Reaction mass of chlorodifluoroacetic acid and trifluoroacetic acid

Endpoint summary

Description of key information

The compounds composing the reaction mass of CDFA and TFA have a very similar structure and their physico-chemical properties are also very close at the exception of vapour pressure which is much higher for TFA.

Both compounds are also corrosive. Consequently their toxicokinetics are supposed to be similar. Absorption is expected by both the inhalation and oral route while dermal absorption is irrelevant because of corrosivity. As the reaction mass is corrosive, its absorption by inhalation should remain very low because of the induction of local effect and prolonged exposition and absorption by inhalation is highly unlikely.
Absorbed CDFA and TFA should be distributed systemically, at least in the hydrophilic tissues, via the blood probably as ionised form. TFA is also known to be submitted to the enterohepatic circulation and to be able to pass through placenta barrier. TFA is not metabolized and CDFA is not expected to be metabolized either.

Excretion of TFA is made through the urine and the bile. CDFA excretion is expected to be similar.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

As the substance is a reaction mass of chlorodifluoroacetic acid (CDFA) and trifluoroacetic acid (TFA) and as no information is available on the reaction mass itself, the toxicokinetic properties of each of the constituents will be evaluated separately.

Actual data are available on TFA toxicokinetic therefore the assessment of absorption, distribution, metabolism and excretion of TFA will be evaluated based on these data, on toxicological studies results and on its physico chemical properties.

No human data are available and no specific toxicokinetic (TK) study using CDFA has been performed. Therefore, the assessment of absorption, distribution, metabolism and excretion of CDFA is based on the physico-chemical properties of the test substance and on the results of the available toxicity studies.

TFA :

Physico-chemical properties:

- TFA is a volatile compound with a vapour pressure of 14700 Pa at.

- The partition coefficient in n-octanol/water is 0.79.

- The water solubility is 1520 g/L.

- Molecular Weight: 114.02 g/mol

Absorption

Inhalation route

The substance is volatile as evidenced by the vapour pressure value: 14700Pa and thus may be absorbed through inhalation. However, because of its corrosive properties and thus the induction of strong local reaction, prolonged exposition and absorption by inhalation is highly unlikely.

Oral route

In a developmental toxicity study, trifluoroacetic acid (TFA) diluted in water at the dose of 75 and 150 mg/kg bw/d was administered to pregnant female rats by oral route for a period of 10 days from the gestation day 10 (GD10) to the GD20. The males used for the mating were not treated with the TFA. The females were not killed before the end of gestation, so that the delivery occurred approximately on gestation day 21.

Maternal body weight change was significantly reduced at 150 mg/kg bw for GD 10-15. Both absolute and relative liver weights were significantly increased at both treatment levels (75 and 150 mg/kg bw/d) providing a clue that TFA is absorbed after oral administration.

Regarding the offspring, there were significant increases in the activities of GLDH and ASAT on PND3. Elevations were dose-dependent and were more potent for GLDH and ASAT. Serum urea concentration was significantly elevated at 150 mg/kg bw/d. These changes should be considered as adaptative and reversible since they were not recorded at PND12 and PND49 in the offsprings. They may provide that the TFA was systemically absorbed after oral exposure of the dams and then distributed inducing in utero exposure.

In a toxicokinetic study, 100 µmol of TFA was administered to rabbits by a duodenal catheter. After enteral administration, TFA appeared rapidly in the circulatory blood and a considerable amount of TFA was reabsorbed in the gastrointestinal tract and then excreted into the urine and the bile.

Dermal Route

As TFA is corrosive to the skin, it is not relevant to evaluate its dermal penetration.

Distribution

The toxicokinetic study presented above also showed that after oral exposure, TFA is submitted to enterohepatic circulation, then distributed in the body via the blood as ionised form.

In the reproductive toxicity study described above, the effects observed on the dams are indicative that TFA is also able to pass through placenta barrier.

Considering these elements as well as its moderate partition coefficient log Kow (0.79) and its high solubility in the water, together with its molecular mass (114 g/mol) are indicative of a systemic distribution at least in the hydrophilic tissues.

Metabolisation

The performed toxicokinetic study showed that TFA is not metabolized.

Excretion

The performed toxicokinetic study showed that after an enteral administration of TFA, TFA appeared rapidly in the circulatory blood and a considerable amount of TFA was reabsorbed in the gastrointestinal tract and then excreted into the urine and the bile.

CDFA :

Physico-chemical properties:

- CDFA is a moderately volatile liquid with a vapour pressure of 1750 Pa.

- The partition coefficient in n-octanol/water is -0.9.

- The water solubility is > 2000 g/L.

- Molecular Weight: 130.48 g/mol

Absorption

Inhalation route

The substance is moderately volatile as evidenced by the vapour pressure value: 1750Pa and thus may be absorbed through inhalation. However, because of its corrosive properties and thus the induction of strong local reaction, prolonged exposition and absorption by inhalation is highly unlikely

Oral route

In an acute oral toxicity with groups of 10 rats per dose (5 males and five females) there was 0, 10, 80, 90 and 100% mortality with doses of 0, 26, 56.6, 75 and 101 mg/kg respectively. For the 26 mg/kg rat who died at Day 12 no clinical sign nor macroscopic issue were observed. For the rats dead at the 56.6 mg/kg dose the observed clinical signs were snorting and subdued behaviour. Macroscopic observations during necropsy showed mostly local effect including perforation of the oesophagus, stomach ulcers (at the highest dose) and areas of pulmonary congestion.

As most of the macroscopic findings were related to local effects, it is not possible to conclude on absorption of CDFA in the gastrointestinal tract.

Dermal Route

As CDFA is corrosive to the skin, it is not relevant to evaluate its dermal penetration

Distribution

An in-vivo mice erythrocyte micronucleus test was performed with diluted (pH>3) CDFA with a maximum CDFA dose of 400 mg/kg. During this study, no marked effect on the body weight and no mortality or signs of systemic toxicity were observed. Moreover, no induction of micronuclei in bone marrow erythrocytes was observed following administration of Chlorodifluoroacetic acid. This study does not allow us to conclude about CDFA distribution as there is no indication of genotoxic properties in other in-vitro studies for CDFA.

During the rat acute oral toxicity, deaths and other observations were related to local effects so it is not possible to conclude on CDFA distribution based on this study.

However, based on TFA results, together with the very high water solubility a systemic distribution at least in the hydrophilic tissues is expected.

Metabolization

Chlorodifluoroacetic acid is not expected to be metabolized.

Excretion

Owing to the low molecular weight and the high water solubility of Chlorodifluoroacetic acid is possibly excreted in the urine.