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Carcinogenicity

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Description of key information

The potential oncogenicity of the test substance was evaluated in oncogenicity studies in rats and mice.

In a 2-year carcinogenicity study with rats, the test substance was administered to groups of Fischer rats for 24 months, at dietary concentrations of 0, 100, 300 or 1000 ppm. No treatment-related abnormalities were noted in mortality, general clinical observation, hematology, organ weight and body weight ratio or gross pathology in any treated groups. Body weights in females in the 1000 ppm group were significantly lower than those in the control group at several test weeks. Food consumptions in females in the same group also decreased significantly for several weeks. Adenocarcinoma of the uterus in females increased significantly in the 1000ppm group, whereas the incidences in the treatment groups were unrelated to the dose levels and no significant differences of the incidences of the tumor were noted in all females in any treatment groups. The study concluded that there was no treatment related carcinogenic dose up to the maximum treatment level of 1000 ppm in males and females (male: 42.7 mg/kg/day, female: 50.8 mg/kg/day). A NOAEL for the study was not reported, but 300 ppm (12.9 for males and 15.5 mg/kg bw/d for females) is consistent with the reported data.

In a second supplemental 2-year carcinogenicity study with rats, the test substance was administered to groups of Fischer rats at dietary concentrations of 0, 1000 or 3000 ppm for a period of 2 years. There were no treatment-related clinical signs or neurobehavioral effects. Toxicity was observed in both sexes at both dose resulting in effects on bodyweight, food consumption, organ weights and gross pathology. Histopathological changes were observed in the liver and kidney. Adenocarcinoma of the uterus in females increased significantly in both the 1000 and 3000 ppm group. The NOAEL for all effects observed in this study was established in a prior rat cancer study.

In an 18-month carcinogenicity study mice (52/sex/dose), ICR [Crlj:CD1(ICR)] mice were given 0,120,700, 4000 (males) or 4000/3000/2000 ppm (females) of the test substance in the diet. At the high dose, treatment to females caused death or moribundity; low body weight, food consumption, and food efficiency; high total leukocyte, lymphocyte, and large unstained cell counts; effects on the spleen and heart; and several histopathological changes including vacuolation in multiple tissues, decreases of hematopoiesis in the bone marrow, and lymphoid depletion. At the dose level of 4000 ppm in males, low body weight, and the effects on the liver (centrilobular hepatocellular hypertrophy) and submandibular gland (depletion in granular ducts) were observed. The no-observed-adverse-effect level (NOAEL) in ICR [Crlj:CD1(ICR)] mice was considered to be 700 ppm (males, 78.7 mg/kg/day; females, 75.8 mg/kg/day) under the conditions of this study. There was no increase in incidence of neoplastic lesions in any treated groups of either sex. There were no increases of rare types of tumors, earlier occurrence of spontaneous neoplasm, or other sign indicating carcinogenicity.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
12.9 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
GLP and guideline compliant

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Analysis of test substance toxicology data indicates a dopamine enhancement mode of action leading to rat uterine adenocarcinomas (see IUCLID section 7.9.3 and MOA justification document attached in IUCLID section 13). This mode of action for uterine adenocarcinoma promotion has no relevance to humans due to both qualitative and quantitative differences between rat and human. Furthermore, kinetics studies indicate that the doses where tumors were observed clearly exceeded a kinetically derived maximum tolerated dose (KMD or MTD).

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008.

An increase of adenocarcinoma in the uteri of female rats were observed at 1000 and 3000 ppm. Based on studies investigating the underlying mode of action, it can be concluded that these uterine adenocarcinoma are not of any relevance to humans. The test substance did not show a carcinogenic potential in mice.

On the basis of the available data, the test substance is not considered to be classified for carcinogenicity under Regulation (EC) No 1272/2008, as amended for the eighth time in Regulation (EU) No 2016/918.

Additional information

WoE: carcinogenicity in rats 2014/8000287

The test substance was given in the feed to F344 rats (50/sex/dose) at doses of 0, 100, 300 or 1000 ppm (equal to 0, 4.4, 12.9 and 42.7 mg/kg bw/d for males and 0, 5.3, 15.5 and 50.8 mg/kg bw/d for females) for 104 weeks.

No treatment-related abnormalities were noted in mortality, general clinical observation, hematology, organ weight and body weight ratio or gross pathology in any treated groups. Body weights and food consumption in the 1000 ppm group (females) were significantly decreased for multiple weeks over the course of the study.

Adenocarcinoma of the uterus in females killed by design increased significantly in the 1000 ppm group. However, the incidences in the treatment groups were unrelated to the dose levels and no significant differences of the incidences of the tumor were noted in all females in any treatment groups. Due to the described increased incidence of spontaneous adenocarcinoma in the uterus in the F344 rat, the occurrence of adenocarcinoma in the uterus in females was considered to be unrelated to the treatment with the test substance.

A NOAEL for the study was not reported, but a NOAEL of 300 ppm (12.9 for males and 15.5 mg/kg bw/d for females) is consistent with the reported data.

WoE: carcinogenicity in rats 2014/1215781

Prior to this study, the Dose Adequacy Review Team (DART) of the Health Effects Division of the US Environmental Protection Agency reviewed the dose levels of an ongoing 2-year rat cancer study (2014/8000287) and concluded that an additional dose of 3000 ppm was required to meet the maximum tolerated dose (MTD) requirements. The agency also requested that the 1000 ppm dose be repeated to bridge the results to the ongoing rat cancer study that was being conducted at dose levels of 100, 300 and 1000 ppm.

The test substance was given in the feed to F344 rats (50/sex/dose) at doses of 0, 1000 or 3000 ppm (equal to 0, 41.6 and 128.2 mg/kg bw/d for males and 0, 50.4 and 146.9 mg/kg bw/d for females) for 104 weeks.

There was a significant increase in the mortality of the 3000 ppm female group. No treatment-related abnormalities were noted in mortality with the males. There were no treatment related clinical observations. Food consumption was decreased in all of the groups treated with the test substance. Body weights for males at 3000 ppm were statistically significantly reduced, but other treatment groups were not significantly different than control.

In the 3000 ppm group, treatment related organ weight changes included an increased absolute and relative weights of the liver, spleen and kidneys in males and females. In males, absolute and relative weights of the epididymides and relative weight of the brain increased significantly. In females, relative weights of the heart increased significantly and absolute weights of the heart and ovaries decreased significantly. At 1000 ppm, absolute and relative weights of the epididymides increased significantly in males. In females, relative weight of the liver increased significantly and absolute weight of the heart decreased significantly.

Gross histopathology of note included a decrease in the incidence of testis atrophy at 3000 ppm in the males as well as a decrease in thyroid nodules in the females. Pituitary cysts were increased in the females at 3000 ppm. Non neoplastic histopathologic findings included liver effects (increased bile duct hyperplasia and microgranuloma in all treatment groups and increased altered foci (male at 3000 ppm). In the kidney an increase in chronic progressive nephrosis (female, 3000 ppm) was noted. The testis showed decreased atrophy as well as decreased hyperplasia at 3000 ppm. In the uterus there was an increase in endometrium hyperplasia at 3000 ppm. Also at 3000 ppm, there was a decrease in the dilation of the mammary gland duct.

Neoplastic lesions present included an increased incidence of uterine adenocarcinoma at both 1000 and 3000 ppm in the females. There was a decreased incidence of testes interstitial tumors in the males at 3000 ppm as well as a decrease in thyroid C-cell carcinoma in both the males and females at 3000 ppm. Based on studies on the mode of action (see IUCLID section 7.9.3), the adenocarcinoma in the uterus are not considered to be relevant to humans.

NOAELs for all findings in this study were established in a prior rat cancer study conducted at lower doses (2014/8000287).

WoE: carcinogenicity in mice 2012/8000283

Mice were administered the test substance in the diet at doses of 0, 120, 700, 4000 (males) or 0, 120, 700, 4000/3000/2000 (females) ppm (equal to 0, 13.3, 78.7 and 445 mg/kg bw/d for males and 0, 12.9, 75.8 and 333 mg/kg bw/d for females) for 78 weeks. Dose levels for females were lowered several times because of treatment related mortality at high doses.

Treatment-related effects were restricted to the high dose level. The test substance at the dose level of 4000/3000/2000 ppm in females caused death or moribundity, low body weight, food consumption, and food efficiency, high total leukocyte, lymphocyte, and large unstained cell counts, effects on the spleen and heart and several histopathological changes including vacuolation in multiple tissues, decreases of hematopoiesis in the bone marrow, and lymphoid depletion. At the dose level of 4000 ppm in males, low body weight, and the effects on the liver (centrilobular hepatocellular hypertrophy) and submandibular gland (depletion in granular ducts) were observed. There was no increase in incidence of neoplastic lesions in any treated groups of either sex. There were no increases of rare types of tumors, earlier occurrence of spontaneous neoplasm, or other signs indicating carcinogenicity.

There were no effects at 120 or 700 ppm.

In conclusion, the test substance had no carcinogenic potential. The no-observed-adverse-effect level (NOAEL) in ICR [Crlj:CD1(ICR)] mice was considered to be 700 ppm (males, 78.7 mg/kg bw/d; females, 75.8 mg/kg bw/d) under the conditions of this study.