1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl )-3-pentanone

Endpoint summary

Description of key information

Subacute NOAEL (rat, male/female): 12.45 mg/L (OECD 412/GLP)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study by the oral route does not need to be conducted because an appropriate inhalation study is available and inhalation is the most appropriate route of administration as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: EEC Directive 92/69, B.8 OECD 412, 1981 Japanese (MITI) guidelines, 1986

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Wistar Crl:(WI)WU BR

Route of administration:

inhalation

Type of inhalation exposure:

nose only

Vehicle:

other: None

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Duration of exposure per day: 6 hours
Dosing regime: 5 days/week

No. of animals per sex per dose:

Male: 10 animals at 0 mg/l
Male: 5 animals at 12.41 mg/l
Male: 5 animals at 49.6 mg/l
Male: 5 animals at 124.7 mg/l
Male: 10 animals at 244.6 mg/l
Female: 10 animals at 0 mg/l
Female: 5 animals at 12.41 mg/l
Female: 5 animals at 49.6 mg/l
Female: 5 animals at 124.7 mg/l
Female: 10 animals at 244.6 mg/l

Details on results:

Clinical observations: No treatment-related abnormalities in clinical signs or behaviour were seen during the exposure and recovery period. Reduced body weight gain, food intake and reduced food conversion efficiency were observed in male rats of the high concentration group.

Laboratory findings: No treatment-related changes in haematological parameters were noted. Clinical chemistry parameters revealed an increase, which was not concentration-related, in glucose content in males and females of the upper mid and high concentration groups and in males of the lower mid concentration group. Significantly increased albumin levels were observed in males of the lower mid, upper mid and high concentration groups. The albumin/globulin ratio was significantly, but not concentration-related, increased in all male exposure groups. GGT was significantly increased in females of the high concentration group. Further, a significant increase in triglyceride levels was found in males of the lower and upper mid concentration groups and in females of the upper mid and high concentrations. Cholesterol levels were significantly, but not concentration-related, decreased in males of the low, lower mid and high concentration groups. A tendency towards a decreased cholesterol content was also seen in males of the upper mid concentration group. Phospholipid levels were increased in all female exposure groups reaching a statistically significant degree in females of the upper midconcentration group only. Finally, creatinine was significantly decreased in female animals of the high concentration group. At the end of the 14-day recovery period, glucose was increased in the exposed animals and the increase was significant in males. Albumin was slightly though significantly increased in exposed male animals, a similar increase in female animals was not significant. The albumine/globulin ratio was significantly increased in exposed male animals and significantly decreased in exposed female animals. Cholesterol was significantly increased in exposed female animals. Phospholipids were increased in both male and female exposed animals. Creatinine was decreased in male exposed animals, a similar decrease in female exposed animals did not reach significance. An increased mean urinary fluoride concentration was observed in males and females of the upper mid and high concentration groups, and in males of the lower mid concentration group at the end of the treatment period. Accordingly, total fluoride excretion in urine and the urinary fluoride /creatinine ratio were also significantly increased in a concentration-related fashion in these male and female groups. These parameters were still slightly increased when compared to controls at the end of the recovery period.

Effects in organs: A strong induction of liver peroxisome proliferation was observed in all male exposure groups, which practically saturated at 4,000 ppm for both lauric acid hydroxylase activity and acyl-CoA oxydase activity. A much weaker effect was observed in female rats of these groups. At the end of the recovery period, the effects of strongly induced peroxisome proliferation had clearly diminished in exposed males and was absent in exposed females. A concentration-related increase in absolute and relative liver weights was observed in all male exposure groups, and in females of the upper mid and high concentration groups. Increases in absolute and relative lung weights were observed in males and females of the upper mid and high concentration groups. Absolute and relative spleen weights were reduced in female exposure groups and in male animals of the upper mid concentration group, but a concentration-response relationship was not observed. At the end of the recovery period, increases in relative liver and lung weights were still observed in males and females of the high concentration group. Inhalation of T-7479 induced histopathological changes in the lungs and liver. Alveolar macrophage accumulation was observed in the lungs of males and females of the upper mid and high concentration group. Nucleolar enlargement was observed in the livers of all male exposure groups. A concentration-response relationship was not obtained. At the end of the recovery period, accumulation of alveolar macrophages was still present albeit to a slightly lesser degree. Liver changes were no longer present.

Dose descriptor:

NOAEL

Effect level:

ca. 12.45 mg/L air

Remarks on result:

other: exposure duration: 6 hours/day

Critical effects observed:

not specified

Conclusions:

Classified as: Not classified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

12 450 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Only 1 study is available and it is a guideline/GLP study.

System:

hepatobiliary

Organ:

liver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

12 450 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Only 1 study is available and it is a guideline/GLP study.

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

There is no subacute oral toxicity study available. A subacute inhalation toxicity study in rats was available.

In a subacute inhalation toxicity study, 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone was administered to Wistar Crl:(WI)WU BR rats (5/10 per sex) by nose only exposure at concentrations of 0; 1,000; 4,000; 10,000 and 20,000 ppm for 6 hours per day, 5 days/week for a total of 28 days.

The actual concentrations were 12.41, 49.6, 124.7 and 244.6 mg/L. General toxic effects induced by 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone consisted of reduced body weights and food intake and reduced food conversion efficiency in male rats of the high concentration group.

Exposure to 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone resulted in local effects in the lungs consisting of accumulation of alveolar macrophages in males and females of the upper mid and high concentration groups. These changes were accompanied by increases in relative lung weights. At the end of the 14-day recovery period, accumulation of alveolar macrophages, though to a slightly lesser extent, and increased relative lung weights were were still present in animals of the high concentration group when compared to controls. Exposed male rats showed various changes indicative of an effect of 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone on the liver, viz. increased relative liver weight, decreased plasma cholesterol, and increased albumin/globulin ratio (all groups), and increased fasting glucose, albumin and triglycerides content (lower mid, upper mid and high concentration groups). In female rats, comparable liver effects were seen consisting of increased relative liver weight, increased fasting glucose, and increased triglycerides content (upper mid and high concentration group), and increased GGT (high concentration group) and increased phospholipids content (upper mid concentration group). In males, these changes were accompanied by histopathological liver changes, viz. nucleolar enlargement, indicative of enhanced activity. Further, 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone caused a treatment-related induction of hepatic peroxisomal and microsomal fatty acid oxidising enzyme activities. In male rats, a no-effect-level for induction of both peroxisomal and microsomal fatty acid oxidising enzyme activities could not be found. For female rats, a no-effect-level of 1,000 ppm was observed for induction of lauric acid hydroxylase activity, whereas for acyl CoA-oxydase activity the no-effect level was below 1,000 ppm. Several of the liver changes (biochemical variables and weight) were still present at the end of the 14-day recovery period, especially in male rats. These changes, however, were not accompanied anymore by histopathological liver changes.

Based on the analysis of the liver and the increases in palmitoyl-CoA B-oxidation, a biomarker for peroxisome proliferation, the generation of the acid in the present 28-day inhalation study most probably resulted in peroxisome proliferation in the rat. Peroxisome proliferation is frequently observed in rats and other laboratory rodents in response to administration of a foreign substance; particularly those that are acids themselves or have metabolic/hydrolysis products that are acids. This correlation is particularly strong for perhalogenated acids. One of the effects produced by chemicals that induce peroxisome proliferation is an induction of hepatic enzymes, with more potent peroxisome proliferators resulting in a greater induction of P450 enzymes. Other changes typically observed with peroxisome proliferators include increased absolute liver weights and liver to body (relative) weight ratios, hepatocyte hypertrophy, and other biochemical changes associated with altered lipid metabolism. Male rats have historically been reported to be more sensitive to the effects of peroxisome proliferation than females (Reddy and Lalwani, 1983; Dirven et al., 1990; Bentley et al., 1993; Lake, 1995). These effects are consistent with those reported in the present 28-day inhalation study on 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone and had clearly diminished at the end of the 14-day recovery period. Except for the low concentration group, urinary fluoride concentration, total fluoride excretion in urine and the urinary fluoride/creatinine ratio were, as expected, concentration-related increased, and were still slightly higher in animals (especially in males) of the high concentration group than in controls at the end of the 14- day recovery period. These increased urinary fluoride concentrations, however, were not accompanied by renal changes. The histopathological examination of the spleen did not indicate any treatment-related effect of toxicity to 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone. It might therefore be concluded that the decreases in the absolute and relative weight of this organ, in the absence of any concentration-response relationship, are not of toxicological importance.

From the results of this study it was concluded that inhalation exposure to 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone for four weeks resulted in pulmonary effects in rats of both sexes exposed to 10,000 or 20,000 ppm. Various changes indicative of hepatic effects - including histopathological changes in males- were also observed at these concentration levels, and at the next lower level tested, i.e. 4,000 ppm. At a level of 1,000 ppm, hepatotoxic effects consisting of increased relative liver weight, changes in a few serum parameters, increased peroxisome proliferation and histopathological liver changes were especially, but not exclusively, observed in male rats, which level was therefore considered to be a Minimum- Observed-Adverse-Effect-Level (MOAEL). The relevance of the hepatic effects observed in the present study are, in large part, driven by an analysis of the impact of peroxisome proliferation in this animal model. The rat, however, has been demonstrated to be much more susceptible to the effects of peroxisome proliferation than the human (Bentley et al., 1993). Given this consideration, other than for effects that can be attributed to species specific peroxisome proliferation, the No-Observed-Adverse- Effect-Level (NOAEL) for humans might be (much) higher.

The NOAEC from this study was 12.45 mg/L air.

Justification for classification or non-classification

Based on available information in the dossier, the substance 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl )-3-pentanone (CAS No. 756-13-8) does not need to be classified for specific target organ toxicity (repeated) when considering the criteria outlined in Annex I of 1272/2008/EC.