Prenatal developmental toxicity studies on di-n-heptyl and di-n-octyl phthalates in Sprague-Dawley rats

This study evaluates the developmental toxicity of two dialkyl phthalate esters, di-n-heptyl phthalate (DHPP) and di-n-octyl (DnOP) phthalate, which have straight-alkyl side chains of seven and eight carbons, respectively. Sprague-Dawley rats were administered 0, 0.25, 0.50, or 1g/kg/day of DHPP or DnOP, by gavage, on gestation days 6-20. DHPP and DnOP had no adverse effect on maternal feed consumption and body weight gain, or on the incidence of post-implantation loss and fetal body weight. There was no increase in the incidence of fetal malformations or external and visceral variations, whatever treatment. A significant increase in rudimentary lumbar ribs was observed at all doses of DHPP and DnOP. The anogenital distance of the male fetuses was significantly decreased at the highest dose of DHPP. This parameter was not affected by DnOP. Thus, the lowest-observed-adverse-effect level (LOAEL) for developmental toxicity was 0.25 g/kg/day for DHPP and DnOP.     

Chronic toxicity and oncogenicity studies of Macrodantin in Sprague-Dawley rats

Chronic toxicity and oncogenicity studies of nitrofurantoin formulated as Macrodantin have been undertaken. The doses ranged from 12 to 116 mg/kg body weight/day. At 116 mg/kg/day, female rats showed a decreased weight gain. In the high-dose groups in the chronic toxicity study (males, 81 mg/kg/day; females, 116 mg/kg/day) there was an increase in testicular degeneration, sciatic nerve degeneration and fibrosis in both males and females, and an increase in focal biliary proliferation in females. There was no evidence of renal toxicity. There was no compound-related effect upon neoplasms at any site. In the oncogenicity study, an increase in focal biliary proliferation was observed in females given 31 or 56 mg/kg/day. There was no treatment-related increase in the incidence of neoplasms at any site. In particular there was no increase in the incidence of mammary or renal tumours. The observations in these studies indicate that therapeutic uses of Macrodantin would not present a carcinogenic hazard to man.     

Reproductive and developmental toxicity studies of pyridostigmine bromide in rats

These studies were performed to evaluate the reproductive and developmental toxicity of pyridostigmine bromide (PB) in rats. Separate male and female fertility/reproductive performance studies, a perinatal/postnatal study and a teratology study were conducted. Dose levels were sufficient to result in overt cholinergic tremors at the high dose in each study. PB did not affect male or female fertility/reproductive performance. Pups born to treated dams did show slight, transient decreases in body weight gain, apparently secondary to the nursing behavior of dams demonstrating overt tremors. PB did not result in an increase in visceral or skeletal malformations. A slight increase in delayed ossification and early resorption were seen at the highest dose tested and were considered secondary to maternal stress/toxicity.     

Prenatal developmental toxicity evaluation of Withania somnifera root extract in Wistar rats

Context: Withania somnifera (L) Dunal (Solanaceae) is an important traditional herbal medicine used for thousands of years and is considered as the Indian ginseng. Reports on the effect of Withania somnifera root (WSR) extract on the developing foetus of pregnant rats including mortality, structural abnormalities, changes in growth and effects on dams are not available. Objective: The present study was performed to evaluate the prenatal developmental toxicity potential of WSR extract in rats. Materials and methods: WSR extract was given orally to pregnant rats during the period of major organogenesis and histogenesis (days 5 to 19 of gestation) at the dose levels of 500, 1000 and 2000?mg/kg/day. Clinical observations including mortality, moribundity, behavioural changes, signs of overt toxicity, body weight, gross pathological changes of dams and foetal analyses including external malformations, skeletal and soft tissue malformations were evaluated. Results: No evidence of maternal or foetal toxicity was observed. WSR extract caused no changes (p?Discussion and conclusion: Under the conditions of the study, the no-observed-effect level (NOEL) of WSR extract for maternal and developmental toxicity was concluded to be at least 2000?mg/kg/day.     

Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats.

Isoeugenol, used as a perfumery and flavoring agent, was evaluated for developmental toxicity. Timed-pregnant CD((R)) outbred albino Sprague-Dawley rats received isoeugenol (250, 500, or 1000 mg/kg/day) or vehicle (5 ml/kg corn oil) by gavage on gestational days (gd) 6 through 19. Maternal food and water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (23-25 per group) were evaluated for gestational outcome. All live fetuses were weighed and examined for external malformations, and approximately 50% were evaluated for visceral or skeletal malformations. There were no treatment-related maternal deaths. Clinical signs associated with isoeugenol exposure included dose-related evidence of sedation and aversion to treatment (rooting behavior) in all isoeugenol groups, as well as an increased incidence of piloerection at >/= 500 mg/kg/day. Maternal body weight, weight gain, and gestational weight gain (corrected for gravid uterine weight) were reduced at all doses in a dose-related manner. Gravid uterine weight was significantly decreased at the mid and high doses, whereas maternal relative liver weight was increased at all three dose levels. During treatment (gd 6 to 20), maternal relative food consumption was significantly decreased at the high dose, and maternal relative water consumption was elevated in the mid- and high-dose groups. Prenatal mortality (resorption or late fetal death) was unaffected. At 1000 mg/kg/day, average fetal body weight/litter was decreased by 7% (male) or 9% (female). Incidences of fetal morphological anomalies were statistically equivalent among groups, except for an increase in the incidence of unossified sternebra(e), a skeletal variation, at the high dose. In summary, the maternal toxicity lowest observed adverse effect level (LOAEL) was 250 mg/kg/day based primarily on reduced body weight and gestational weight gain (corrected for gravid uterine weight), and the maternal toxicity no observed adverse effect level (NOAEL) was not determined in this study. The developmental toxicity LOAEL was 1000 mg/kg/day based on intrauterine growth retardation and mildly delayed skeletal ossification. The developmental toxicity NOAEL was 500 mg/kg/day.     

Evaluation of the developmental toxicity of formamide in Sprague-Dawley (CD) rats.

Timed-pregnant CD(R) outbred albino Sprague-Dawley rats received formamide (50, 100, or 200 mg/kg/day) or vehicle (5 ml/kg deionized/distilled water, po) on gestational days (gd) 6 through 19. Maternal food and water consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (21-23 per group) were evaluated for clinical status and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. There were no maternal deaths and no dose-related clinical signs. At 200 mg/kg/day, maternal body weight on gd 20, weight gain, and gravid uterine weight were significantly decreased. Maternal weight gain, corrected for gravid uterine weight, liver weight (absolute or relative), and food and water consumption (absolute or relative), were not affected. Formamide did not affect prenatal viability or incidences of fetal malformations or variations. Average fetal body weight/litter was decreased at 100 and 200 mg/kg/day. Fetal body weight was affected at lower daily doses than in previously published studies, possibly due to the longer total exposure period and/or lack of a recovery period between cessation of exposure and termination. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 100 mg/kg/day and the low observed adverse effect level (LOAEL) was 200 mg/kg/day under the conditions of this study. Similarly, the developmental toxicity NOAEL was 50 mg/kg/day and the LOAEL was 100 mg/kg/day.     

Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats.

Melatonin (MEL) is a widely used, over-the-counter sleep aid, and it has putative contraceptive, antioxidant, antiaging, and anticancer effects. The developmental toxicity potential for repeated oral doses of MEL had not previously been evaluated. In the present studies, time-mated, Sprague-Dawley-derived (CD) rats were administered MEL or vehicle by gavage on gestation days (gd) 6-19. MEL-treated groups received 1-, 10-, 100-, 150-, or 200-mg/kg body weight/day in the screening study (15 rats/group), and 50, 100, or 200 mg/kg/day in the definitive study (25 rats/group). In both studies, maternal food/water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20, both studies), maternal liver and gravid uterine weights, number of ovarian corpora lutea, conceptus survival, fetal sex, and fetal body weight were evaluated. Fetal morphological examination included external structures (both studies) as well as visceral and skeletal structures (definitive study). In the screening study, maternal serum levels of 17beta-estradiol, progesterone, prolactin, and luteinizing hormone were determined by radioimmunoassay, and mammary tissue was fixed, stained, and evaluated for percent glandular area within the fat pad. No maternal morbidity/mortality was found in either study. In the screening study, aversion to treatment (> or =100 mg/kg/day) and reduced maternal weight gain (> or =150 mg/kg/day) were noted, but reproductive/endocrine parameters and fetal development were not affected. In the definitive study, aversion to treatment was noted at > or =50 mg/kg/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg/day. MEL had no effect on prenatal survival, fetal body weight, or incidences of fetal malformations/variations. Thus, in the definitive study, the maternal toxicity NOAEL and LOAEL were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL was > or =200 mg/kg/day.     

Oral (drinking water) developmental toxicity study of ammonium perchlorate in Sprague-Dawley rats

A developmental toxicity study was conducted with ammonium perchlorate (AP) in the drinking water at doses of 0.0, 0.01, 0.1, 1.0, and 30.0 mg/kg-day beginning 14 days before cohabitation and continuing through sacrifice. Twenty-four rats/group were cesarean-sectioned on day of gestation (DG) 21 and fetuses examined for visceral and skeletal alterations. An additional 16 litters/group were sacrificed on DG 21 for maternal and fetal serum TSH, T(3), and T(4) (thyroid-stimulating hormone, triiodothyronine, and thyroxine) levels and thyroid histopathology. Clinical and necropsy observations, body weights, feed and water consumption, and cesarean-sectioning parameters were comparable among the groups with only delays in ossification observed in the 30 mg/kg-day group. Maternal thyroid weights were increased in the 30.0 mg/kg-day group. Decreased colloid was present in male and female fetal thyroids in the 1.0 and 30.0 mg/kg-day groups. Maternal TSH was increased and T(4) was decreased at all levels, and T(3) was reduced at 30.0 mg/kg-day. Fetal TSH was increased at 1.0 and 30.0 mg/kg-day, T(4) was reduced at 30.0 mg/kg-day, and T(3) was decreased at all levels. The maternal no-observable-adverse-effect level (NOAEL) was 1.0 mg/kg-day; exposures of 30.0 mg/kg-day increased absolute and relative maternal thyroid weights and histopathology findings. The developmental NOAEL was 1.0 mg/kg-day; developmental delays in ossification occurred in the 30.0 mg/kg-day group. The colloid depletion in the thyroids and increased TSH and decreased T(3) and T(4) levels at lower exposures were considered adaptive and not adverse. No adverse effects on development at occurred levels that did not cause maternal toxicity. AP is not a selective developmental toxicant.     

Developmental toxicity of di-isodecyl and di-isononyl phthalates in rats

The developmental toxicity of di-isodecyl phthalate (DIDP; CAS RN 68515-49-1) and di-isononyl phthalate (DINP; CAS RN 68515-48-0) were investigated in Sprague-Dawley rats. DIDP and DINP were administered by gavage to mated rats at doses of 0, 100, 500, and 1000 mg/kg/d on Gestation Days (GD) 6 through 15. Cesarean sections were performed on GD 21 and the fetuses removed for evaluation. Maternal weight gain and food consumption were significantly reduced at 1000 mg/kg/d during the exposure period. No treatment-related effects were noted at cesarean section, nor were there any fetal morphologic observations except for an increased frequency of seventh cervical and rudimentary lumbar ribs at the maternally toxic exposure level of 1000 mg/kg/d. Under these study conditions, mild maternal and developmental effects were observed at 1000 mg/kg/d. Both maternal and developmental NOAELs were therefore established at 500 mg/kg/d. The results indicate that neither DIDP nor DINP is teratogenic or a selective developmental toxicant.     

Prenatal oral (gavage) developmental toxicity study of decabromodiphenyl oxide in rats

Decabromodiphenyl oxide (DBDPO) is a highly effective flame retardant that is primarily used in electrical and electronic equipment with a secondary, but important, application in upholstery textiles. DBDPO, the second largest volume brominated flame retardant in use today, has undergone a wide range of toxicology tests in mammalian species with the results indicating a no-adverse-effect level of approximately 1000 mg/kg/day in oral repeated-dose studies. An oral prenatal developmental toxicity study of the commercial DBDPO product (97% purity) was performed under current EPA OPPTS and OECD guidelines. Female Sprague-Dawley rats (25 mated females/group) received 0,100, 300 or 1000 mg DBPDO/kg/ day via gavage in corn oil during gestation days 0 through 19. All females survived until scheduled sacrifice. No clinical signs of toxicity were observed. Pregnancy rates in the control and treated groups ranged from 96% to 100% and provided 23 or more litters in each group for evaluation on gestation day 20. No effect of treatment was seen in maternal gestational parameters (body weight, body weight gain, and food consumption), uterine implantation data, liver weight, or necropsy findings. Likewise, no effect of treatment was seen in fetal body weights, fetal sex distribution, or during the fetal external, visceral, or skeletal examinations. The NOEL (no-observable-effect level) for maternal and developmental toxicity was 1000 mg DBPDO/kg/day, the highest dose level administered on gestation days 0 to 19.     

Subchronic and developmental toxicity studies of n-butyl propionate vapor in rats

Two inhalation studies were conducted to evaluate the possible subchronic and developmental toxic effects of n-butyl propionate. In the subchronic study, Sprague-Dawley rats (15/sex/group) were exposed to 0, 250, 750, or 1500 ppm vapor for 6 h/d, 5 d/wk for 13 wk. Five of the rats per sex per group were held after the final exposure for an 8-wk recovery period. Standard parameters of subchronic toxicity were measured throughout the study, and at the end of exposure and recovery periods, necropsies were performed, organs weighed, and tissues processed for microscopic examination. Exposure did not produce marked treatment-related deaths or adversely affect clinical signs, hematology, clinical chemistries, organ weights, or the histology of major visceral organs. The only systemic toxic effects were significant decreases in body weight, body weight gain, and feed consumption that occurred in 1500 ppm group rats. Morphologic changes were limited to the nasal cavity as evidenced by a concentration-related increased incidence and severity of olfactory epithelium degeneration in rats of the 750 and 1500 ppm groups. These degenerative microscopic alterations were primarily confined to the olfactory epithelium within the dorsal portion of the medial meatus, with lesser involvement of the olfactory mucosae overlying the tips of some of the adjacent ethmoturbinates. Both the systemic and nasal cavity effects appeared reversible after exposure ceased. In the developmental toxicity study, pregnant Sprague-Dawley rats (24/group) were exposed to 0, 500, 1000, or 2000 ppm vapor for 6 h/d on gestation d 6-15 and sacrificed on gestation d 20. All treatment-group dams exhibited significant reductions in body weight, body weight gain, and feed consumption. Gestational parameters were equivalent across all groups and there were no treatment-related developmental or teratogenic effects. The no-observed-adverse effects levels (NOAELs) determined for nbutyl propionate were 250 ppm for subchronic toxicity (based on the olfactory epithelium degeneration) and 22000 ppm for developmental toxicity (no developmental effects at top dose tested). Under the conditions of this study, a NOAEL was not determined for maternal toxicity.     

Subchronic and developmental toxicity studies in rats with Ac-Di-Sol croscarmellose sodium

Studies were conducted to evaluate the subchronic and developmental toxicity of Ac-Di-Sol (croscarmellose sodium). In the subchronic study, groups of Sprague-Dawley rats (20/sex/group) received 0 (control), 10000, or 50000 ppm Ac-Di-Sol in the diet for 90 consecutive days (equivalent to 757 and 893 mg/kg/day for males and females fed 10000 ppm, respectively, and to 3922 and 4721 mg/kg/day for males and females fed 50000 ppm, respectively). No mortality, clinical signs of toxicity, or adverse toxicological effects on hematology or serum chemistry parameters, feed consumption, or ophthalmologic examinations were noted in any treatment group. Body weight gain was depressed in high-dose males during the final 3 weeks. The only treatment-related histological lesion noted was moderate renal mineralization at the corticomedullary junction in one high-dose female. This lesion was not considered a specific effect of Ac-Di-Sol, but rather a secondary effect resulting from a potential increase in urinary pH and renal excretion of sodium due to the high intake of sodium associated with Ac-Di-Sol. In the developmental toxicity study, groups of pregnant Sprague-Dawley rats (25/group) received 0 (control), 10000, or 50000 ppm Ac-Di-Sol in the diet on gestational days 6 to 15. No evidence of maternal, fetal, or embryo toxicity was noted. The no-observed-adverse-effect level (NOAEL) for Ac-Di-Sol in both studies exceeds 50000 ppm in the diet, which represents doses of 3922 and 4712 mg/kg/day, for males and females, respectively. The results of these studies demonstrate the low subchronic oral toxicity and developmental toxicity of Ac-Di-Sol, and support the safe use of Ac-Di-Sol in oral applications such as pharmaceuticals, dietary supplements, and sweetener tablets.     

Subchronic toxicity of vomitoxin in Sprague-Dawley rats

Purified vomitoxin was incorporated into the diet at a level of 20 ppm and fed to male Sprague-Dawley rats ad lib. for 90 days. Few clinical signs of toxicity were observed. Rats in the vomitoxin treatment group were less efficient in converting feed into body mass, but there was no feed refusal. Terminal body weight was reduced in the vomitoxin treatment group. There were no statistically significant effects on serum enzyme levels, haematological parameters or tissue lesions, or on liver detoxification systems, as reflected in levels of microsomal cytochrome P-450 or in glutathione S-transferase activity.     

Developmental toxicity of thiodiglycol in Sprague-Dawley rats

Thiodiglycol (TG), a hydrolysis product of sulfur mustard (HD), is a potential contaminant of soil and water at certain military sites. To establish developmental toxicity criteria for TG, an oral developmental toxicity study was conducted in Sprague-Dawley rats. Neat thiodiglycol (99.9 %) was administered orally to mated female rats from gestation days (GDs) 5 through 19. The day of positive mating was considered day 0. A pilot study was conducted with TG at dose levels 250, 500, 1,000, 2,000, or 5,000 mg/kg to select suitable doses for the main study. In the main study, three groups of rats (25/group) received TG by gavage at dose levels of 430, 1,290, or 3,870 mg/kg/day. A fourth group served as a sham control. On day 20 of gestation, all females were euthanized and a cesarean section performed. Litters were examined for soft tissue and skeletal alterations. Maternal toxicity was limited to dams receiving TG at 3,870 mg/kg/day. At this dose, body weights and food consumption were reduced during certain periods of gestation. Fetuses derived from those dams exhibited a nonstatistically significant increased incidence of variations when compared to controls. Fetal body weights in the 3,870 mg/kg/day group were significantly lower than controls. There was no increased incidence of anomalies when thiodiglycol-treated fetuses were compared to controls. It was concluded that TG did not produce terata. Developmental toxicity (decreased fetal weights and associated delays in development) occurred only at the maternally toxic dose of 3,870 mg/kg. It appears that 1,290 mg/kg/day could be considered no observed adverse effect level (NOAEL) for oral developmental toxicity. The lowest observed adverse effect level (LOAEL) was 3,870 mg/kg for maternal toxicity.     

Subchronic toxicity studies of the aqueous extract of Aristolochiae fructus in Sprague-Dawley rats

The subchronic toxicity of Aristolochiae fructus containing aristolochic acids (AAs), a natural component in the Aristolochiaceae family, was investigated. The A. fructus was daily administered by gavage to male and female rats for 90 d at dose levels of 21.35, 213.5, and 2135 mg/kg (equivalent to 0.05, 0.5, and 5 mg/kg as AAs, respectively). During the test period, clinical signs, mortality, body weights, food and water consumption, hematology, serum biochemistry, organ weights, and histopathology were examined. Significant decreases in body weight gain were noted in the high-dose group receiving both the aqueous extract of A. fructus and AAs. Decreases in food consumption were noted beginning at 50 d and did not recover in the high-dose group of aqueous extract of A. fructus and AAs. Irrespective of dose, water consumption was not affected. There was no mortality or adverse clinical signs, hematology, or serum biochemistry in the treatment groups versus control. Nephrotoxicity and hyperplasia of epithelial cells in the forestomach were observed in rats receiving the highest dose of aqueous extract of A. fructus and at doses of >or= 0.5 mg/kg/day AAs. For both genders, the no-observed-adverse-effect level (NOAEL) for A. fructus based on this subchronic study in rats was considered to be 21.3 mg/kg/d.     

Prenatal developmental toxicity study with 7-hydroxymatairesinol potassium acetate (HMRlignan) in rats

Plant lignan 7-hydromatairesinol, a novel precursor of the mammalian lignan enterolactone was evaluated in a prenatal developmental toxicity study conducted in the Wistar rat. Mated female rats were fed diets containing 0, 0.25, 1, and 4% (w/w) of 7-hydroxymatairesinol in the form of potassium acetate complex (HMRlignan; potassium acetate level approximately 20% w/w within the preparation) for days 0-21 of gestation. Test substance intake was calculated to be 0.14-0.18, 0.46-0.74, and 1.19-2.93 g/kg body weight/day for the low, mid, and high-dose groups, respectively. The rats were sacrificed on day 21 of the gestation period and examined for standard parameters of reproductive performance (fecundity index, gestation index, number of corpora lutea, number of implantations, pre- and post-implantation loss, number of early- and late resorptions, number of live- and dead fetuses, sex-ration and the weight of the reproductive organs). The fetuses were examined for external, visceral, and skeletal alterations. The results from this study showed no effects on reproductive performance or any treatment related findings following external, visceral, and skeletal examination of the fetuses. However, approximately half of the mated dams of the high-dose failed to thrive due to an unexpected large decrease in their food intake, and were sacrificed early. Body weights of the remaining animals of the high-dose group were decreased. Food consumption was decreased in all treatment groups during the first three days of the gestation period as a result of decreased palatability of the feed. In conclusion, the no-observed-effect level (NOEL) for maternal effects was 1%, whereas the NOEL for fetal development following daily oral HMRlignan administration throughout the gestation was equivalent to 4% in the diet.     

Prenatal toxicity of acyclovir in rats

Pregnant rats were treated during organogenesis with s.c. injections of acyclovir and the embryos were evaluated on day 11.5 of gestation (crown-rump length, somites, protein content, score, abnormalities, histological examination). After eight injections of 50 mg/kg body wt on days 9, 10, and 11 of pregnancy a reduction of the crownrump length was noticed. After 100 mg/kg this effect was more pronounced. With two or three applications of this dose on day 10 specific embryonic abnormalities were visible: the shape of the head was abnormal, the width of the skull had decreased resembling a beak-like visceral cranium. With a single administration of 200 mg/kg on day 10 we found a similar but slightly more pronounced outcome. A drastic change of all variables was obtained after eight injections of 100 mg/kg on days 9, 10, and 11. Comparatively we measured maternal plasma concentrations of acyclovir 1 h after the administration of 50, 100 or 200 mg/kg body wt. After an injection of 50 mg/kg on days 9, 10, and 11 of gestation (three injections/day) the plasma levels ranged from 19.1 to 40.0 mg/l (1 mg/l = 4.44 M). No cumulation was observed. In contrast, a cumulative effect was detected following a dose of 100 mg/kg. After the first injection of this dose a mean value (± SD) of 60.3±14.7 mg/l (n = 16) was obtained. In this case a third injection increased the mean plasma level to 124.6±16.6 mg/l (n = 5). Further injections, however, led to decreasing levels. One hour after administration of 200 mg/kg body wt acyclovir levels ranged from 120.0 to 163.9 mg/l. We conclude that acyclovir, at doses leading to plasma concentrations well above the therapeutic level in the dam, interferes with the embryonic development in the rat. Acyclovir induces typical gross structural abnormalities which have been first observed using a whole embryo culture system.     

Subacute toxicity of chitosan oligosaccharide in Sprague-Dawley rats

A subacute oral toxicity study of chitosan oligosaccharide was performed in Sprague-Dawley rats of both sexes. Each 36 male and female rats were administered by gavage with 500, 1,000 and 2,000 mg/kg/day for 4 weeks (7 days/week), respectively. Examinations regarding clinical signs, body weights, hematological and biochemical parameters, and histopathological examinations were carried out. There were no significant differences in behavior or external appearance, body weight and food consumption between control and treated rats. In addition, no significant differences in urinalysis, hematology, blood biochemistry, relative organ weights and histopathological findings were found in both control and treated rats. In conclusion, it was suggested that subacute toxicity of chitosan oligosaccharide was low and the no-observed adverse effect level was considered to be over 2,000 mg/kg in rats.     

Prenatal developmental toxicity study of the basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats

Pregnant rats were given 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 10, 20 or 40 mg/kg bw/day on days 6–19 of pregnancy and the pregnancy outcome was determined on day 20 of pregnancy. At 40 mg/kg bw/day, deaths were observed in four out of 24 females. The incidences of females showing mydriasis at 20 and 40 mg/kg bw/day and showing decreased locomotor activity at 40 mg/kg bw/day were significantly increased. Alopecia, bradypnea, prone position and tremor were also observed at 40 mg/kg bw/day. The maternal body weight gain at 20 and 40 mg/kg bw/day and food consumption at 40 mg/kg bw/day were significantly reduced. A significantly decreased weight of the gravid uterus, increased incidence of postimplantation loss, decreased number of live fetuses, and lowered weights of fetuses and placentae were found at 40 mg/kg bw/day. The incidences of the total number of fetuses with external malformations at 40 mg/kg bw/day and with skeletal malformations at 20 and 40 mg/kg bw/day were significantly increased. Significantly higher incidences of fetuses with brachydactyly and short tail and defects of caudal vertebrae, phalanges and metacarpals were observed at 40 mg/kg bw/day. Delayed ossification was also noted at 40 mg/kg bw/day. The data indicate that DTG is teratogenic at maternal toxic doses and the NOAELs of DTG for maternal and developmental toxicity are 10 mg/kg bw/day in rats.     

Prenatal developmental toxicity study of the basic rubber accelerator, 1,3-di-o-tolylguanidine,in rats

Pregnant rats were given 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 10, 20 or 40 mg/kg bw/day on days 6–19 of pregnancy and the pregnancy outcome was determined on day 20 of pregnancy. At 40 mg/kg bw/day, deaths were observed in four out of 24 females. The incidences of females showing mydriasis at 20 and 40 mg/kg bw/day and showing decreased locomotor activity at 40 mg/kg bw/day were significantly increased. Alopecia, bradypnea, prone position and tremor were also observed at 40 mg/kg bw/day. The maternal body weight gain at 20 and 40 mg/kg bw/day and food consumption at 40 mg/kg bw/day were significantly reduced. A significantly decreased weight of the gravid uterus, increased incidence of postimplantation loss, decreased number of live fetuses, and lowered weights of fetuses and placentae were found at 40 mg/kg bw/day. The incidences of the total number of fetuses with external malformations at 40 mg/kg bw/day and with skeletal malformations at 20 and 40 mg/kg bw/day were significantly increased. Significantly higher incidences of fetuses with brachydactyly and short tail and defects of caudal vertebrae, phalanges and metacarpals were observed at 40 mg/kg bw/day. Delayed ossification was also noted at 40 mg/kg bw/day. The data indicate that DTG is teratogenic at maternal toxic doses and the NOAELs of DTG for maternal and developmental toxicity are 10 mg/kg bw/day in rats.