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EC number: 271-784-1 | CAS number: 68608-50-4
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This study was conducted for to evaluate the possible adverse effects of the test article, Fatty acids C18-(unsaturated) lithium salts
, following repeated exposure and to evaluate reversibility, progression, or delayed appearance of any observed changes following a 2-week postdose observation period. The evaluation included systemic toxicity, male and female reproductive performance (gonadal function, estrous cycle, mating behavior, conception, development of the conceptus, and parturition) and neurologic potential in rats. Three treatment groups of ten P (parental) CD®[Crl:CD®(SD)] rats/sex/group were administered the test article at nominal dose levels of 100, 300, or 1000 mg/kg bw/day at a dose volume of 2.5 mL/kg. Actual dose levels were 111.25; 345.00, and; 1089.75 mg/kg bw/day. One additional group of ten P animals/sex served as the control and received the vehicle, distilled water. The vehicle or test article was administered to all groups via dermal application once daily for approximately 6 hours. The males were dosed for 43 days, beginning 14 days prior to pairing. Dosing of the females began 14 days prior to pairing, through the mating period, up to and including Gestation Day (GD) 19.
Additionally, two groups of five animals/sex/group at 0 (vehicle) or 1000 mg/kg bw/day were dosed for a total of 43 days and then began a 14-day recovery period. Observations of these animals included clinical signs, neurobehavioral observations, dermal irritation scores, body weights, food consumption, and clinical pathology parameters. At the end of the recovery period, necropsy examinations were performed, organ weights were recorded, and selected tissues were collected and preserved.
Observations of the P animals included clinical signs, neurobehavioral observations, behavioral indices, dermal irritation scores, body weights, and food consumption during the premating/mating, gestation, and lactation periods, clinical pathology parameters, and parturition and litter data. Observations of the offspring (F1) included survival at birth and during lactation, individual pup body weights, and gross abnormalities. At study termination, necropsy examinations were performed on all P animals, organ weights were recorded, and selected tissues were collected and microscopically examined. On LD 4, surviving F1pups were examined externally, euthanized, and discarded.
All animals on study survived to scheduled terminal and recovery necropsies. The most significant clinical observations consisted of dose responsive localized dermal effects at the test site (dorsal surface), consisting of scabbed postdose findings and elevated dermal scores. These findings were most pronounced at 1000 mg/kg bw/day and were seen most frequently at this dose level. The findings at 300 mg/kg bw/day were at a lower incidence and with lower dermal scores. Dermal scores and findings at 100 mg/kg bw/day were comparable to the controls. Mean body weight showed decreasing trends during the course of the study in males at 1000 mg/kg bw/day. For the remaining animals there were no consistent patterns of adverse effects on body weight or food consumption at the dose levels tested. The results of the neurobehavioral and behavioral evaluations did not reveal any definitive patterns consistent with treatment-related effects.
At termination, there were no adverse test article-related effects on hematology or clinical chemistry parameters evaluated.
The results at scheduled necropsy showed test article-related macroscopic findings that were limited to the dose site in the skin, consisting of minimal to moderate abrasion/scab formation at the dose site in both sexes. At the recovery necropsy, the incidence and overall severity of abrasion/scab formation was reduced at 1000 mg/kg bw/day, indicating partial resolution of this finding over the recovery period.
Possible test article-related organ weight differences at terminal necropsy included the increased spleen and adrenal gland weights (relative to body weight) of animals at 1000 mg/kg bw/day. The increased spleen/body weight ratio of males may have been associated with the lower mean body weight at this dose level and, possibly, increases in extramedullary hematopoiesis noted microscopically. There was no microscopic correlate for the increased adrenal gland/body weight ratio of females at this dose level.
Test article-related microscopic findings were present in treated skin at 300 and 1000 mg/kg bw/day, and possible test article effects were also noted in the thymus and spleen at 1000 mg/kg bw/day.
Test article-related findings in treated skin included an increase in the incidence and/or severity of erosion/ulceration, epidermal hyperplasia and exudate, acute to subacute/chronic inflammation, and edema. At recovery necropsy, test article-related microscopic findings in treated skin in animals at 1000 mg/kg bw/day were morphologically similar, although they occurred at a lower incidence and severity indicating partial resolution of these findings over the recovery period.
Minimal to mild cortical lymphoid depletion was noted in the thymus in animals of both sexes at 1000 mg/kg bw/day at the terminal necropsy. However, there were no statistically significant differences in the mean thymus weight. Thymic lymphoid depletion in animals at 1000 mg/kg bw/day may have been a secondary finding due to stress associated with the test article-related lesions in treated skin. Splenic extramedullary hematopoiesis was slightly increased in both sexes at 1000 mg/kg bw/day. The increased severity of splenic extramedullary hematopoiesis in control and treated females may have been due to recent parturition, but the slight increase in the incidence of this finding in animals at 1000 mg/kg bw/day may have also reflected an adaptive response secondary to test article-related inflammation in treated skin.
In conclusion, dermal application of Fatty acids C18-(unsaturated) lithium salts
to the dorsal surface of Parental male and female rats at dose levels of 100, 300, and 1000 mg/kg bw/day did not result in any adverse reproductive effects or any definitive test article-related changes in the development or survival of the offspring. In addition, results from the clinical pathology evaluations and neurobehavioral testing did not reveal any definitive effects that could be attributed to treatment at the dose levels tested.
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