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EC number: 200-929-3
CAS number: 76-05-1
In a GLP compliant Extended One Generation Reproduction Study in rat according to OECD 443, sodium trifluoroacetate was adminstered daily by oral gavage to Wistar rats. In the F0 generation, three groups of 25 rats/sex received Sodium Trifluoracetate at dietary concentrations of 120, 600 or 3000 ppm, corresponding to nominal dose levels of ca. 10, 50 and 250 mg/kg bw/day, for 10 weeks premating, gestation and lactation. To compensate for the higher food intake during lactation, dietary concentrations were reduced in females to 60, 300 and 1500 ppm during lactation. A similarly constituted Control group received untreated basal diet. Males were treated for ten weeks before pairing, up to necropsy after litters were weaned. Females were treated for ten weeks before pairing, throughout pairing up to necropsy on Day 28 of lactation. During the lactation period, the F1 animals were not administered with test item directly. The F1 animals consisted of 2 cohorts (Cohort 1A and Cohort 1B) from weaning and were treated with the test item directly from weaning (Day 21 of age) up to 13 and 14 weeks, respectively. Cohort 1A was allocated for primary assessment of effects upon reproductive systems and of general toxicity, and Cohort 1B for possible histopathology follow-up assessment of reproductive system. The Cohort 1A and 1B animals (20/sex/group) were treated from Day 21 to nominal Day 35 of age at dietary concentrations of 60, 300 or 1500 ppm and from Day 35 of age to their scheduled termination at dietary concentrations of 10, 600 or 3000 ppm. A similarly constituted Control group received untreated basal diet.
Criteria for evaluation included viability (morbidity/mortality), clinical observations, body weight, food consumption, estrus cycle, cohabitation duration, sperm analysis, fertility data, gestation duration, parturition observation, litter evaluation, litter data, development landmarks, clinical pathology (hematology, serum chemistry, urinalyses), thyroid hormone analysis (TSH and T4), spleen lymphocyte subpopulations, gross (necropsy) evaluation, organ weight, and histopathological evaluation (F1 Cohort 1B animals were not examined microscopically).
No test item-related mortality was observed in both F0 and F1 animals during the study period. There were no test item-related changes on body weight or food consumption. There were no test item related changes in mating performance, fertility, gestation duration, litter evaluation, litter data (number of corpora lutea, implantation sites, and litter size, pre- and postimplantation loss, sex ratio, pup viability). There were no test item-related changes on developmental landmarks (including nipple retention, testes descent, and vaginal opening), anogenital distance, hematology, urinalysis, spleen lymphocyte subpopulations percentage (including Total T cells, Helper T cells, Cytotoxic T cells, B cells and NK cells) and TSH levels in this study.
Test item-related microscopic findings were observed in the fundic portion of the glandular stomachs of the F0 females and F1 Cohort 1A females with an increased incidence of minimal to slight gland dilatation in the F0 females at 600/300 ppm and 3000/1500 ppm and the F1 cohort 1A females at 1500/3000 ppm. The F1 cohort 1A females at 1500/3000 ppm also exhibited a high incidence of minimal to slight decreased secretion in the mucous neck cells located in the fundic region of the glandular stomach. As the severity of these findings were minimal to slight, the general condition of the females was unaffected and both bodyweight performance and food consumption of the females showed no adverse effects of treatment, these findings were considered non-adverse in this study. In the F0 and F1 generation body weight relative liver weight was high at 3000/1500ppm in both male and female animals. In the F0 and F1 generation males and females showed low plasma glucose levels and low levels of non-esterified fatty acids, males at all dose levels also showed low triglyceride concentrations. Bilirubin plasma concentrations were low for F0 females at all dose levels, for F1 males at 600/300 or 3000/1500 ppm and F1 females at 3000/1500 ppm. The increased liver weight and changes in the biochemistry of the plasma indicate some alteration in liver metabolism however in the absence of any macroscopic or microscopic liver pathology, these effects are considered to be non-adverse.
Kidney weights were high for F0 males and females at 3000/1500 ppm and for F0 males at 600 ppm. Plasma sodium levels in F0/F1 males and potassium levels in F0/F1 females were high, however in the absence of an effect on kidney weight in the F1 animals, with no adverse effects on the urinary composition in the F1 generation or any correlative microscopic changes in either the F0 or F1 generation these changes were considered non-adverse within the context of this study. In F1 generation Cohort 1A and 1B males had slightly low testes weights, however sperm assessment showed that the spermatid count in the Cohort 1A animals although slightly low was with in the historical control range. Histopathological examination of the Cohort 1A testes showed that the majority exhibited normal progression of the spermatogenic cycle, and the expected cell associations and proportions in the various stages of spermatogenesis were present. Tubular degeneration and atrophy occurred at a low incidence in both treated and control males but was considered unrelated to treatment as the incidence was similar across the groups.
Mean serum T4 concentrations in F0 males at 3000 ppm and females receiving 3000/1500 ppm were low when compared with Controls (p<0.01). At 1500 ppm mean serum T4 concentrations for F1 male and female offspring on Day 22 of age were low when compared with Controls (p<0.01), with most individual values below the lowest value in the concurrent controls. Mean serum T4 in F1A males at 600 or 3000 ppm were low when compared with Controls (p<0.01), with most individual values below the lowest value in the concurrent Controls. In the absence of any effects on reproductive performance, parturition, offspring, survival, clinical condition or sexual maturation, and changes in the reproductive organs (all parameters/processes depending on normal thyroid function), the low T4 levels seen in F0 males and females, male and female offspring on PND22 and F1A males are considered no to represent an adverse effect of treatment.
Based on the available results it is concluded that 3000/1500 ppm (approximating 242 -265 mg NaTFA/kg/day) was the No Observed Adverse Effect Level (NOAEL) for both both reproductive performance/offspring development and for general systemic toxicity.
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