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EC number: 906-170-0 | CAS number: -
Clinical observations and survival
Except for the deaths two animals (one male, one female, thought to be not treatment related) there were no test article-related deaths. There were no test article-related clinical observations. Clinical findings observed in the test article-treated groups were noted similarly in the control group, were not present in a dose-related manner, were noted at a low incidence, typically in single animals and/or were those types of clinical signs commonly observed in rats of this strain and age.
Low incidences of test article-related erythema and/or edema, generally graded as very slight, were observed for DMA, DMS, DMG and DBE treatment groups in at least one sex. Erythema was observed for one to four males in each of the 300 and 1000 mg/kg/day DMA and DBE groups, the 1000 mg/kg/day DMS group and all three DMG groups. For females, erythema was noted for one to five animals in all DMA and DMG groups and for the 100 and 1000 mg/kg/day DBE groups. Erythema was not observed for females treated with DMS at any dose level. Edema was limited to single males in the 1000 mg/kg/day DMA, DMS and DMG groups and one female in the 1000 mg/kg/day DMG group. Erythema and edema were not observed until the second week of dosing for any dose group and were not observed in the control group. The most prevalent sign of dermal irritation observed during the dosing period was eschar (scab) formation, mostly focal. Focal eschar formation (scabbing) was typically first observed near the end of the first week or beginning of the second week of dosing. This finding was observed at higher incidences than in the control group for all groups treated with DMA, DMG and DBE and the 300 and 1000 mg/kg/day DMS male groups. The number of animals with focal eschar/eschar was greater in the DMG and DBE groups than in the DMA and DMS groups. However, the most severe scores recorded were for male no. 41569 (1000 mg/kg/day DMS group), which was observed with eschar for eight consecutive days beginning on study day 6, reduced to focal eschar on the day of primary necropsy. In addition, fissuring was noted for one 1000 mg/kg/day DMA group female on the final day of the dosing period. The only other dermal finding was desquamation, generally first observed during the second week of dosing. Desquamation was noted for all groups, but with the highest incidence in the test article-treated groups. This increased incidence was considered to be possibly test article-related for most dosage levels in both sexes for DMA, DMG and DBE. The following table summarizes the dermal findings during the dosing period:
DMA, dimethyl adipate; DMS, dimethyl succinate; DMG, dimethyl glutarate; DBE, dibasic ester.
Mean body weights were unaffected by dermal exposure to DBE. Occasional statistically significant variations from the control group in mean body weight gain and/or mean cumulative gain were noted in the test article-treated groups. However, no consistent effects were observed and mean body weights were comparable to the control throughout the study.
Food consumption was unaffected by exposure to any of the test articles. Statistically significant changes in food efficiency were only observed during the recovery period and were considered random occurrences.
No test article-related effects on hematologic parameters were observed. A few statistically significant (p 0.05) differences from the control group were noted; however, the changes were not observed in a dose-related manner or were not of sufficient magnitude to be toxicologically relevant.
There were no test article-related changes in serum chemistry parameters. Slight increases (p 0.05) in mean sorbitol dehydrogenase levels were noted in the 300 mg/kg/day DMG and 1000 mg/kg/day DBE group females when compared to the control group. However, the changes were slight, present in only one sex, changes in other liver enzymes measured (i.e., ALP, ALT, AST or GGT) were not observed and there were no corresponding macroscopic or microscopic findings in the liver. Therefore, these changes were mostlikely random occurrences unrelated to test article treatment. Other statistically significant (p 0.05) changes from the control group were not observed in a dose-related manner and/or were not observed with
sufficient magnitude to be toxicologically relevant.
No test article-related effects on urinalysis parameters were noted. Specific gravity was decreased (p 0.05) 100 mg/kg/day DBE group females. These changes were slight and not observed in a dose-related manner. Therefore, a relationship to test article exposure was not apparent.
No oculopathic lesions indicative of a toxic effect were observed. All findings were typical for this species and strain.
A pale liver was noted for the 300 mg/kg/day DBE group male that was found dead on study day 10. There were no internal macroscopic findings for the 100 mg/kg/day DBE group female that was found dead. At the study week 2 primary necropsy, scabbing of the treated skin was observed for one 300 mg/kg/day DMA group male, one 1000 mg/kg/day DMS group male, two 1000 mg/kg/day DMG group males and one male in each of the DBE groups. Findings for the treated skin of females consisted of scabbing for one 1000 mg/kg/day DMA group female and dark red areas for one 1000 mg/kg/day DBE group female. No microscopic findings correlated with the dark red areas noted for the 1000 mg/kg/day DBE group female. Scabbing of the treated skin was not observed for any animals at the study week 4 recovery necropsy. No other test article-related macroscopic findings were noted at the scheduled necropsies.
No changes attributed to test article exposure were observed in organ weights. Mean and relative (to final body weight and brain weight) lung weights were increased (p 0.05) in the 100 mg/kg/day DBE group females.
A 14-day dermal toxicity study was performed in the rat in accordance with the OECD Guideline 410 and under GLP Regulations. There were no test article or treatment related deaths or clinical observations following administration of DBE for 14 consecutive days. Minimal to mild dermal irritation was observed for all treatment levels near the end of the first week or during the second week of dosing. Scabbing of the treated skin was observed at necropsy for one male in each of the DBE-treatment groups and dark red areas on the treated skin was observed for one female in the 1000 mg/kg/day DBE group; however, microscopic findings did not indicate a generalized reaction of the treated skin to DBE. There were no other test article-related microscopic findings. Body weights and food consumption were unaffected by DBE treatment. There were no test article-related changes in hematology, serum chemistry, urinalysis, ophthalmoscopy, neurobehaviour or organ weight parameters. Based on these study results, the no-observed-effect level (NOEL) for systemic toxicity for dermal application of DBE for 14 consecutive days was considered to be 1000 mg/kg/day.
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