2,2-Difluoroethyl Acetate

Endpoint summary

Description of key information

2,2-Difluoroethyl acetate presents physico-chemical properties favorable for absorption by passive diffusion across the gastrointestinal and respiratory tracts when exposed via oral and inhalation routes. The observation of systemic effects in the available 28- and 90-day repeated dose toxicity studies in rats by oral and inhalation routes support the fact that absorption occurs when exposed by these routes. 2,2-Difluoroethyl acetate is transported via the blood stream to the organs and is expected to remain in the circulating blood and not to distribute into organ tissues based on its physico-chemical properties. 2,2-Difluoroethyl acetate is excreted in the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No toxicokinetics study is available for 2,2-Difluoroethyl acetate. Therefore, and according to Column 1 of REACH Annex VIII, the toxicokinetic profile (i.e. absorption, metabolism, distribution and excretion) of this substance was qualitatively assessed to the extent that can be derived from the relevant available information, i.e. physico-chemistry and systemic toxicity information. For this assessment, section R.7.12.2.1 of ECHA Guidance R.7c (v. 3.0, June 2017) was taken as a guide.

 

ABSORPTION

 

Oral route

 

2,2-Difluoroethyl acetate has a low molecular weight (124.09 g/mol), a high water solubility (31.3 g/L at 20 °C) and a low Log Kow (0.45 at 20 °C), all of these parameters being favorable for absorption by passive diffusion. The 28-day repeated dose toxicity study by oral route in rats further supports the fact that absorption occurs for 2,2-Difluoroethyl acetate. In this study, systemic effects were indeed observed (see IUCLID section 7.5.1 for further details) as evidenced by reduced body weight in males (statistically significant at 1000 mg/kg/day, present but not statistically significant at 300 and 100 mg/kg/day), decreased leucocyte counts, decreased blood glucose and increased urine ketones in males and females at the three doses tested.

 

Inhalation route

 

With a vapour pressure of 6800 Pa at 25 °C, 2,2-Difluoroethyl acetate may be available for inhalation as a vapour. The Log Kow value falls within the range from -1 to 4 which is favorable for absorption directly across the respiratory tract epithelium by passive diffusion. The 28- and 90-day repeated dose toxicity studies by inhalation route in rats further supports the fact that absorption occurs for 2,2-Difluoroethyl acetate. In these studies, systemic effects were indeed observed (see IUCLID section 7.5.2 for further details) as evidenced by reduced body weight in males and females in the 28-day study (at 750 and 1500 ppm) and in females in the 90-day study (at 100 ppm), decreased blood glucose and increased urine ketones in males and females at the three concentrations tested in the 28-day study (i.e. 100, 750 and 1500 ppm) and at 100 ppm in the 90-day study.

 

Dermal route

 

It is generally considered that liquids are taken up readily. However, absorption of a liquid across the skin may be limited by its volatility potential. Indeed, although a substance may readily partition into the stratum corneum, it may be too volatile to penetrate further. This can be the case for substances with vapour pressures above 100 - 10000 Pa at 25°C. With a vapour pressure of 6800 Pa at 25 °C, 2,2-Difluoroethyl acetate could be in this case. In addition, the water solubility being above 10 g/L and the Log Kow close to 0, 2,2-Difluoroethyl acetate may be too hydrophilic to cross the lipid rich environment of the stratum corneum. On the basis of this pool of evidence, dermal uptake does not seem to be a main route for absorption for 2,2-Difluoroethyl acetate. In the absence of any systemic effect, the available acute toxicity study by dermal route does not allow to assess absorption through this route further.

 

DISTRIBUTION

 

After absorption, 2,2-Difluoroethyl acetate is transported via the blood stream to the organs. The high water solubility, the low Log Kow and the absence of clear, organ-specific adverse findings in the available repeated-dose toxicity studies may constitute supportive evidence that 2,2-Difluoroethyl acetate should remain in the circulating blood and should not distribute into organ tissues (in particular in fatty tissues). The presence of fluoride in blood was detected in the 90-day study with plasma fluoride concentrations at the end of the exposure period being statistically significantly higher in females at 10 and 100 ppm as compared to the control treatment. Such a finding was not reported in males in the same study or in any animals in the 28-day study. There is no evident explanation to the fact that fluoride was detected or not in blood in the different studies; this can be due to several parameters as for example variable length of the fasting period before blood sample collection (study reports mention that fasting lasted at least 15 hours, but no exact duration was given). The fact that fluoride was not detected in blood in some animals can reflect the fact that 2,2-Difluoroethyl acetate has already been eliminated (urinalysis indeed demonstrated the presence of fluoride in the urine, see the “EXCRETION” section below).

 

METABOLISM

 

No information is available on the metabolism of 2,2-Difluoroethyl acetate.

 

EXCRETION

 

The low molecular weight and the high water solubility of 2,2-Difluoroethyl acetate are characteristics favorable to urinary excretion. Urinary excretion is further supported by the findings of the 28- and 90-day repeated dose toxicity studies by inhalation route in rats. At the end of the exposure period in the 28-day study, urine fluoride concentrations were increased in males and females from all exposure groups (i.e. 100, 750 and 1500 ppm) as compared to controls. At the end of the exposure period in the 90-day study, urine fluoride concentrations were increased in males and females exposed to the two highest concentrations (i.e. 10 and 100 ppm) as compared to controls.

 

REMARK

 

2,2-Difluoroethyl acetate presents a potential for hydrolysis under specific pH conditions. Hydrolysis is indeed expected to contribute to the degradation of this substance at pH 7 and 9, but not at pH 4 at which it was demonstrated to be hydrolytically stable. The available hydrolysis study report (see IUCLID section 5.1.2) reports the following half-lives at 35 °C: more than 1 year at pH 4 (i.e. default ½-life value assigned to hydrolytically stable substances), 10.3 days at pH 7 and 0.28 day at pH 9. Under the pH conditions prevailing in the human body, hydrolysis of 2,2-Difluoroethyl acetate should thus not proceed so quickly. And in the absence of further data, it does not seem irrelevant to assess the toxicokinetic profile on the basis of data on the mother substance.