmax, values in rats and rabbits were approximately 234 and 150 times higher, respectively, than the mean steady-state serum concentration in adults following chronic oral administration of 250 mg every 4 hr. In both the reproduction/fertility study and a periand postnatal study in rats, liveborn offspring showed no adverse effects on survival, growth, or developmental measurements.

Developmental toxicity of Exell, a surfactant mixture, in rats and rabbits.

A surfactant mixture (C.A.S No. 104559-06-2), is used in combination with foliar-acting herbicides to improve herbicidal performance by increasing plant uptake. It was administered by gavage as an aqueous solution to groups of 25 assumed pregnant Crl:CD BR rats from days 7-16 of gestation at daily dosage levels of 0, 3, 8, 20 or 50 mg/kg body weight. The dams were euthanized on Day 22 of gestation and the offspring were weighed and examined for external, visceral, and skeletal alterations. The surfactant mixture was maternally toxic at levels of 20 mg/kg/day and above as evidenced by reduced maternal weight gain and by an increased incidence of lung noise (wheezing and/or rattling) and sneezing. In addition, maternal food consumption was reduced in the high dosage group. There was no evidence of developmental toxicity at any dosage level. In the rabbit study, groups of 20 artificially inseminated adult Hra:(NZW)SPF rabbits were similarly dosed from Days 6-18 of gestation at daily dosage levels of 0, 12, 35, or 100 mg/kg body weight. The dose were euthanized on Day 29 of gestation and the offspring were weighed and examined for external, visceral, and skeletal alterations. Dosages of 35 and 100 mg/kg/day resulted in reduced maternal body weight gain, food consumption and fetal body weight. Thus, in the rat, the maternal and developmental no-observed-adverse-effect levels (NOAELs) were 8 mg/kg/day and greater than 50 mg/kg/day, respectively. In the rabbit, the maternal and developmental NOAELs were 12 mg/kg/day. This surfactant mixture was, therefore, not demonstrated to be uniquely toxic to either the rat or rabbit conceptus.