4-chloro-α,α,α-trifluorotoluene

Carcinogenicity

Description of key information

Evidence of carcinogenic activity via inhlation route

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

T25

738.45 mg/m³

Study duration:

chronic

Species:

rat

System:

other: hepatobiliar, respiratory tract

Organ:

alveoli

bronchioles

liver

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

According to the CLP Regulation n. 1272/2008, for the purpose of classification for carcinogenicity, substances are allocated to one of two categories based on the following criteria: 

Category 1A:  known to have carcinogenic potential for humans, classification is largely based on human evidence

Category 1B: presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.

The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:

— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or

— animal experiments for which there is sufficient evidence to demonstrate animal carcinogenicity (presumed human carcinogen).

In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.

CATEGORY 2:

Suspected human carcinogens

The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.

The test substance shows carcinogenic effects on several organs in the studies carried out on rats and mice. Only studies on rodents are however available, showing limited evidence in animals. No data on human is available.

For this reason, the substance is classified as Carc. 2 according to the CLP Reagulation n. 1272/2008.

Additional information

Two chronic studies are available on PCBTF, one on mice and the other one on rats.

In the study on rats, groups of 50 male and 50 female rats were exposed by whole body inhalation to p-chloro-α,α,α-trifluorotoluene at concentrations of 0, 100, 300, or 1,000 ppm for 6 hours plus T90 (12 minutes) per day, 5 days per week for 104 to 105 weeks. There was a significant negative trend in survival of males and survival of 1,000 ppm males was significantly less than that of the chamber controls; survival of other exposed groups of males and all exposed groups of females was similar to that of the chamber controls. Mean body weights of 100 and 300 ppm males and females were similar to those of the chamber controls throughout the study. The mean body weights of 1,000 ppm males were approximately 10% less than the chamber controls at the beginning of the study and subsequently were within 5% to 10% of the chamber controls for the remainder of the study. Female body weights in the 1,000 ppm group were within 10% of the chamber controls until week 72 and were approximately 10% less than the chamber controls for the remainder of the study.
In the thyroid gland, there were significantly increased incidences of C-cell adenoma in 1,000 ppm males and 100 and 1,000 ppm females.
There were occurrences of alveolar/bronchiolar adenoma and alveolar/bronchiolar carcinoma in the 100 and 1,000 ppm groups of male rats; these neoplasms were not observed in the chamber controls. There were significantly increased incidences of chronic inflammation of the lung in all exposed groups of males and females. There were significantly increased incidences of fibrosis of the lung in all exposed male groups and in 300 and 1,000 ppm females and of hemorrhage in all groups of exposed males and 1,000 ppm females.
In the adrenal medulla, there was a significantly increased incidence of benign pheochromocytoma in 1,000 ppm females, and the incidences of medullary hyperplasia were significantly increased in 300 and 1,000 ppm females.
In the uterus, there were positive trends in the incidences of adenocarcinoma and atypical hyperplasia of the endometrium and a significantly increased incidence of stromal polyp in 300 ppm females.
In the liver, there were significantly increased incidences of centrilobular hepatocyte hypertrophy in all exposed groups of males and in 300 and 1,000 ppm females and of fatty change in 300 and 1,000 ppm males and females. There were significantly increased incidences of eosinophilic focus in 1,000 ppm males and mixed cell focus and clear cell focus in 1,000 ppm females.
The severity of kidney nephropathy increased with increasing exposure concentration in male rats.
There was a significantly increased incidence of exudate in the nose of 1,000 ppm males.

 

In the study on mice, groups of 50 male and 50 female mice were exposed by whole body inhalation to p-chloro-α,α,α-trifluorotoluene at concentrations of 0, 100, 200, or 400 ppm for 6 hours plus T90 (12 minutes) per day, 5 days per week for 104 to 105 weeks. Survival of 400 ppm males was significantly less than that of the chamber controls; survival of 400 ppm females was similar to that of 400 ppm males, but was not significantly different from the chamber controls. Survival of other exposed groups of males and females was similar to that of the chamber controls. Mean body weights of exposed groups of males were similar to those of the chamber control group throughout the study. The mean body weights of 100 ppm females were at least 10% greater than those of the chamber control group generally after week 69. The mean body weights of 200 and 400 ppm females were at least 10% greater than those of the chamber controls after weeks 13 and 2, respectively. Clinical observations included increased occurrences of distended abdomen at removal. Thinness also occurred in 400 ppm males and females.
In the liver of 200 and 400 ppm groups, there were significantly increased incidences of multiple hepatocellular adenoma in males and hepatocellular adenoma (including multiples) in females. There were significantly increased incidences of hepatocellular carcinoma in all exposed groups of males and in 400 ppm females. There were significantly increased incidences of hepatoblastoma in 400 ppm males and females. There were significantly increased incidences of eosinophilic focus in 400 ppm males and in 200 and 400 ppm females. There were significantly increased incidences of centrilobular hepatocyte hypertrophy in all exposed groups of males and in 200 and 400 ppm females. There were significantly increased incidences of multinucleated hepatocytes in 200 and 400 ppm males and in 400 ppm females. The incidences of hepatocyte necrosis were significantly increased in 400 ppm males and females. There were also significantly increased incidences of intrahepatocellular erythrocytes in 200 and 400 ppm males.
In the Harderian gland, there was a significantly increased incidence of adenoma in 400 ppm females, and significantly increased incidences of adenoma or adenocarcinoma (combined) in 200 and 400 ppm females.
There were significantly increased incidences of alveolar/bronchiolar epithelium hyperplasia and peribronchiolar fibrosis of the lungs in all exposed groups of males and females.
There was a significantly increased incidence of epithelium hyperplasia in the forestomach of 400 ppm females. In males, there were significantly increased incidences of inflammation in the 100 and 400 ppm groups.
In the larynx, there was a significantly increased incidence of squamous epithelium hyperplasia in 400 ppm males.