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EC number: 601-478-9 | CAS number: 117428-22-5
2-Year Rat Diet: Not Carcinogenic. OECD 453; Reliability = 1
18-Month Mouse Diet: Not Carcinogenic. OECD 451; Reliability = 1
Five groups of young adult male and female Crlj:CD1(ICR) mice (60/sex/group) were administered diets that contained 0, 100, 600, 2400, or 4800 ppm of the test substance for approximately 18 months. Samples of the diets were analyzed and demonstrated homogeneity, stability, and targeted concentrations of the test article in the diet. Body weights and food consumption were evaluated weekly for the first 13 weeks, then every other week thereafter. Detailed clinical observations were evaluated weekly. Ophthalmological assessments were performed prior to the start of dietary exposure and near the end of the exposure period. White blood cell differential counts were evaluated in surviving mice at the end of the exposure period and in mice that were sacrificed in extremis. After approximately 18 months of dietary exposure, mice were sacrificed and given a gross and microscopic pathological examination.
The overall mean daily intakes of the test substance in the 0, 100, 600, 2400, and 4800 ppm male groups were approximately 0, 12, 71, 293, and 583 mg/kg/day, respectively. In females, mean daily intakes were approximately 0, 16, 99, 412, and 799 mg/kg/day, respectively.
No test article-related changes were observed in the following observations in male and female mice fed up to 4800 ppm of the test substance: clinical observation, body weight parameters, food intake parameters, ophthalmology, white blood cell differential counts, cause of death, and gross pathological parameters, and neoplastic changes.
Test article-related and biologically adverse microscopic findings were limited to non-neoplastic effects in the duodenum and consisted of increased incidences and severity of mucosal hyperplasia in males fed dietary concentrations of 2400 or 4800 ppm. Female mice did not exhibit treatment-related duodenal mucosal hyperplasia at any concentration.
Test article-related (non-adverse) increases in liver weights were observed in males and females fed dietary concentrations of ≥2400 ppm. In female mice, the increased liver weights correlated with the test article-related microscopic finding of hepatocellular hypertrophy. Both the liver weight increases and hepatocellular hypertrophy were consistent with hepatic enzyme induction and were interpreted to be not adverse.
The test substance is not an oncogen in mice. Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) was 600 ppm for male mice and 4800 ppm for female mice, equivalent to 71 and 799 mg/kg/day, respectively.
This study was conducted to evaluate the potential chronic toxicity and oncogenicity of the test article when administered over the major portion of the life span of CD® [Crl:CD®(SD)] rats. Five groups of 80 animals/sex/group received untreated diet or the test article orally via dietary admixture approximately 105 weeks (males) or 103 weeks (females) at diet concentrations of 0, 50, 200, 1000, and 3500 ppm. Following 12 months of treatment, ten animals/sex/group were submitted to an interim necropsy.
Observations for morbidity, mortality, injury, and the availability of food and water were conducted for all animals twice daily through Week 52 and three times daily thereafter. Detailed clinical and mass observations were conducted weekly. Body weights were measured and recorded weekly from Weeks -1 to 13 and every fourth week thereafter. Food consumption was measured and recorded weekly from Weeks -1 to 13, every fourth week from Weeks 17 to 85, and weekly beginning on Week 88. Body weight gain, food efficiency, and compound consumption were calculated. Ophthalmoscopic examinations were conducted pretest and prior to the interim and terminal necropsy. Blood and urine samples for clinical pathology evaluations were collected from designated animals at 3, 6, and 12 months and from all surviving animals at the terminal necropsy (haematology only). Necropsy examinations were performed, organ weights were recorded, and selected tissues were collected for microscopic examination from 10 animals/sex/group at the interim necropsy on Day 365 and from all remaining animals at the terminal necropsy. Serological health screens were conducted on five unassigned animals/sex pretest and on an additional 15 animals/sex co-housed with study animals at 6, 12, and 18 months.
Diets containing 1000 and 3500 ppm were at the targeted concentration and mixed homogeneously throughout the study. Diets containing 50 or 200 ppm were generally at targeted concentrations but were not homogeneously mixed on numerous occasions. This did not impact the study as these groups were not needed to determine the no-observed-adverse- effect level (NOAEL).
Over the first year on study, the mean compound consumption in the 50, 200, 1000, and 3500 ppm group was 2.6, 10.4, 52.1, and 185.7 mg/kg/day, respectively, for males and 3.2, 13.0, 64.9, and 228.5 mg/kg/day, respectively, for females. Over the duration of study, the mean compound consumption in the 50, 200, 1000, and 3500 ppm groups was 2.2, 8.8, 45.3, and 162.1 mg/kg/day, respectively, for males and 2.8, 11.0, 57.1, and 203.3 mg/kg/day, respectively, for females.
Survival in the 3500 ppm male and female groups and in the 1000 ppm female group was significantly greater than in controls, This increase is likely due to lower body weight in these groups (not statistically significant in females at 1000 ppm). There were no adverse clinical or ophthalmological observations attributed to test article exposure. There was an increase in the incidence of soft faeces at 1000 and 3500 ppm primarily in males that was considered possibly test article-related but not adverse.
Mean body weight and body weight gain were reduced during the study in both sexes at 3500 ppm. In males and females, mean body weight was 9% and 17% below control, respectively, at Week 49, and 11% and 17% below control, respectively, on the last weigh day before final sacrifice. Mean body weight gain in this group was 15% and 33% below control for males and females, respectively, over weeks 1 to 49, and 18% and 28% below control, respectively, over the two year exposure period. All of these differences were statistically significant except the male final body weight and overall body weight gain. However, these values were significantly different from control for most of the study. These body weight findings were associated with significantly lower mean food consumption and food efficiency over the first year at this exposure level which continued for the duration of the study (variable statistical significance). Body weight and nutritional parameters in lower concentration groups were generally comparable to control over the study.
No test article-related effects were noted on any clinical pathology parameters, organ weights, macroscopic findings, or incidence of masses. There were no test article-related microscopic findings following 1 year of treatment. At the end of the study, statistically significant increases in the incidences of interstitial cell hyperplasia and benign adenoma in the testes were observed in male rats at 3500 ppm. Although survival was increased, the majority of adenomas and hyperplasia occurred in terminal or near terminal animals, and the percent incidence of adenomas fell within the historical limits of the laboratory, it is considered likely that the increases in testicular interstitial cell adenoma and hyperplasia in the 3500 ppm males were related to exposure to the test article.
Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) was 1000 ppm, equivalent to 45.3 and 57.1 mg/kg/day in males and females, respectively. This NOAEL is based on reduced body weight and nutritional parameters observed in both sexes at 3500 ppm and increased incidence of interstitial cell hyperplasia and benign adenoma in the testes in males at 3500 ppm (equivalent to 162.1 and 203.3 mg/kg/day for males and females, respectively).
The oncogenic potential of the test substance was assessed in an initial set of chronic feeding studies in rats and mice where the maximum dietary concentration administered was 750 and 800 ppm, respectively. In both studies there was no evidence of a treatment-related effect on the incidence of any specific tumour types. In the 2-year rat study, an apparent slight increase in the incidence of large granular cell leukaemia was noted in males at the highest dose level (750 ppm), which was within the historical control range of the testing facility. This difference from control was concluded to be a reflection of the higher survival rate in the high dose male animals with consequently more animals in this group being at risk for development of this late onset, common spontaneous tumour and, therefore, unrelated to treatment with the test substance.
In a second set of chronic rat and mouse studies, higher dietary concentrations were evaluated (maximums up to 3500 ppm in rats and 4800 ppm in mice). In mice, test article-related and biologically adverse effects were limited to non-neoplastic changes in the duodenum and consisted of increased incidences and severity of mucosal hyperplasia in male mice feed dietary concentrations of 2400 and 4800 ppm. Test article increases in liver weights were observed in males and females fed 2400 and 4800 ppm; the liver weight increase in female mice was associated with microscopic evidence of hepatocellular hypertrophy. Both the liver weight increases and hepatocellular hypertrophy were consistent with hepatic enzyme induction and were interpreted as not adverse. A higher incidence in hepatocellular adenoma (a common spontaneous tumour in mice) in the 4800 ppm male mice was within the range of historical controls from the animal supplier and considered secondary to a marked increase in survival in this group (93%) compared to the concurrent control group (72%). It was concluded that the test substance displays no carcinogenic potential in mice.
The primary observations in the second chronic rat study included a marked increase in survival in males (2-fold relative to controls) and females at 3500 ppm and in females at 1000 ppm, most likely due to the lower body weights in these groups. Reductions in body weight gain, food consumption, and food efficiency were also lower in the high dose group during the first year of the study. At study termination, a statistically significant increase in interstitial (Leydig) cell hyperplasia and benign adenoma in the testes was observed in male rats at 3500 ppm. The incidence of Leydig cell adenoma was within the historical limits of the laboratory and was similar to the upper range of control values reported by the animal supplier. Therefore, the small increase in the incidence of interstitial (Leydig) cell adenoma of the testes observed in high dose males (3500 ppm) in the second 2-year study is insufficient for classification based on the following rationale: 1) Leydig cell adenomas are common in aged rats, and rats are known to be highly sensitive to forming these tumours spontaneously. 2) The maximum tolerated dose was exceeded at the high dose (3500 ppm) where marked reductions in body weight and body weight gain were noted relative to controls. 3) Survival at study termination was markedly increased (2-fold) in the 3500 ppm males (49%) relative to control males (24%), presumably due to the body weight reductions, and thereby put more animals at risk of developing this common spontaneous tumour in aged rats. 4) The incidence of Leydig cell adenoma (10%) was within the range of controls for the testing facility (0-14%) and similar to the maximum for the control range reported by the animal supplier (1.1-9.3%). 5) There was no progression to carcinoma and no decrease in latency period. All tumors were classified as adenoma, and animals bearing Leydig cell adenomas were those that either died late in the study or reached study termination. 6) A very clear threshold was present where the increase in Leydig cell adenoma was observed only at the high dose correlating with the increase in survival at the same dose level. 7) Based on an assessment of the robust genetic toxicity data for this substance, the test substance is not genotoxic. 8) Data mining of the U.S. EPA ToxCast and EDSP21 online databases indicates an overall lack of interaction by the test substance with the estrogen, androgen, and steroidogenesis pathways based on the results of 50 in vitro assays. These data are consistent with the fact that there is no indication within the breadth of toxicology studies conducted with the test substance that it adversely affects any relevant component of the endocrine system that would support a possible relationship of treatment with Leydig cell tumour induction.
Based on the results of chronic feeding studies in rats and mice, it can be concluded that the test substance does not pose a carcinogenic concern for humans. Therefore, the test substance is not classified for carcinogenicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.
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