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Biomedical subjects

R Valentine

Publications and source records attributed to R Valentine.

At least 19 recordsLinked to original sources
PubMed2006

Reproductive and developmental toxicity of inhaled 2,3-dichloro-1,3-butadiene in rats.

Inhalation developmental and reproductive toxicity studies were conducted with 2,3-dichloro-1,3-butadiene (DCBD), a monomer used in the production of synthetic rubber. In the reproductive toxicity study, Crl:CD(SD)IGS BR rats (24/sex/group) were exposed whole body by inhalation to 0, 1, 5, or 50 ppm DCBD (6 h/day) for approximately 10-11 weeks total, through premating (8 weeks; 5 days/week), cohabitation of mating pairs (up to 2 weeks, 7 days/week), post-cohabitation for males (approximately 7 days) and from conception to implantation (gestation days 0-7 [GD 0-7]), followed by a recovery period (GD 8-21) for presumed pregnant females. Estrous cyclicity was evaluated during premating (last 3 weeks) and cohabitation. Reproductive organs and potential target organs, sperm parameters, and GD 21 fetuses (viability, weight, external alterations) were evaluated. In the developmental study, pregnant Crl:CD(SD)IGS BR rats (22/group) were exposed whole body by inhalation to 0, 1, 10, or 50 ppm DCBD (6 h/day) on GD 6-20; dams were necropsied on GD 21 (gross post-mortem only) and fetuses were evaluated (viability, weight, and external, visceral and skeletal exams). During the in-life portion of the studies, body weight, food consumption, and clinical observation data were collected. At 50 ppm, gasping and labored breathing occurred in both studies during the first few exposures; body weight and food consumption parameters were affected in parental animals from both studies, but were more severely affected in the developmental study. Fetal weight was decreased in the developmental study at 50 ppm. Degeneration of the nasal olfactory epithelium was observed in the reproduction study at 50 ppm. There were no effects on reproductive function, embryo-fetal viability, or increases in fetal structural alterations in either study. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity was 50 ppm. The NOAEL for systemic toxicity in the reproduction study was 5 ppm based on adverse effects on body weight and food consumption parameters and nasal olfactory epithelial toxicity at 50 ppm in parental rats. The NOAEL for maternal and developmental toxicity was 10 ppm based on reduced maternal weight gain and food consumption and reduced fetal weight at 50 ppm in the developmental toxicity study.

Administration, Inhalation↗
PubMed2004

Inhalation toxicology of fumed dodecanediamine.

Dodecanediamine (DDDA) is used in the production of specialty polymers. Exposure to this chemical was associated with dermal sensitization in pilot-plant workers, and the possibility that the chemical could produce dermal sensitization was confirmed in a guinea pig test. This property and its dermal irritative properties demonstrate the need to limit skin contact. The possibility of exposure via inhalation also exists. Although stable under ambient conditions, DDDA is processed at elevated temperatures where it may fume, forming a carbamate after reaction with atmospheric carbon dioxide. Some of the carbamate may be converted back to the diamine after hydrolysis in tissue. The rat was used to evaluate the effects of both acute and repeated exposure following inhalation. Fumed DDDA was found to be moderately toxic following a single 4-h exposure with lethality seen at concentrations of 680 mg/m3 or higher. Rats were then exposed to concentrations of either 0 (control), 11, 34, or 98 mg fumed DDDA/m3, 6 h/day, 5 days/wk for 2 wk. Mortality was seen at the highest concentrations, along with increased lung weights. In these rats, laryngeal and tracheal lesions consisting of acute necrosis and inflammation were seen, but surviving rats given a 14-day recovery period showed almost complete recovery. Tracheal and laryngeal lesions were not seen in rats exposed to either 11 or 34 mg/m3. Degenerative and necrotizing lesions were seen in the nasal regions, primarily the respiratory mucosa, of rats in all three treatment groups. The lesions were exposure related with regard to incidence and severity, but regeneration was seen following the recovery period. No evidence of systemic toxicity was seen. The dose-response characteristics of the nasal lesions and the sensitization potential suggest that workplace control levels of 0.1 mg/m3 should be sufficient to protect workers against the untoward effects of fumed DDDA.

Administration, Inhalation↗
PubMed2001

Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.

Polyunsaturated fatty acids (PUFAs) are essential membrane components in higher eukaryotes and are the precursors of many lipid-derived signaling molecules. Here, pathways for PUFA synthesis are described that do not require desaturation and elongation of saturated fatty acids. These pathways are catalyzed by polyketide synthases (PKSs) that are distinct from previously recognized PKSs in both structure and mechanism. Generation of cis double bonds probably involves position-specific isomerases; such enzymes might be useful in the production of new families of antibiotics. It is likely that PUFA synthesis in cold marine ecosystems is accomplished in part by these PKS enzymes.

Anaerobiosis↗
PubMed2001

In vitro genotoxicity testing of (1-chloroethenyl)oxirane, a metabolite of beta-chloroprene.

(1-Chloroethenyl)oxirane (CEO) is a metabolite of beta-chloroprene (2-chloro-1,3-butadiene, CD). The purpose of this study was to evaluate the in vitro mutagenic and clastogenic (chromosome breaking) potential of CEO. For comparative purposes, the study also included an evaluation of the racemic compounds, 3,4-epoxy-1-butene (EB) and 1,2:3,4-diepoxybutane (DEB). Mutagenicity was evaluated in a bacterial reverse mutation test (Ames), using the pre-incubation method in the presence and absence of an exogenous metabolism system (Aroclor)-induced rat liver S9). Four Salmonella typhimurium tester strains, TA97a, TA98, TA100 and TA1535 were used. The exposure concentrations in the sealed incubation vials ranged from 0 to 69 mM for CEO, 0 to 102 mM for EB, and 0 to 83 mM for DEB. All three compounds showed signs of toxicity, with DEB being substantially more toxic than either CEO or EB. Mutagenic activity was observed with all three chemicals in primarily the base pair substitution strains (S. typhimurium TA100 and TA1535), but some activity was also seen in the frameshift elimination strains (S. typhimurium TA97a and TA98). The observed mutagenic responses after exposure with CEO or EB were greater than the observed response for DEB, most likely because of the higher toxicity of DEB. Generally, the mutagenic responses were unchanged in the frameshift strains and base pair substitution strains in the presence of S9 metabolism. In vitro clastogenicity was evaluated using the cytochalasin-B blocked micronucleus test in cultured Chinese hamster V79 cells. The test was conducted without S9 metabolism because of the absence of substantial changes in the Ames test. Exposure concentrations ranged from 0 to 0.943 mM for CEO, 0 to 3.0 mM for EB, and 0 to 0.035 mM for DEB, with the upper exposure concentrations dictated by cytotoxicity. Cytotoxicity, measured as a reduction in the proportion of binucleated cells and altered cell morphology, was observed for CEO at concentrations > or =0.175 mM. Exposure to EB led to a reduced proportion of binucleated cells at concentrations > or =2.0 mM, and cell death was observed after DEB exposure at concentrations > or =0.025 mM. No clastogenicity was observed in the V79 cells when tested up to cytotoxic concentrations of CEO, whereas an elevated frequency of micronuclei was observed after exposure to either EB (> or =1.0 mM) or DEB (> or =0.0125 mM). These results suggest that CEO-induced mutagenicity, but not clastogenicity, may contribute to the observed beta-chloroprene-induced carcinogenicity in the rodent bioassay studies.

Animals↗
PubMed2001

The metabolism of beta-chloroprene: preliminary in-vitro studies using liver microsomes.

Based on analogy with butadiene and isoprene, the metabolism of beta-chloroprene (2-chloro-1,3-butadiene, CD) to reactive intermediates is likely to be a key determinant of tumor development in laboratory rodents exposed to CD by inhalation. The purpose of this study is to identify species differences in toxic metabolite (epoxide) formation and detoxification in rodents and humans. The in-vitro metabolism of CD was studied in liver microsomes of B6C3F1 mice, Fischer/344 and Wistar rats, Syrian hamsters, and humans. Microsomal oxidation of CD in the presence of NADP(+), extraction with diethyl ether, and analysis by GC-mass selective detection (MSD) indicated that (1-chloroethenyl)oxirane (CEO) was an important metabolite of CD in the liver microsomal suspensions of all species studied. Other potential water-soluble oxidative metabolites may have been present. The oxidation of CD was inhibited by 4-methyl pyrazole, an inhibitor of CYP 2E1. CEO was sufficiently volatile at 37 degrees C for vial headspace analysis using GC-MSD single ion monitoring (m/z=39). CEO was synthesized and used to conduct partition measurements along with CD and further explore CEO metabolism in liver microsomes and cytosol. The liquid-to-air partition coefficients for CD and CEO in the microsomal suspensions were 0.7 and 58, respectively. Apparent species differences in the uptake of CEO by microsomal hydrolysis were hamster approximately human>rats>mice. Hydrolysis was inhibited by 1,1,1-trichloropropene oxide, a competitive inhibitor of epoxide hydrolase. A preliminary experiment indicated that the uptake of CEO in liver cytosol by GSH conjugation was hamster>rats approximately mice (human cytosol not yet tested). In general, the results suggest that metabolism may help explain species differences showing a greater sensitivity for CD-induced tumorigenicity in mice, for example, compared with hamsters. Additional experiments are in progress to quantify the kinetic parameters of CD oxidation and CEO metabolism by enzymatic hydrolysis and conjugation by glutathione S-transferase for in cytosol. A future goal is to use the kinetic rates to parameterize a physiologically based toxicokinetic model and relate the burden of toxic metabolite to the cancer dose-response observed in experimental animals.

Animals↗
PubMed2001

Overview of the acute, subchronic, reproductive, developmental and genetic toxicology of beta-chloroprene.

beta-Chloroprene (CD), the 2-chloro derivative of 1,3-butadiene, is used for the manufacture of the synthetic rubber, polychloroprene. Acute inhalation studies show that CD is lethal to Crl:CD rats at >2300 p.p.m. (4 h); the primary target organ effects were pulmonary hemorrhage and edema, and hepatic necrosis. In 2- and 4-week inhalation studies in Fischer 344 (F344) and Wistar rats, early deaths occurred at 500 and > or =161 p.p.m., respectively. Organ system injury was found in the nose (degeneration/metaplasia of olfactory epithelium), liver (centrilobular necrosis), and blood (decreased red blood cell count in F344 rats only). In a 90-day inhalation study with F344 rats, degeneration/metaplasia of the olfactory epithelium and reduced nonprotein sulfhydryl content of lungs and liver were found in animals exposed to 80 p.p.m., and anemia, hepatocellular necrosis, and forestomach inflammation were observed at 200 p.p.m. In a 90-day study with B6C3F1 mice, CD caused deaths at 200 p.p.m., the highest concentration tested, and epithelial hyperplasia of the forestomach at 80 p.p.m. Other than a slight (<10%) reduction in sperm motility in male rats at 200 p.p.m., all other reproductive parameters (sperm count or morphology in males, and estrous cyclicity or cycle length in females) were unaffected in these 90-day rat/mouse studies. There were no significant indications of neurological toxicity. The study No-Observable Adverse Effect Level was 32 p.p.m. based on nasal injury in rats. Despite some early reports of reproductive system abnormalities at levels <1 p.p.m., recent studies show no embryotoxic or developmental toxicity in female Wistar or Crl:CD rats, or in New Zealand White rabbits at CD exposure concentrations up to 25 or 175 p.p.m., respectively. In a one-generation reproduction study with Wistar rats, CD produced growth retardation in the F(0) generation exposed to 100 p.p.m., and in the F(1) offspring at 33 and 100 p.p.m.; no effects on reproductive parameters or histopathology were found. CD is nonmutagenic in standard plate incorporation bacterial reverse mutation assays (Ames assays) but positive using direct gas-phase incubation methods. Bacterial mutagenicity (primarily base pair substitution) was either negative or weakly positive when freshly prepared CD was tested. Mutagenicity increased markedly with time, presumably from CD dimer formation, and also by addition of liver S9 metabolic activation system. In vivo micronucleus, chromosome aberration and sister chromatid exchange studies in mice showed no structural chromosomal damage. Overall, the pathological effects in the liver and nose dominate the subchronic toxicity of CD. The genotoxicity of CD is inconsistent and requires further study.

Administration, Inhalation↗
PubMed2001

Inhalation toxicity of Dioxole and Dioxolane compounds in the rat.

Four chemicals (Dioxole 418, Dioxolane 418, Dioxolane 416 and Dioxolane 456) which are used as stabilizers in highresolution image were tested or both their acute and repeated inhalation toxicity in the rat using nose-only exposures. Acute studies determined the lethal concentrations following a single 4-hour exposure; repeated exposure inhalation studies determined the potency and target tissue(s) following 6-hour/day exposures, 5 days/week for 2 weeks. Each of the chemicals was at least mildly toxic acutely with approximate lethal concentrations of > 1,500 ppm for Dioxole 418, 1,300 ppm for Dioxolane 418, 1,700 ppm for Dioxolane 416, and 4,300 ppm for Dioxolane 456. No specific unusual clinical signs of response were seen in the rats exposed acutely. Repeated exposures with Dioxole 418 and Dioxolane 418 resulted in no evidence of toxicity with NOAEL's being 440 and 500 ppm respectively (the highest concentrations tested). Repeated exposures to 250 ppm Dioxolane 456 were not tolerated with mortalities observed after exposure. Severe bone marrow hypoplasia along with reductions in platelet and neutrophil counts were observed at this concentration with less severe hemopoietic changes seen also at 10 and 51 ppm. The no-effect level for Dioxolane 456 was determined to be 10 ppm in female rats and I ppm in males. The same hemopoietic effects were seen with Dioxolane 416 at exposures of 53 ppm or greater in males but not in females exposed to 53 ppm Dioxolane 416. Hepatocellular hypertrophy and depression of serum alkaline phosphatase activity were seen in male rats exposed to 500 but not 53 ppm Dioxolane 416. Testicular degeneration was also seen in rats exposed to 500 ppm Dioxolane 416. The NOAEL was 5 ppm for the chemical.

Administration, Inhalation↗
PubMed2000

Necrotizing pulmonary granulomata in a marijuana smoker.

We describe the case of a heavy marijuana and tobacco smoker who presented with progressive exertional dyspnea of 2 months' duration, and bilateral nodular lung infiltrates. Examination of the lung fields was normal, and lung function tests showed mild airflow obstruction with moderately reduced gas transfer. BAL returned green-black fluid consisting predominantly of macrophages laden with carbon pigment. Thoracoscopic lung biopsy showed miliary necrotizing granulomata with an alveolar exudate of carbon-laden macrophages within macroscopically blackened lung. The differential diagnosis of pulmonary granulomata in this patient is discussed.

Adult↗
PubMed2000

Microsatellite instability in gastrointestinal tract tumours.

Although a number of studies have documented microsatellite instability (MSI) in gastrointestinal tumours, the clinical significance is uncertain. In this study the MSI status and clinicopathological features were examined in gastric and colorectal tumours. Eighty-four gastrointestinal tumours were examined for MSI. Normal and tumour DNA isolated from the same patients were analysed at five different microsatellite loci. Clinical features of these patients were also collated and compared with MSI status. High level MSI (MSI-H) (as defined by instability in 2 or more microsatellites) was detected in 6 out of 47 (13%) colon tumours and 6 of 37 (16%) gastric tumours. The frequency of MSI-H between these groups was not statistically significant (P = 0.36). There was no significant correlation with patient age or gender, UICC stage, or degree of differentiation of the tumour. This was true both when analysed as a group, as well as when divided into colon and gastric sites. Our results confirm that a proportion of sporadic tumours from the colon and stomach exhibit an MSI-H phenotype. However, there was no significant relationship between the presence of MSI and any of the clinicopathological characteristics studied.

Colonic Neoplasms↗
PubMed1999

Subchronic inhalation toxicity of diglyme.

Diglyme [1,1'-oxybis(2-methoxyethane)] is an organic solvent belonging to the glycol ether class of compounds. To assess the inhalation toxicity of diglyme, groups of 20 male and 10 female rats were exposed by nose-only inhalation 6 hours/day, 5 days/week for 2 weeks to either 0 (control), 110, 370 or 1100 ppm diglyme. To compare potency, 2-methoxyethanol was also tested at 300 ppm. Rats were sacrificed either immediately following exposure, after a 14-day recovery period, or after 42 and 84 days of recovery (males only). Parameters investigated included in-life observations and body weights, clinical pathology, and histopathology with organ weights. Exposure to diglyme produced a variety of concentration-related haematological, clinical chemical and histopathological changes in both sexes. The most striking effect produced in all test groups was cellular injury involving the testes, seminal vesicles, epididymides and prostate. Although these effects were more severe at the higher concentrations tested, partial or complete recovery was seen by 84 days post-exposure. Changes in the haematopoietic system occurred in both sexes and involved the bone marrow, spleen, thymus, leucocytes and erythrocytes. The testicular effects of diglyme were somewhat less pronounced than those seen with 2-methoxyethanol. The no-observed-effect level (NOEL) for repeated inhalation exposure to diglyme in female rats is 370 ppm. For males, all concentrations tested produced effects to the reproductive system, hence a no-observed-effect level could not be demonstrated.

Administration, Inhalation↗
PubMed1998

Developmental toxicity of diglyme by inhalation in the rat.

Diglyme (Diethylene glycol dimethyl ether, CAS No. 111-96-6) is a glycol ether which has been used in solvent formulations. To assess the potential developmental toxicity of this chemical, groups of pregnant Crl:CD BR rats were exposed to either 0 (control, room air only), 25, 100, or 400 ppm diglyme by inhalation for 6 hrs/day for Days 7 through 16 or gestation (day on which the copulation plug was detected was designation Day 1 G). All female rats were euthanized on day 21G and the fetuses were examined. An additional group of rats was treated with 25 ppm 2-methoxethanol (2ME) to serve as a positive control and for comparison of relative potencies. Maternal toxicity evident as depressed feed consumption at 400 ppm and increased liver weights at 100 ppm. There were no dams in the 400 ppm group with live fetuses (all litters consisted on resorbed conceptuses). Embryo viability was unaffected by concentrations of diglyme as high as 100 ppm. 2ME produced increased liver weights and depressed feed consumption at 25 ppm. Embryo-fetal toxicity was evident as a concentration-related decrease in fetal weight at diglyme concentrations as high as 100 ppm (and with 2ME). There were no fetuses derived from the 400 ppm diglyme-treated dams. A low incidence of structural malformations was observed in all diglyme groups (as well as with 2ME). The incidence of variations, (primarily delayed skeletal ossification and rudimentary ribs) was increased in the 25 and 100 ppm diglyme groups. The incidence and severity in the diglyme and 2ME groups exposed to 25 ppm was essentially the same suggesting similar potency for producing structural variations. In this study, diglyme was embryolethal at 400 ppm; a level that otherwise was only marginally toxic to the dam. Maternal and fetal toxicity also were demonstrated at 100 ppm. Although the fetal defects detected following diglyme exposure at 25 ppm were not significantly different from control values (with the exception of the incidence of skeletal developmental variations), the pattern, type, and incidence of variations were similar to those seen at 100 ppm, suggesting that 25 ppm was an effect level that approaches the lower end of the developmental toxicity response curve. Therefore, the no-observable-effect level (NOEL) for diglyme exposure in the dam is 25 ppm and a NOEL was not clearly demonstrated for the conceptus.

Administration, Inhalation↗
PubMed1997

Frequency and clinico-pathological associations of ras mutations in colorectal cancer in the Victorian population.

BACKGROUND: Mutations in the oncogene ras occur in 20-50% of colorectal cancers. The presence of these mutations allows screening tests to be developed based on the identification of mutant DNA in cells derived from cancers. A study of the prevalence and clinicopathological associations of ras mutations was undertaken. METHODS: The frequency of mutations in codons 12 and 13 of the K-ras gene was investigated in 103 colorectal carcinomas using restriction fragment length polymorphism. RESULTS: Mutations were detected in 32% (33/103) of the tumours, predominantly in codon 12 (25/33). No mutations were detected in normal-appearing mucosa from the same patients. CONCLUSIONS: Analysis of the frequency of ras mutations compared with various independent clinical variables revealed a sex-linked relationship between the presence of a ras mutation and nodal status but no correlation with any other clinical parameter was found. The findings suggest that screening tests based on ras mutation detection may lack sensitivity because of the presence of mutations in only 32% of tumours.

Aged↗
PubMed1995

Developmental toxicity of inhaled N-methylformamide in the rat.

The developmental toxicity of N-methylformamide (MMF), an industrial chemical intermediate used in the production of agrichemicals, was examined in pregnant rats. MMF was administered by nose-only inhalation, 6 hr daily on Days 7-16 of gestation (the day copulation was confirmed was termed Day 1 of gestation, Day 1G) at exposure concentrations of 0, 15, 50, or 150 ppm. Dams were regularly monitored throughout gestation for body weight gain, feed consumption, and clinical signs. Cesarean sections were performed on Day 22G and the offspring were examined. Maternal toxicity was evident in dams exposed to 50 or 150 ppm; one dam exposed to 150 ppm died on Day 14G (considered to be treatment-related) and dams in the 50 and 150 ppm groups exhibited concentration-related clinical findings. Clinical signs of wheezing and rattling were observed both during and after the exposure period. The 150 ppm group also showed significant decreases in weight gain and feed consumption. A significant increase in the mean number of resorptions per litter at the 150 ppm level indicated an embryolethal effect. Developmental toxicity was apparent by a significant decrease in mean fetal body weight and increases in fetal malformations (subcutaneous cysts on the head, microphthalmia, anophthalmia, fused ribs and/or vertebra, and distended brain ventricles) and variations (misaligned and fused sternebrae) due to retarded development at 150 ppm. Significant fetal body weight decreases were also present at 50 ppm. Thus, in this study, the no-observable-adverse-effect level for both dam and fetus was 15 ppm MMF, indicating that for the parameters included in this study, the conceptus is not uniquely sensitive to MMF.

Administration, Inhalation↗
PubMed1994

Dimethylacetamide pharmacokinetics following inhalation exposures to rats and mice.

Whole-body inhalation exposures to N,N-dimethylacetamide (DMAC) were conducted with male rats (Crl:CD BR) and mice (Crl:CD-1 (ICR)BR). Exposure concentrations were 50, 150, 300 and 500 ppm. The exposure routines consisted of single 1-, 3-, or 6-h exposures and ten 6-h exposures (10 exposure days in 2 weeks). Area under the plasma concentration curve (AUC) values were determined for DMAC and its metabolite N-methylacetamide (NMAC), following 6-h exposures (single exposure or last in a series of 10 exposures). The range of exposures was chosen to assess the exposure-dependent nature of DMAC pharmacokinetics in rats and mice. Plasma profiles indicated mice metabolized DMAC rapidly with plasma half-lives from 0.3 to 0.5 h for DMAC. The DMAC AUC values from mice were underestimated due to the required time (< 30 min) between termination of exposure and the initial blood sample. DMAC plasma half-life in rats ranged from 0.6 to 1.5 h. The AUC values for DMAC in rats increased approximately 5-fold and 3-fold as exposure concentrations increased from 150 to 300 ppm and 300 to 500 ppm, respectively. NMAC persisted in plasma for at least 24 h after the 150, 300 and 500 ppm exposures to rats. NMAC was not detected in plasma from mice beyond the 12-h post-exposure timepoint for the 300 and 500 ppm exposures. Regardless of exposure level, repeated DMAC exposures to both rats and mice resulted in plasma profiles of DMAC and NMAC similar to those from a single exposure. The dose-dependent nature of the DMAC AUC data and the absence of effects of repeated 300 and 500 ppm DMAC exposures supported a toxicity-driven upper limit of 350 ppm for a chronic inhalation study.

Acetamides↗
PubMed1994

Intravascular endometrial tissue in an ovary of a patient with abnormal endometrial histology.

A case of ovarian intravascular endometrial tissue in a 46 yr old woman with a strong family history of endometrial carcinoma and abnormal endometrial histology is presented. The diagnosis was supported by histological and immunohistochemical findings. Although recognized at other sites, intravascular endometrial tissue has not been described previously in the ovary.

Endometriosis↗
PubMed1993

Developmental toxicity of inhaled trans-1,2-dichloroethylene in the rat.

The developmental toxicity of trans-1,2-dichloroethylene (t-DCE), a component of certain Freon cleaning agents, was examined in pregnant rats. t-DCE was administered by inhalation 6 hr daily on Days 7-16 of gestation (the day copulation was confirmed was termed Day 1 of gestation) at exposure levels of 0, 2000, 6000, or 12,000 ppm. The offspring were then examined on Day 22 of gestation. Overt maternal toxicity was expressed as a significant reduction in weight gain at 12,000 ppm and in feed consumption at 6000 and 12,000 ppm. During the exposure period, lacrimation and stained periocular hair, and signs of ocular irritation, were observed in all groups. In addition, increased incidences of alopecia, lethargy, and salivation were observed in the high-dose dams. Significant increases in the mean number of resorptions per litter were seen in the litters of dams exposed to 6000 and 12,000 ppm of t-DCE; however, these values are within the range of historical controls and not considered to be treatment related. The mean combined and female fetal weights were significantly reduced in the litters of dams exposed to the highest concentration (12,000 ppm) of t-DCE. Marginal effects on feed consumption, unaccompanied by other changes and reflective of the pattern seen at higher doses, were seen at 2000 ppm. Thus, marginal maternal toxicity was seen at 2000 ppm and exposures to 6000 ppm t-DCE or higher caused frank maternal toxicity while the fetus was affected only at 12,000 ppm. Therefore, t-DCE is not considered to be uniquely toxic to the rat conceptus.

Abnormalities, Drug-Induced↗