Developmental toxicity study with triethylene glycol given by gavage to CD rats and CD-1 mice

Triethylene glycol (TEG) is a liquid industrial chemical with a potential for human exposure. The likelihood for developmental toxicity was investigated in two species. Timed-pregnant CD rats and CD-1 mice were dosed daily by gavage with undiluted TEG over gestational days (gd) 5-15 at 0.0 (water control), 1126, 5630 or 11,260 mg kg(-1) day(-1) with rats and 0.0, 563, 5630 or 11,260 mg kg(-1) day(-1) with mice. They were examined daily, and gestational body weights and food and water consumption measured throughout gestation. At necropsy on gd 21 (rats) or gd 18 (mice) dams were examined for body, gravid uterine, liver and kidney weights, and implantation sites. Maternal kidneys were examined histologically. Fetuses were weighed, sex determined, and examined for external, soft tissue and skeletal variations and malformations. Rat dams had reduced body weights, body weight gains, and food consumption, and increased water consumption and relative kidney weights at 11,260 mg kg(-1) day(-1). They also had reduced body weight and increased water consumption at 5630 mg kg(-1) day(-1). Mice had clinical signs and increased relative kidney weight at 11,260 mg kg(-1) day(-1). Renal histology was normal in both species. Neither species had treatment-related effects on corpora lutea or implantations. Fetal body weights were reduced at 11,260 mg kg(-1) day(-1) (both species) and 5630 mg kg(-1) day(-1) (mice). In rat fetuses there was a pattern of delayed ossification in the thoracic region at 11,260 mg kg(-1) day(-1). Mouse fetuses had delayed ossification in the frontal and supraoccipital bones, cervical region, hindlimb proximal phalanges and reduced caudal segments at 11,260 mg kg(-1) day(-1), and in the skull bones at 5630 mg kg(-1) day(-1). These patterns of delayed ossification are consistent with reduced fetal body weights. No biologically significant embryotoxicity or teratogenicity was observed at any dosage in either species. The NOEL for TEG given by gavage over the period of organogenesis was 1126 mg kg(-1) day(-1) in the rat and 5630 mg kg(-1) day(-1) in the mouse for maternal toxicity, and 5630 mg kg(-1) day(-1) (rat) and 563 mg kg(-1) day(-1) (mouse) for developmental toxicology.     

Developmental toxicity study with diethylene glycol dosed by gavage to CD rats and CD-1 mice.

Diethylene glycol (DEG; CAS Number 111-46-6) is a widely used industrial liquid chemical with a potential for human exposure. In view of the established teratogenic effects caused by ethylene glycol in laboratory animals, the developmental toxicity of DEG was investigated in mice and rats, species known to be sensitive to the developmental toxicity of ethylene glycol. Timed-pregnant CD-1 mice and CD rats were dosed daily by gavage with undiluted DEG over gestational days (gd) 6-15. Based on probe studies, mouse dosages were 0 (distilled water), 559, 2795 and 11,180 mg/kg/day, and those for rats 0, 1118, 4472 and 8944 mg/kg/day. They were examined daily for clinical signs of toxicity, and body weights, food consumption and water consumption measured periodically throughout gestation. At necropsy, on gd 18 (mice) or gd 21 (rats), dams were examined for gross pathology and body, gravid uterus, liver and kidney weights were measured. Maternal rat kidneys were examined histologically. Fetuses were weighed, sex determined, and examined for external, visceral and skeletal variations and malformations. With mice there was maternal toxicity at 11,180 mg/kg/day (mortality, signs, increased water consumption) and at 2795 mg/kg/day (increased water consumption). Implantations were comparable across all groups. Fetal body weights were significantly reduced at 11,180 mg/kg/day. There were no increases in variations or malformations, either total, by category, or individually. With rats, maternal toxicity was present at 8944 mg/kg/day (mortality, signs, reduced body weight gain, reduced food consumption, increased water consumption, increased liver weight, increased kidney weight, and renal histopathology), and 4472 mg/kg/day (increased water consumption). There were no treatment-related effects on corpora lutea or implantations. Fetal body weights were reduced at 8944 mg/kg/day. There were no significant effects with respect to total or individual external or visceral variations. Individual skeletal variations were significantly increased at 8944 mg/kg/day (poorly ossified interparietal, poorly ossified thoracic centra number 10 and number 13, and bilobed thoracic centrum number 10) and 4472 mg/kg/day (split anterior arch of atlas and bilobed thoracic centrum number 10). This pattern of delayed ossification is consistent with reduced fetal body weight. Malformations, total, by category, or individually, were similar between the control and DEG groups. Thus, under the conditions of these studies, the no-observed-effect-level (NOEL) for DEG given by gavage over gd 6-15 was 559 mg/kg/day with the mouse and 1118 mg/kg/day with the rat for maternal toxicity, and 2795 mg/kg/day with mice and 1118 mg/kg/day with rats for developmental toxicity (fetotoxicity). There were no indications of embryotoxicity or teratogenic effects at any dosage in either species.     

Developmental toxicity of methylamines in mice

Monomethylamine (MMA), dimethylamine (DMA), and trimethylamine (TMA) are endogenous substances as well as metabolites of methyl isocyanate, the chemical involved in the 1984 accident at Bhopal, India. Although methylamines exert several toxic effects including inhibition of protein turnover and oocyte RNA synthesis, their reproductive toxicity has not been investigated. We therefore studied the possible developmental toxicity of these amines using pregnant CD-1 mice and mouse embryo culture as experimental models. Intraperitoneal injections (daily from d 1 to 17 of gestation) of TMA at 2.5 and 5 mmol/kg/d significantly (p less than .001) decreased fetal body weight but not the placental weight or maternal body weight gain; however, 5 of 11 mice treated with 5 mmol/kg TMA died. Similar treatment with DMA and MMA did not exert any obvious maternal or fetal effects. All three methylamines, when added to embryos in culture, caused dose-dependent decreases in size, DNA, RNA, and protein content as well as embryo survival; the order of toxicity was TMA greater than DMA greater than MMA. The ability of methylamines to adversely affect fetal development suggests that these amines, especially trimethylamine, may act as endogenous teratogens under certain conditions.     

Developmental toxicity of Spinosad administered by gavage to CD® rats and New Zealand White rabbits

The insecticide Spinosad was administered by gavage to pregnant CD® rats at 0, 10, 50 or 200 mg/kg/day on gestation days (gd) 6–15 and to New Zealand White rabbits at 0, 2.5, 10 or 50 mg/kg/day on gd-7–19. Rats and rabbits were monitored for clinical signs of toxicity and body weight gains. At gd-21 (rats) or gd-28 (rabbits), maternal organ weights, reproductive parameters, fetal body weights, and fetal external, visceral and skeletal structures were evaluated. Rats given 200 mg/kg/day exhibited a 4% lower body weight on gd-12 and decreased body weight gains on gd-6–16 relative to controls. There was no maternal toxicity at 10 or 50 mg/kg/day, and no developmental toxicity in rats at any dose level. Rabbits given 50 mg/kg/day exhibited decreased feed consumption, reduced fecal output, body weight loss during the initial dosing period (gd-7–10) and a non-statistically significant decrease (31%) in body weight gain during the dosing period (gd-7–20). Two litters aborted due to maternal inanition. There were no maternal effects at lower doses, and no signs of developmental toxicity at any dose. Thus, the maternal no-observed-effect levels (NOEL) were 50 and 10 mg/kg/day in rats and rabbits, respectively, and the embryonal/fetal NOELs were 200 mg/kg/day in rats and 50 mg/kg/day in rabbits.     

Developmental toxicity of triphenyltin hydroxide in mice

Triphenyltin-hydroxide (TPTH) is used as agricultural fungicide in Brazil and elsewhere. This study was undertaken to evaluate the developmental toxicity of TPTH in mice. Swiss Webster mice were treated by gavage with TPTH (0, 3.75, 7.5, 15 and 30 mg/kg bw/day) on gestation days (GD) 6-17. Caesarean sections were performed on GD 18, and implantations, resorptions and live and dead fetuses were counted. Half of each litter was fixed and examined for visceral anomalies while the remaining fetuses were cleared and stained with Alizarin Red S for skeleton evaluation. A reduced pregnancy weight gain (after subtraction of uterine weights), smaller thymus, spleen and liver, and deaths indicated that doses > or = 7.5mg/kg body wt/day were toxic to mothers. At the two highest doses, TPTH enhanced embryolethality and reduced fetal body weight. The incidence of cleft palate (not seen in controls) was augmented (36.8%) at the highest dose of TPTH, while palatine bone defects were increased at the lowest dose (3.75 mg/kg bw/day). Soft-tissue anomalies, such as misshapened thymus, and malpositioned testes and uteri, were more frequent at doses of TPTH > or = 7.5 mg/kg bw/day. TPTH also caused a dose-related increase of fetal skeleton variations (e.g. poorly ossified skull bones) and malformations (misshapened Axis and skull bones). In conclusion, TPTH was toxic to the embryos (NOAEL <3.75 mg/kg bw/day) at doses that were not overtly toxic to their mothers.     

Developmental toxicity of perfluorononanoic acid in mice

Perfluorononanoic acid (PFNA) is a ubiquitous and persistent environmental contaminant. Although its levels in the environment and in humans are lower than those of perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA), a steady trend of increases in the general population in recent years has drawn considerable interest and concern. Previous studies with PFOS and PFOA have indicated developmental toxicity in laboratory rodent models. The current study extends the evaluation of these adverse outcomes to PFNA in mice. PFNA was given to timed-pregnant CD-1 mice by oral gavage daily on gestational day 1–17 at 1, 3, 5 or 10 mg/kg; controls received water vehicle. Dams given 10 mg/kg PFNA could not carry their pregnancy successfully and effects of this dose group were not followed. Similar to PFOS and PFOA, PFNA at 5 mg/kg or lower doses produced hepatomegaly in the pregnant dams, but did not affect the number of implantations, fetal viability, or fetal weight. Mouse pups were born alive and postnatal survival in the 1 and 3 mg/kg PFNA groups was not different from that in controls. In contrast, although most of the pups were also born alive in the 5 mg/kg PFNA group, 80% of these neonates died in the first 10 days of life. The pattern of PFNA-induced neonatal death differed somewhat from those elicited by PFOS or PFOA. A majority of the PFNA-exposed pups survived a few days longer after birth than those exposed to PFOS or PFOA, which typically died within the first 2 days of postnatal life. Surviving neonates exposed to PFNA exhibited dose-dependent delays in eye opening and onset of puberty. In addition, increased liver weight seen in PFNA-exposed offspring persisted into adulthood and was likely related to the persistence of the chemical in the tissue. Evaluation of gene expression in fetal and neonatal livers revealed robust activation of peroxisome proliferator-activated receptor-alpha (PPARα) target genes by PFNA that resembled the responses of PFOA. Our results indicate that developmental toxicity of PFNA in mice is comparable to that of PFOS and PFOA, and that these adverse effects are likely common to perfluoroalkyl acids that persist in the body.     

Developmental toxicity evaluation of gallium nitrate in mice

Gallium nitrate, a drug with antitumor activity, is presently undergoing clinical trials as a chemotherapeutic agent for the treatment of certain malignancies. Since there are very limited published animal toxicity data available, this study was conducted to investigate the potential adverse developmental effects of this drug. Pregnant Swiss mice were administered intraperitoneally gallium nitrate at 12.5, 25, 50, and 100 mg/kg/day on days 6, 8, 10, 12, and 14 of gestation. Monitors for maternal toxicity were body weight, food consumption and clinical signs. At sacrifice (day 18) maternal weight, liver and kidney weights, and gravid uterine weights were measured. Gestational parameters monitored were numbers of total implants, resorptions, postimplantation losses, and dead fetuses. Live fetuses were sexed, weighed, and examined for external, internal and skeletal malformations and variations. Maternal toxicity was noted in all the gallium nitrate-treated groups. Embryo/fetal toxicity was evidenced by a decrease in the number of viable implants, a reduction in fetal weight, and an increase in the number of skeletal variations (12.5, 25, 50 and 100 mg/kg). No significant increase in the incidence of malformations was observed at 12.5, 25, or 50 mg/kg. The no-observable-adverse-effect level (NOAEL) for both maternal and developmental toxicity of gallium nitrate was <12.5 mg/kg.     

妊娠中期可卡因对小鼠的发育毒性

目的:探讨可卡因对小鼠妊娠中期的发育毒性,尤其是对脑发育的影响.方法:建立妊娠中期给药的小鼠动物模型,体重相近的妊娠母鼠被分为三组:(1)可卡因注射自由饮食组(COC);(2)盐水注射伴有饮食对照组(SPF),饮食参考体重相近、妊娠时间相同的COC组母鼠;(3)盐水注射自由饮食组(SAL).从妊娠第8天(E8)至第12天(E12)给药,记录母鼠、胎鼠和仔鼠的各项生理指标,并用HPLC分析各组胎鼠纹状体中多巴胺、5-HT含量的变化.结果:尽管COC和 SPF组母鼠与 SAL组母鼠相比摄食量少,体重增加量少,但E17 天取材时,仅COC组胎鼠表现为脑和纹状体重量低;COC组仔鼠生后第 1天(P1)双顶径(BPD)也小于其它两组仔鼠.此外,COC组胎鼠表现出脑/体重比的降低,说明宫内暴露可卡因引起的胎鼠的发育迟缓是一个不平衡过程,脑组织的受累比其它组织严重.神经递质分析和组织学分析表明 COC组胎鼠脑内多巴胺和5-羟色胺的水平增高,肝脏呈现出形态学改变.结论:妊娠中期暴露可卡因可引起胎鼠宫内发育迟缓,尤其是脑发育迟缓.单纯母体营养不良在宫内暴露可卡因引起的后代发育迟缓过程中不能起决定性作用,而可能是药物直接作用的结果.     

Developmental toxicity of Guthion in rats and mice

The purpose of this study was to assess the effects of Guthion, a pesticide with anticholinesterase activity, on development in rats and mice. A preliminary toxicity study with Guthion indicated that a 35-day LD₅₀ dose for virgin rats and a 10-day LD₅₀ dose for virgin mice was between 4 and 8 mg/kg/day for both species. On the basis of these data, doses of 0, 1.25, 2.5, and 5.0 mg/kg/day were selected for the developmental study, which consisted of two phases. During the first phase, pregnant rats and mice were treated for 10 days starting on gestational day 6. The high dose affected maternal welfare only in rats. Guthion did not significantly increase in a dose-related manner any of the specific anomalies observed in either rats or mice. During the second phase, pregnant rats were treated from gestational day 6 to postpartum day 21. Dams in the high dose group were more sensitive to Guthion later in gestation with the result that deaths and signs of anticholinesterase toxicity increased during this time. Guthion also adversely affected maternal welfare in this group. As a result of Guthion toxicity, only one litter survived until weaning. The inability to dissociate toxicity in adult and developing animals suggests that Guthion has little primary effect on the development of rats or mice.     

Developmental toxicity of an octyltin stabilizer in NMRI mice

The octyltin stabilizer ZK 30.434 is a mixture of 80% dioctyltin diisooctylthioglycolate (DOTTG) and 20% of monooctyltin triisooctylthioglycolate (MOTTG) and is used as stabilizer for rigid polyvinylchloride (PVC) materials. One of the applications of such stabilized films is the packaging of foodstuffs. Exposure to humans occurs via migration of DOTTG/MOTTG from PVC materials. In the present study the developmental toxicity of DOTTG/MOTTG in NMRI mice was investigated. Dams were treated orally with doses of 20, 30, 45, 67, or 100 mg/kg/day DOTTG/MOTTG from gestation day 6 through 17 (plug = day 1). Resorption rates were significantly increased and fetal weights significantly reduced in the study group at the 2 highest doses. External anomalies, such as bent forelimbs, cleft palate, and exencephaly were reported in the group treated with 100 mg/kg/day DOTTG/MOTTG, with the 67-mg/kd dose also exhibiting a significant increase in cleft palate. Moreover, an increase in skeletal anomalies was reported in fetuses exposed to 100 mg/kg/day. The doses of 20, 30, and 45 mg/kg/day elicited a significant increase in supernumerary lumbar ribs. It can be concluded that DOTTG/MOTTG is embryo-fetotoxic and induces developmental effects. The study revealed the need for the establishment of different No-Observed Adverse Effect Levels (NOAEL) for the endpoints investigated.     

Developmental toxicity of vanadium in mice after oral administration

Vanadium, as vanadyl sulphate pentahydrate, was evaluated for its embryotoxic, fetotoxic and teratogenic potential in Swiss mice. The compound was administered by gavage to pregnant mice at doses of 0, 37.5, 75 or 150 mg kg-1 day-1 on days 6-15 of pregnancy. On gestation day 18, all live fetuses were examined for external, visceral and skeletal malformations and variations. Maternal toxicity was observed in the vanadium-treated animals, as evidenced by reduced weight gain, reduced body weight on gestation day 18 (corrected for gravid uterine weight) and decreased absolute liver and kidney weights at 75 and 150 mg kg-1 day-1. The number of total implants, live and dead fetuses, late resorptions, the sex ratio and the post-implantation losses were not significantly different between the vanadium-treated mice and the controls. However, there was a significant increase in the number of early resorptions per litter at all dose levels. Fetotoxicity was evidenced by lower fetal weights and fetal lengths, and the presence of developmental variations. Malformation incidence also was increased by the administration of vanadium. Thus, the 'no observable effect level' (NOEL) for maternal toxicity, embryofetotoxicity and teratogenicity for vanadyl sulphate pentahydrate under these test conditions was below 37.5 mg kg-1 day-1 for Swiss mice.     

Reproductive toxicology of acephate in male mice

The reproductive toxicity of the insecticide acephate was studied in male mice. Adult male mice were treated by gavage with acephate at doses of 0, 7, 14, and 28 mg/kg/day for 4 weeks before mating with untreated females. Signs of cholinergic effects were observed in the 28 mg/kg/day group. Brain and skeletal muscle acetylcholinesterase activity was inhibited only in this group. Acephate treatment was associated with a decreased number of implantations and live fetuses, and an increased number of early resorptions at 28 mg/kg/day. The percent morphologically normal spermatozoa was unaffected in all dose groups; however, sperm motility and count were decreased in the 14 and 28 mg/kg/day groups compared to the control. Histologic examination of brain did not reveal any abnormalities. Dose related histologic changes, including degeneration of muscle fibers, were observed in the muscles of male mice treated with any of the doses of acephate. The current study demonstrated adverse effects of male acephate exposure on pregnancy outcome with effects on sperm parameters at 14 and 28 mg/kg/day.     

Developmental toxicity potential of grayanotoxin I in mice and chicks

Developmental toxicity potential of grayanotoxin I (GTX I), a toxic diterpenoid contained in plants of the family Ericaceae, with sodium ionophore activity, was studied in mice and chicks. In mice, intraperitoneal injections of 1.5 mg GTX I/kg body weight of mouse for three consecutive days during the organogenetic period caused some dams to die, but neither embryotoxicity nor teratogenicity was detected. In chicks, a single injection of 0.1-1.0 microgram GTX I per egg into the extraembryonic coelom on day 1.5 or 2 of incubation, or into the amnionic cavity on day 3 or 4 of incubation induced neither embryotoxic nor teratogenic signs, but 10 micrograms GTX I per egg showed lethal effects when applied on each of those days.     

Developmental toxicity assessment of arsenic acid in mice and rabbits

To evaluate potential effects of exposure to inorganic arsenic throughout major organogenesis, CD-1 mice and New Zealand White rabbits were gavaged with arsenic acid dosages of 0, 7.5, 24, or 48 mg/kg/d on gestation days (GD) 6 through 15 (mice) or 0, 0.19, 0.75, or 3.0 mg/kg/d on GD 6 through 18 (rabbits) and examined at sacrifice (GD 18, mice; GD 29, rabbits) for evidence of toxicity. Two high-dose mice died, and survivors at the high and intermediate doses had decreased weight gains. High-dose-group fetal weights were decreased; no significant decreases in fetal weight or increases in prenatal mortality were seen at other dosages. Similar incidences of malformations occurred in all groups of mice, including controls. At the high dose in rabbits, seven does died or became moribund, and prenatal mortality was increased; surviving does had signs of toxicity, including decreased body weight. Does given lower doses appeared unaffected. Fetal weights were unaffected by treatment, and there were no effects at other doses. These data revealed an absence of dose-related effects in both species at arsenic exposures that were not maternally toxic. In mice, 7.5 mg/kg/d was the maternal No-Observed-Adverse-Effect-Level (NOAEL); the developmental toxicity NOAEL, while less well defined, was judged to be 7.5 mg/kg/d. In rabbits, 0.75 mg/kg/d was the NOAEL for both maternal and developmental toxicity.     

Developmental toxicity of orally administered thiabendazole in ICR mice.

Thiabendazole (TBZ) is a potent anthelmintic and fungicide used in the treatment of parasitic infections in humans and domestic animals and post-harvest protection of agricultural commodities. TBZ is not teratogenic or selectively foetotoxic in rats or rabbits, in contrast to several other benzimidazole derivatives. However, when administered orally to pregnant (Jcl:ICR) mice at lethal dosages, malformations were observed in treated fetuses. To assess whether the effects found in this previous study were attributable to maternal toxicity or TBZ the present study was conducted. TBZ doses of 25, 100 or 200 mg/kg/day were selected based on a preliminary range-finding study in which maternotoxicity was evident at doses of 200 mg/kg/day or above. The compound was administered during gestation days 6-15 as a solution in olive oil. Caesarean sections were completed on gestation day 18 and complete fetal examinations conducted. Decreases in maternal weight gain relative to controls were found at doses of 100 mg/kg/day or above, which paralleled decreases in foetal weights in these same dose groups. However, there were no treatment-related external, visceral or skeletal anomalies in any treatment group. Therefore, TBZ was not teratogenic or selectively foetotoxic in mice, with no-observed-effect levels (NOEL) of 25 and greater than 200 mg/kg/day for maternal and fetal weight effects and teratogenicity, respectively. These results indicate that foetal effects noted in previous studies in mice were probably secondary to severe maternal toxicity.     

Evaluation of the teratogenic potential of phosphamidon in mice by gavage

Phosphamidon, an organophosphate pesticide, is an established cholinesterase inhibitor. Alteration of tissue and plasma cholinesterase activity at a critical developmental period may influence cellular division and growth sufficiently to produce anatomically or functionally abnormal tissue or organ. The present study was, therefore, undertaken to evaluate the teratogenic potential of phosphamidon in pregnant Swiss albino mice, when administered at different gestational days during the period of organogenesis. The animals were sacrificed on day 18 of gestation for routine teratological examinations. It was observed that phosphamidon was more embryotoxic than teratogenic. Maximum effects were observed when administered on day 7 and day 13. Treatment on day 10 produced little effects. Repeated exposure during the organogenetic phase also produced significant adverse effects. This possibly indicates that phosphamidon is more embryotoxic during the post-implantation period (day 7) and during late organogenesis (day 13) as compared to the early organogenesis period (day 10).     

Subchronic toxicity of plant sterol esters administered by gavage to Sprague-Dawley rats.

The purpose of this study was to investigate the potential subchronic toxicity of plant sterol esters by a 13-week repeated oral dose in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 1000, 3000 and 9000 mg/kg/day for 13 weeks. At the end of treatment period, 10 rats/sex/group were sacrificed, while six rats/sex in the negative control and highest dose groups were sacrificed after a 4-week recovery period. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. Slight decreases in body weight gain were noted at lower doses but were only statistically different from the control animals in the highest dose group. In histopathological examinations, an increase in the incidence of cardiomyopathy with mononuclear cell infiltration was observed in males of the 9000 mg/kg group. Decreased body weight gain and increased incidence of cardiomyopathy observed in the highest dose group were not recovered until the end of the recovery period. There were no adverse effects on mortality, clinical signs, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings and organ weights in any treatment group. Based on these results, it was concluded that the 13-week repeated oral dose of plant sterol esters resulted in the suppression of body weight gains in both sexes and cardiomyopathy in males at a dose level of 9000 mg/kg/day. The target organ was determined to be heart in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 3000 mg/kg/day for both sexes.     

Comparison of the toxicity of cinnamaldehyde when administered by microencapsulation in feed or by corn oil gavage

The toxicity of cinnamaldehyde (CNMA) was compared after administration by gavage and in dosed feed. Rats and mice of both sexes received CNMA by daily corn oil gavage (for 2 wk), or in microencapsulated form in feed (2 wk for rats, 3 wk for mice). Feed formulations contained 0–10% CNMA microcapsules, equivalent to approximate daily doses of 0–3000 mg CNMA/kg body weight for rats and 0–10,000 mg CNMA/kg body weight for mice. Concentrations were chosen to deliver CNMA doses approximately equal to doses in the gavage study. Gavage doses of 2620 mg/kg/day and above in mice and 940 mg/kg/day and above in rats produced nearly 100% mortality; there were no deaths in animals receiving microencapsulated CNMA. Rats and mice receiving CNMA in feed showed a dose-related decrease in body weight gain, which was accompanied in rats by hypoplastic changes in reproductive organs and accessory sex glands. CNMA administration by either route caused hyperplasia of the forestomach mucosa. These results demonstrate that microencapsulation in feed can present a useful alternative to gavage dosing for repeated-dose or prolonged-exposure studies, in that (1) the toxic effects of CNMA were similar after gavage dosing and after administration in microencapsulated form in feed, (2) ingestion of chemical in the feed more closely approximates human exposures, and (3) microencapsulation allows the delivery of higher net doses of chemical, while avoiding the acutely toxic effects of a bolus dose.     

Differential toxicity of water versus gavage exposure to trichloroethylene in rats

Trichloroethylene (TCE) is a persistent environmental contaminant that causes male reproductive toxicity. We investigated whether transient increases in TCE exposure modulated male reproductive toxicity by exposing rats via daily oral to repeated gavage exposures (1000 mg/kg/day) and through drinking water (0.6% TCE) for 14 weeks. The gavage route resulted in reversible reduction of epididymis weight, and reduced body weight that persisted for up to 12-weeks after cessation of exposure. Physiologically-based pharmacokinetic modeling predicted that the gavage route results in higher C_max and AUC exposure of TCE compared to drinking water exposure, explaining the observed differences in toxicity between dosing regimens.