4-chloro-α,α,α-trifluorotoluene

Endpoint summary

Description of key information

The lowest available oral NOAEL is a 90-d value of 40 mg/kg bw/day and the lowest available inhalation 90-d NOAEC is 51 mg/m³. No information on dermal effects of subchronic exposure is available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

40 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

51 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose studies via oral route

In the key study, Fischer 344 rats, 5 to 6 weeks age, were dosed orally by gavage each day for 3 months with corn oil solutions containing PCBTF. The doses, administered on an equal volume basis, were 0, 10, 40, 150 or 500 mg/kg body weight. Fifteen animals of each sex were included in each group. One low dose male and two high dose males died during the study. There were no treatment related physical or behavioral changes noted in any of the treated or control animals. Effects in this study were: elevated levels of blood urea nitrogen, total birilubin and alkaline phosphatase; induction of hepatic p-nitroanisole O-demethylase activity, increased liver and kidney weights, tubular degeneration in the kidneys and centrilobular hyperthrophy in the liver. Males were more sensitive to the effects of PCBTF than females. Compound induced changes were dose-related and were more pronounced at doses of 150 and 500 mg/kg. The lowest dose employed, 10 mg/kg, was tolerated for 90 days without significant toxicity in the rat. Based on this data, the NOAEL was established to be 40 mg/kg bw/day while the LOAEL 150 mg/kg bw/day.

Two supporting studies are also available. In the first one, the substance was administered to rats for 14 days at 0,50,400, 1000 mg/kg body weight/day in corn oil by gavage and 0,10,50, 400 mg/kg body weight/day in microencapsulated form. 5 males and 5 females per groups were used. Effects such as mild anaemia and increased relative liver and kidney weight were found. The NOEL was established to be 10 mg/kg bw/day for males and 50 mg/kg bw/day for females.

In the second supporting study, rats were orally administered for 28 days at 10, 100 and 1000 mg/kg bw/day. No deaths or clinical signs of toxicity occurred, but reduced body weight gain was evident in the male rats at the top dose level, even though feed intake was not affected. In addition, dose-dependant increases in blood cholesterol and triglycerides were found in male rats at the end of the study (significant from 100 mg/kg body weight) from which the authors concluded that fat metabolism was disturbed. The only effect in the females was a slight but dose-dependant increase in the activity of lacatate deghydrogenase (significant at 1000 mg/kg body weight). Post-mortems revealed increased relative kidney weights in the males and increased relative liver weights in both sexes at the top dose level. Histological examination primarily showed hyaline droplet nephrosis and increased lipid vacuoles in the adrenal cortex in the males at the top dose level. Mild nephrosis was also observed in the males in the 1000 mg/kg group. Therefore, it can be concluded that the NOEL is 10 mg/kg body weight/day.

Repeated dose studies via inhalation route

In the first key study, used for classification purposes, 10 Sprague Dawley rats/sex/dose were exposed to 10, 51, or 252 ppm of the test item for 6 hours/day, 5 days/week for 13 weeks. No PCTB-related effects were observed either during exposures or weekly clinical evaluations; no changes observed in body weight gain or measured haematological and clinical chemistry parameters; increase (11%) in relative liver weights in both sexes at highest dose tested correlated with centrilobular hypertrophy. NOEL (hepatocyte hypertrophy) was established to be 51 ppm.

In the supporting study, the sub-chronic inhalation toxicity of PCBTF was studied in male rats exposed over a period of 4 months, 24 hours daily. Four concentration levels (5.5, 20.5, 71.6 and 440 mg/m³) and a negative control were tested and repeated measurements of a number of haematological and biochemistry parameters were made. The function of the central nervous system was also studied. The rat's body weight was not affected even at the highest concentrations. The two top concentrations led to effects on almost the studied parameters. The lowest effective concentration was 20.5 mg/m3 while 5.5 mg/m3 was without effects. The effects on the blood count were the limiting factor.

Two sub-chronic studies on rats and mice are also available and data was generated from the National Toxicology Program. Doses used in both studies are above the threshold for classification set out in the CLP Regulation n.1272/2008, however due to the high quality of database and considering the toxic effects observed in both species on reproductive organs, these two studies are considered as key studies leading to a classification for reproductive toxicity.

Justification for classification or non-classification

The substance is not classified for subchronic toxicity based on the results of repeated dose oral and inhalation studies showing that the threshold for classification was not reached.