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

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone is an organic mono-constituent liquid with a purity of 99.7% and impurities at 0.3%.

A full ADME toxicokinetic study in the rat is not available. The toxicokinetic analysis is based on the physicochemical and in vivo toxicological data. In vivo studies covering the oral route (acute toxicity), dermal route (guinea pig Buehler test) and inhalation route (acute toxicity, 28-day repeated dose toxicity, toxicity to reproduction (screening)) are available. Further details on the endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical data and available in vivo toxicological data, 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone hydrolyses quickly to pentafluoropropionic acid and fluorocarbon gas.  Absorption via the oral and inhalation routes, and to a lesser extent, via the dermal route is expected. The hydrolysis products will be excreted unchanged in the urine and air, respectively.

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

1.Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone in the body.

The hydrolysis data indicates that 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone hydrolyses very quickly at pH 1.2 – 9.0 (t(1/2) = <2.5 minutes at 20°C or 37°C) which indicates that the parent compound may only be present in the body for a very limited period. Hence, the caveat that any that toxicokinetic prediction based on the characteristics of the parent compound, 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone, may be of limited relevance, is included in this analysis. Reference will be made to the hydrolysis products, pentafluoropropionic acid and fluorocarbon gas, where relevant.

Absorption - oral

The molecular weight of 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone (316.04 g/mol) is in the range for favourable oral absorption (<500 g/mol). The substance is moderately soluble in water (336 mg/L; predicted) and the hydrolysis product, pentafluoropropionic acid, is known to be highly soluble in water (9070 mg/L; predicted), so the latter should readily dissolve in the gastrointestinal fluids. The log Kow of 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone (2.79; predicted) and pentafluoropropionic acid (1.47; predicted) are in the range favourable for passive diffusion.

Absorption – dermal

The molecular weight, log Kow and water solubility of 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone and pentafluoropropionic acid are in the favourable range for dermal absorption.  However, as the parent substance is a highly volatile liquid (31.6 ± 0.6 kPa at 20°C), the amount available for uptake may be reduced.

Absorption – inhalation

1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone is a highly volatile liquid (31.6 ± 0.6 kPa at 20°C), so there will be exposure via the inhalation route. Most of the material will be exhaled unchanged with the remaining fraction being hydrolysed to the highly water soluble pentafluoropropionic acid and fluorocarbon gas. The latter will be exhaled while the former will be absorbed perhaps via aqueous pores, due to the hydrophilicity.

Metabolism/Excretion

As described, the hydrolysis data indicates that 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone hydrolyses very quickly at pH 1.2 – 9.0 (t(1/2) = <2.5 minutes at 20°C or 37°C). Pentafluoropropionic acid is highly water soluble and will be excreted in the urine unchanged; fluorocarbon gas will be exhaled unchanged.

2. Information from other studies in the dossier

Absorption - oral

In an acute oral toxicity study (OECD 423/GLP), the LD50 was > 2000 mg/kg bw with minimal clinical signs up to day 7.

Based on the physicochemical data and available in vivo toxicological data, there is systemic absorption after oral administration. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

Absorption – dermal

In a Buehler sensitization study (OECD406/GLP), there were no signs of skin irritation and the substance is not a skin sensitiser.

Based on the physicochemical data and available in vivo toxicological data, dermal absorption is likely to be low. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption – inhalation

In a subacute inhalation toxicity study (OECD 412/GLP), 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 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. 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. 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.

In a screening for reproductive/developmental toxicity test (OECD 421/GLP), 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone was administered to four groups of Wistar rats (12 animals/sex/group) via inhalation (nose only) at dose levels of 0, 300, 1000 and 3000 ppm for 6 hours per day during the first 2 weeks for 5 days per week. Thereafter, the animals were exposed until gestation day 19. Male animals were exposed for 4 weeks and then sacrificed. Females were allowed to litter and were sacrificed at or shortly after day 4 of lactation.

The mean daily concentrations were 300 ±1 ppm, 995 ±1 ppm and 2992 ±1 ppm. No treatment related mortalities were seen. Body weights were comparable between the control and exposed animals during premating, gestation and lactation. Food consumption was comparable between the control and exposed animals. All females of the control and exposed groups, except one animal in the low dose group, became pregnant within 4 days. No treatment related effects were seen in any of the reproduction or developmental parameters. No gross changes were noted at necropsy. The NOAEC by inhalation for parental toxicity, fertility, and developmental toxicity was at least 3000 ppm.

Based on the physicochemical data and available in vivo toxicological data, there is systemic absorption after inhalation administration. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, using a conservative approach.

Distribution/Metabolism/Excretion

Based on the physicochemical data and available in vivo toxicological data, 1,1,1,2,2,4,5,5,5-nonafluoro-4-(trifluoromethyl)-3-pentanone hydrolyses very quickly to pentafluoropropionic acid and fluorocarbon gas and the former can distribute throughout the body. Both will be excreted unchanged in the urine and air, respectively.