Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study

Butyl benzyl phthalate (BBP), a plasticizer, has been shown in in vitro studies to be weakly estrogenic, and in in vivo studies to possess testicular toxicity and teratogenicity, but few experimental data on BBP multigeneration effects on reproduction in mammals are available. The present two-generation reproductive study was conducted in male and female Sprague-Dawley rats using oral doses of 0, 20, 100, and 500 mg/kg/day BBP. Endpoints were chosen in order to evaluate both subchronic and reproductive toxicity. In the parent animals (F₀), a decrease in body weight gain was observed in males in the 500 mg/kg/day group, although no significant decrease in food consumption was found. No dose-related changes were observed in estrous cyclicity, fertility, or lactation. A dose-dependent increase in kidney weight in rats of both sexes, an increase in liver weight in males, and a decrease in the weight of the ovaries in females were observed. No macroscopic or microscopic changes were found in the reproductive system of males or females. Oral administration of BBP caused a decrease in the serum concentration of testosterone, and an increase in FSH. In the next generation (F₁), the body weight of male and female offspring at birth in the 100 and 500 mg/kg groups was significantly decreased, and the body weight in the 500 mg/kg group was lower throughout the study, while viability was not affected. Anogenital distance (AGD) at birth was decreased in male pups and was increased in female pups of the 500 mg/kg/day group. Preputial separation for male offspring in the 500 mg/kg/day group was delayed, while vaginal opening for female offspring in this group was not affected. BBP did not affect reproductive ability, including delivery and lactation, at any dose whereas macroscopic and microscopic changes of the testis, and decreased serum concentrations of testosterone were observed in male offspring of the 500 mg/kg/day group after puberty. From these data, it would appear that 20 mg/kg BBP is a no observed adverse effect level (NOAEL) for reproductive effects on parent animals and the next generation.     

A two-generation reproduction study with transgenic Bt rice TT51 in Wistar rats

TT51 is a transgenic Bt rice created by fusion a synthetic CryAb/CryAc gene into rice MingHui63. A significant number of animal feeding studies with transgenic crops have been carried out with the rapid development of transgenic crops. However, the evidence is far from identifying whether certain novel transgenic crops possess potential danger for human or animal health after long-term consumption. Rice-based diets, containing 60% ordinary grocery rice, MingHui63 rice or TT51 rice by weight, were fed to two generations of male and female rats in order to determine the potential reproductive effects of TT51. In this study, both clinical performance variables and histopathological responses were examined and compared between groups. There were no significant differences between groups on body weights, food consumption, reproductive data and relative organ/body weights. There were some statistically significant differences in hematology and serum chemistry parameters, but no histological abnormalities were seen in the brain, heart, liver, spleen, kidneys, stomach, small intestine, thymus, ovaries, uterus, testes and epididymides. Based on the results, under the circumstance of this study TT51 show no significant differences on reproduction performance of rats compared with MingHui63 and the control.     

Oral two-generation reproduction toxicity study with NM-200 synthetic amorphous silica in Wistar rats

Synthetic amorphous silica (SAS) like NM-200 is used in a wide variety of technological applications and consumer products. Although SAS has been widely investigated the available reproductive toxicity studies are old and do not cover all requirements of current OECD Guidelines. As part of a CEFIC-LRI project, NM-200 was tested in a two-generation reproduction toxicity study according to OECD guideline 416. Male and female rats were treated by oral gavage with NM-200 at dose levels of 0, 100, 300 and 1000 mg/kg bw/day for two generations. Body weight and food consumption were measured throughout the study. Reproductive and developmental parameters were measured and at sacrifice (reproductive) organs and tissues were sampled for histopathological analysis. Oral administration of NM-200 up to 1000 mg/kg bw/day had no adverse effects on the reproductive performance of rats or on the growth and development of the offspring into adulthood for two consecutive generations. The NOAEL was 1000 mg/kg body weight per day.     

A two-year dietary carcinogenicity study of cyadox in Sprague-Dawley rats

To investigate the potential carcinogenicity of cyadox, an antimicrobial agent, four groups of Sprague-Dawley rats (50 rats/sex/group) were fed diets containing cyadox (0, 200, 600 or 2000 mg/kg) for up to two years. There were significant decreases in body weight, feed intake and feed efficiency in both genders during most of the period in the 2000 mg/kg group. Significant decreases in serum ALT were observed in the 2000 mg/kg group at weeks 52, 78 and 104. For the control, 200, 600, and 2000 mg/kg groups, the tumor incidence in females was 33.3%, 37.2%, 40.0% and 19.0%, while it in males it was 18.9%, 2.6%, 17.1% and 13.6%, respectively. At histopathology, no increases in tumor incidence were attributed to treatment with cyadox. The mild swelling and fatty degeneration in hepatocytes, and mild swelling and tubular necrosis in the kidney were observed in 2000 mg/kg group. The no-observed-effect-level (NOEL) for carcinogenicity of cyadox fed to rats was 2000 mg/kg diet (132.18–156.28 mg/kg b.w./day). In conclusion, cyadox was not carcinogenic to rats with the liver and kidney as the target organs, and the side chain may be involved in toxicity and carcinogenicity mediated by QdNOs.     

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.     

Safety assessment of dietary diacylglycerol oil: A two-generation reproductive toxicity study in rats

Diacylglycerol (DAG) oil is a novel edible oil with similar taste and usability characteristics as conventional edible oils. Recent studies suggest that DAG oil may be helpful in the prevention and management of obesity. The objective of the present two-generation study was to evaluate potential adverse effects of DAG oil on reproductive processes. DAG oil was administered via gavage to rats (30/sex/group) for at least 70 days prior to mating, at dose levels of 0, 1.25, 2.5 or 5.0ml/kg/day (0, 1160, 2320 and 4630mg/kg/day). An additional group received a triacylglycerol (TAG) oil with a similar fatty acid composition to DAG oil. The rats were treated throughout the mating, gestation and lactation periods. Administration of DAG or TAG oil did not reveal any toxicologically significant effects on reproductive performance (mating, fertility and copulation/conception indices). DAG oil did not affect mean gestation lengths, the process of parturition, spermatogenic parameters, organ weights, histopathologic findings, mean numbers of pups born, implantation sites and unaccounted sites. F1 and F2 pup viability, live litter sizes, body weights, mean age of attainment of balanopreputial separation and vaginal patency were similar to those in the control group. Based on the results of this study, a dose level of 5.0ml/kg (4630mg/kg/day) was considered as the no-observed-adverse-effect level for reproductive and systemic toxicity, and neonatal toxicity.     

Nonylphenol alters the activity of splenic NK cells and the numbers of leukocyte subpopulations in Sprague-Dawley rats: a two-generation feeding study

Nonylphenol (NP) has been identified at low levels in surface waters throughout North America. This industrial chemical is primarily used for the production of certain non-ionic surfactants, and has been reported to have weak estrogen-like activity. As estrogen has immunoregulatory properties and is crucial for normal fetal development, it was hypothesized that adult and developmental exposures to NP had the potential to adversely affect the immune system. Furthermore, developmental exposure to NP might also produce differential immunomodulation in F(1) male and female rats. Thus, a two-generation feeding study was conducted to evaluate the potential for NP to modulate certain immune parameters. Pregnant female Sprague-Dawley rats were exposed to NP (0, 25, 500, and 2000 ppm) in their feed for 65 days, beginning 7 days into gestation. The F(1) generation male and female offspring were exposed in utero at the respective treatment levels, commencing the 7th day of gestation, and continuing through to 64 days of age. Changes in splenic antibody-forming cell response, natural killer cell activity, and leukocyte numbers were used to evaluate NP immunotoxicity. The results from the present study indicate that dietary exposure to NP can increase splenic natural killer (NK) cell activity and splenocyte subpopulation numbers in the F(1) generation rats, without similar changes to the F(0) generation. The immunological changes that were observed in the F(1) generation also appeared to be gender-specific.     

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.     

Assessment of a two-generation reproductive and fertility study of mercuric chloride in rats.

Effects of mercuric chloride (MC) on the reproductive performance of two successive generations of rats was evaluated. F(0) rats were exposed to 0.0:0.0 (males:females), 0.50:0.75 (males:females), 1.00:1.50 (males:females) and 1.50:2.50 (males:females) mg/kg/day MC. Selected parental F(1) males and females were exposed to the same doses received by their parents (F(0)). Significant differences resulting from exposure of the F(0) generation to MC were found in implantation efficiency, fertility, live births and day 4 survival indices, litter size, and the body weight of F(1) pups. However, the continued exposure of the F(1) generation to MC did not affect fertility index or litter size, but did significantly affect implantation efficiency, live births and day 4 survival indices. In F(0) males, body weight and weights of the kidneys, testes, epididymides, prostate and seminal vesicles were significantly different, while in F(1) males, body weight, kidney weight, brain weight, liver weight and the weights of the testes, prostate and seminal vesicles were significantly different. In F(0) females, body weight and the weights of the kidneys, brain and liver were significantly different, while in F(1,) females, body weight, as well as the weights of the kidneys, liver, adrenals, uterus and ovaries were significantly different. These data showed that exposure to MC resulted in more adverse reproductive effects in the first generation and that these effects moderated in the second generation.     

Chronic dietary toxicity and carcinogenicity study with ammonium perfluorooctanoate in Sprague-Dawley rats

In order to assess the potential chronic toxicity and tumorigenicity of ammonium perfluorooctanoate (APFO), a 2-year dietary study was conducted with male and female rats fed 30 ppm or 300 ppm (approximately 1.5 and 15 mg/kg). In males fed 300 ppm, mean body weights were lower across most of the test period and survival in these rats was greater than that seen either in the 30 ppm or the control group. Non-neoplastic effects were observed in liver in rats fed 300 ppm and included elevated liver weight, an increase in the incidence of diffuse hepatocellular hypertrophy, portal mononuclear cell infiltration, and mild hepatocellular vacuolation without an increase in hepatocellular necrosis. Mean serum activities of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were elevated up to three times the control means, primarily at the 300 ppm dose. A significant increase in Leydig cell tumors of the testes was seen in the males fed 300 ppm, and tumors of the liver and acinar pancreas, which are often observed in rats from chronic exposure to peroxisome proliferating agents, were not observed in this study. All other tumor types were those seen spontaneously in rats of this stock and age and were not associated with feeding of APFO.     

Evaluation of the reproductive and developmental toxicity of aluminium ammonium sulfate in a two-generation study in rats

Aluminium ammonium sulfate (AAS) was tested for reproductive/developmental toxicity in a two-generation study. Male and female rats were continuously given AAS in drinking water at 0, 50, 500 or 5000 ppm. Water consumption was decreased in all AAS-treated groups, and the body weight of parental animals transiently decreased in the 5000 ppm group. In either generation, no compound-related changes were found in estrous cyclicity, sperm parameters, copulation, fertility and gestation index, number of implantations and live birth pups, sex ratios of pups or viability during the preweaning period. Male and female F1 pups in the 5000 ppm group showed a lower body weight on postnatal day 21, while there were no differences in the birth weight of F1 and F2 pups between the control and AAS-treated groups. Preweaning body weight gain in F2 males and females indicated a similar decreasing tendency at 5000 ppm. In F1 and F2 weanlings, the weight of the liver, spleen and thymus decreased at 5000 ppm, but no histopathological changes were found in these organs. In F1 females in the 5000 ppm group, vaginal opening was delayed slightly. There were no compound-related changes in male preputial separation or in other developmental landmarks. In behavioral tests conducted for F1 animals at 4-6 weeks of age, no compound-related changes were found in spontaneous locomotor activity and performance in a water-filled multiple T-maze. In conclusion, the NOAEL of AAS for two-generation reproductive/developmental toxicity was considered to be 500 ppm in rats. Considering the aluminium content in the basal diet, the total ingested dose of aluminium from drinking water and food in this 500 ppm group was calculated to be 5.35 mg Al/kg bw/day.     

Rat two-generation reproduction and dominant lethal study of acrylamide in drinking water

Fischer 344 (F344) F(0) weanling rats, 30/sex/group, were exposed to acrylamide in drinking water at 0.0, 0.5, 2.0, or 5.0 mg/kg/day for 10 weeks and then mated. Exposure of F(0) females continued through gestation and lactation of F(1) litters. F(0) males, after F(0) mating, were removed from exposure and mated (one male: two untreated females) for the dominant lethal (DL) assay. Thirty F(l) weanlings/sex/group were exposed for 11 weeks to the same dose levels as their parents, and then mated to produce F(2) offspring. F(0) and F(l) parents and F(1) and F(2) weanlings were necropsied. Prebreeding exposure of F(0) and F(l) animals resulted in systemic toxicity at 2.0 to 5.0 mg/kg/day, with head tilt and/or foot splay increased at 0.5 to 5.0 mg/kg/day. F(0) and F(l) reproductive indices and gestational length were unaffected. Implantations and live pups/litter at birth were reduced at 5.0 mg/kg/day. Survival of F(l) and F(2) pups was reduced at 5.0 mg/kg/day for PND 0 through 4 only. In the DL assay, total and live implants were reduced, pre- and postimplantation loss was increased, and the frequency of DL factors (F(L)%) was increased at 5.0 mg/kg/day. At 5.0 mg/kg/day, adult F(l) male peripheral nerves exhibited axonal fragmentation and/or swelling; F(l) female spinal cord sections were unremarkable. The NOEL for prenatal DL was 2.0 mg/kg/day; the NOEL for adult systemic toxicity, including neurotoxicity, was < or = 0.5 mg/kg/day. Therefore, neurotoxicity and DL were differentially affected.     

Three-generation evaluation of dietary para-nonylphenol in CD (Sprague-Dawley) rats.

This study evaluated the potential for dietary para-nonylphenol (NP; CAS No. 84852-15-3) to affect parental fertility and growth and development of three offspring generations in CD (Sprague-Dawley [SD]) rats, including sperm counts across generations to determine the validity of equivocal reductions observed in the F2 generation by R. E. Chapin et al. (1999, Toxicol. Sci. 52, 80-91). Male rat kidney toxicity was also examined based on inconsistent observations in NP-exposed rats at 2000 ppm but not at 200 or 650 ppm in Purina 5002 (H. C. Cunny et al., 1997, Regul. Toxicol. Pharmacol. 26, 172-178) and at all of these NP concentrations in NIH-07 diet (R. E. Chapin et al., 1999, Toxicol. Sci. 52, 80-91). Concentrations were 0, 20, 200, 650, and 2000 ppm NP in Purina 5002 diet and 0 and 650 ppm NP in NIH-07 diet. 17beta-estradiol (E2) was used as a positive control at 2.5 ppm in Purina 5002 diet. There were no NP effects on any reproductive parameters in any generation, including sperm counts. Kidney toxicity (histopathology) occurred at 650 and 2000 ppm with no clear difference for the two diets. Ovarian weight was decreased at 2000 ppm NP in all generations, with no effect on reproduction. Dietary E2 at 2.5 ppm caused renal, reproductive, and developmental (lactational and peripubertal) toxicity in all generations. This study confirmed that dietary NP is not a selective reproductive toxicant with an no observable adverse effect level (NOAEL) of > 2000 ppm ( approximately > 150 mg/kg/day) and provided an NOAEL for male rat kidney toxicity of 200 ppm NP (approximately 15 mg/kg/day).     

Carcinogenicity assessment of lonidamine by dietary administration to Sprague-Dawley rats.

Following chronic dietary administration of 20, 60 and 180 mg/kg per day of lonidamine for 2 years to groups of Sprague-Dawley rats, treatment-related non-tumour findings seen microscopically included the following: atrophy of the testis with associated changes in epididymis and pituitary at all dosages; neuropathy in the sciatic nerve accompanied by skeletal muscle atrophy which was dose-related, particularly in male animals. Neither the incidence of tumour-bearing animals, nor the spectrum of tumours seen, was significantly changed. In the females given 180 mg/kg per day an overall reduction in tumour incidence was noted, which was reflected in a significant reduction (P < 0.001) in mammary tumours.     

Reproductive effects of nonylphenol in rats after gavage administration: a two-generation study

The potential reproductive toxicity of nonylphenol (NP) was assessed in a two-generation reproductive toxicity study. Groups of 25 male and female Crj:CD (SD) IGS rats were given NP by gavage at levels of 2, 10, or 50 mg/kg, and 25 males and females were given corn oil as controls. No adverse changes in clinical signs were observed in any rats throughout the study. Significant increases in the liver, kidney and pituitary gland weights in males, and decreases in thymus weight in males and in ovary weight in females were observed in the 50 mg/kg group. NP did not affect sperm characteristics or the estrous cycle at any dose administered. A significant increase in the TSH level was observed in males in the 50 mg/kg group. No adverse effects of NP on reproduction were found. At necropsy, no treatment-related alterations were observed in any organs including the reproductive tissues in any group. Histopathologic changes were found in the liver of male and female rats and kidneys of males in the 50 mg/kg group. The viability of offspring from postnatal day 0 to 4 in the 50 mg/kg group was reduced as compared with that in the controls, although growth was not affected by NP administration. On postnatal day 22, an increase in the serum FSH level and decrease in T(3) level for males, and decreases in LH and TSH levels and an increase in T(3) levels for females were observed in the 50 mg/kg group. NP did not affect the timing of preputial separation, while vaginal opening was accelerated in the 50 mg/kg group. No adverse changes were found in behavior or learning in the offspring of NP-treated groups. There were no treatment-related changes in any reproductive parameter, including estrous cycle, mating, fertility, delivery, and lactation, except for significant decreases in the numbers of implantation sites and live pups, and a significant decrease in ovary weight in the 50 mg/kg group. Kidney and liver weight were increased in males in the 50 mg/kg group. Histopathologic examination revealed changes in the liver of males and females of the 50 mg/kg group. No treatment-related changes were observed in the sperm characteristics. Hormone data should be interpreted cautiously until the findings are repeated and confirmed by further studies. These results of NP suggested that the no observed adverse effect level (NOAEL) on reproductive capacity is 50 mg/kg/day or greater in parent animals, and 10 mg/kg/day in the next generation under the present experimental condition.     

Oral (gavage) two-generation (one litter per generation) reproduction study of pentachlorophenol (penta) in rats

The potential for pentachlorophenol (penta) to induce general and reproductive/developmental toxicity was evaluated in Crl Sprague-Dawley rats, employing a two-generation reproduction toxicity study. Penta was administered by gavage at doses of 0, 10, 30, and 60 mg/kg/day. In both generations, the parental animals (30/sex/group) were intubated daily for 10 weeks before cohabitation and continuing through cohabitation, gestation, and lactation periods. Intubation of the F1 generation was begun 28 days postpartum. Animals were evaluated daily for mortality and general toxicity (clinical observations, body weights and gains, feed consumption). Organ weights were recorded and histopathological evaluations were made. Specific indices of reproductive function evaluated included estrous cycles, mating and fertility, parturition, lactation, viability, and growth and development of offspring, including sexual maturation, sperm parameters, and numbers of ovarian primordial follicles. All deaths in the parental rats were unrelated to penta. Expected metabolic effects of penta, sporadic increased liver weights associated with hepatocellular centrilobular hypertrophy and vacuolation and lipofuscin pigmentation, were evident in the 10-, 30-, and 60-mg/kg/day dose group P1 and F1 animals. Toxicity, in the form of liver pathology (single cell necrosis), reduced body weights and associated reductions in organ weights, and reduced feed consumption were noted in both generations at the 30- and 60-mg/kg/day doses. Developmental toxicity associated with these doses included reduced pup weights and viability. The 60-mg/kg/day dose also resulted in delayed sexual maturation, decreased spermatid counts, small prostates and testes, decreased implantations, reduced fertility, and increased resorptions of embryos. Based on these results, it was concluded that 30 mg/kg/day is the lowest-observable-adverse-effect level (LOAEL) and 10 mg/kg/day is the no-observable-adverse-effect level (NOAEL) for both reproductive and general toxicity. These findings are consistent with results from previously conducted studies wherein reproductive/developmental toxicity was observed only at doses that also induced general toxicity. It differs from previous findings in that the NOAEL for general toxicity is two to three times higher for the more pure product than for products produced and tested previously. In addition, the results did not indicate bioaccumulation of penta. Thus, penta did not selectively affect reproduction or development of the offspring of rats at a dose of 10 mg/kg/day, a dose that is 7000 to 20,000 times higher than human exposure.     

A 90-day oral (dietary) toxicity study of rebaudioside A in Sprague-Dawley rats

Rebaudioside A is one of several glycosides found in the leaves of Stevia rebaudiana (Bertoni) Bertoni (Compositae) stevia that has been identified as a potential sweetener. The present study (initiated in April 2006 and completed in October 2006) evaluated the safety of this sweetener when administered as a dietary admix at target exposure levels of 500, 1000, and 2000 mg/kg/day to Sprague-Dawley rats for 90 days. There were no treatment-related effects on the general condition and behavior of the animals as determined by clinical observations, functional observational battery, and locomotor activity assessments. Evaluation of clinical pathology parameters revealed no toxicologically relevant, treatment-related effects on hematology, serum chemistry, or urinalysis. Macroscopic and microscopic findings revealed no treatment-related effects on any organ evaluated. Lower mean body weight gains were noted in males in the 2000 mg/kg/day group throughout the study, which was considered to be test article related; however, given the small magnitude of the difference as compared to controls, this effect was not considered to be adverse. Results of this study clearly demonstrate that dietary administration of high concentrations of rebaudioside A for 90 consecutive days to Sprague-Dawley rats was not associated with any signs of toxicity.     

Toxicity of trans-nonachlor to Sprague-Dawley rats in a 90-day feeding study.

The chlordane constituent trans-nonachlor and its metabolite oxychlordane are among the most persistent chlordane-related contaminants and are found in tissues and milk from humans ingesting diets high in Arctic marine mammal fat. Although chlordane is no longer registered in North America, there is a need for toxicological data on chlordane-related contaminants found in food and the environment which are either structurally different or relatively more abundant than the constituents of the original chlordane mixture. Thus, a feeding study was undertaken to provide toxicological data on trans-nonachlor. Male and female Sprague-Dawley rats were exposed to 0, 5, 13 or 50 ppm trans-nonachlor in feed for 90 days and clinical, hematological and histopathological changes were assessed in each rat. Female rats were less able than males to metabolize and eliminate trans-nonachlor and, as a result, accumulated more trans-nonachlor in their adipose tissues. trans-Nonachlor, like technical chlordane and other organochlorines, induced liver microsomal enzymes in a pattern similar to phenobarbital. Endocrine effects included functional and morphological changes in the thyroid and adrenals. In male rats exposure to trans-nonachlor was associated with changes in endpoints indicative of increased oxidative stress, which may be related to both direct action on cellular targets or to secondary effects resulting from cytochrome P450 induction. The results indicate that subchronic trans-nonachlor exposure in rats induced hepatic changes with far-reaching metabolic and endocrine effects. Differences in target organ responses in male and female rats indicate that the sex-related metabolic differences affecting trans-nonachlor bioaccumulation and elimination merit further study.     

Two-generation reproduction study of lewisite in rats.

Lewisite, a potent toxic vesicant and chemical warfare agent, is used in a number of research laboratories, is stored in large quantities at depot sites throughout the USA and is occasionally transported to distant sites. Thus, the potential for environmental or occupational exposure exists where lewisite is present. A 42-week two-generation study was conducted to determine the reproductive consequences of lewisite in parental male and female rats and their offspring. Rats were administered lewisite in sesame oil (0, 0.10, 0.25 or 0.60 mg kg-1 day-1 for 5 days a week) via intragastic intubation before mating, during mating and after mating until the birth of their offspring. The dams continued to receive lewisite during lactation. At weaning, male and female offspring of each group were selected to continue the study, receiving lewisite during adolescence, mating and throughout gestation and lactation. Lewisite had no adverse effect on reproduction performance, fertility or reproductive organ weights of male or female rats through two consecutive generations. No adverse effects to offspring were attributed to lewisite exposure. Minor changes in growth were the only maternal effects observed. Lewisite exposure of parental rats caused no gross or microscopic lesion in testes, epididymis, prostate, seminal vesicles, ovaries, uterus or vagina. The no-observable-effect level (NOEL) for the reproductive effects of Lewisite would be > 0.60 mg kg-1 day-1.