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Effects on fertility

Description of key information
Toxicity to reproduction: in vitro, Leydig and Sertoli cell cultures (K, William,  reliability 2): Trifluoroacetic acid, relevant for TFAH (see § 7.1) did not alter the function and/or integrity of the principal cell types of the testis. 
Similar results were observed in in vitro supporting study (S, Lloyd, reliability 4)
Effect on fertility: via oral route
Dose descriptor:
NOAEL
25 mg/kg bw/day
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
300 mg/m³
Additional information

Trifluoroacetic acid (TFA), relevant substance for TFAH, administered in a single oral dose of 25 mg/kg bw did not induce any effect on the male reproductive system in the rat (LLOYD, 1988, Kr.4). After a single four-hour inhalation exposure to vapours of TFA up to 300 mg/m3, no macroscopic nor microscopic changes were observed on the rat testes (see §7.2.2: Muijser, 2010).

Furthermore, TFA did not induce any effect on the fertility of male rats both in vivo and in vitro studies using testes target cells such as Sertoli cells (Weight of evidence approach).

Particular concern regarding the female reproductive system should be highlighted. However, it is scientifically unjustified to perform a reproduction study to detect any effects on the reproduction at doses recommended by the guidelines since strong corrosive effects of TFA would be observed. Moreover, it would be unlikely for effects to occur at low doses where corrosivity is not already observed in the animals.


Short description of key information:
Trifluoroacetic acid (TFA), as relevant substance for Trifluoroacetic anhydride (TFAH), administered in a single oral dose of 25 mg/kg bw did not induce any effect on the male reproductive system in the rat (LLOYD, 1988, Kr.4). After a single four-hour inhalation exposure to vapours of TFA up to 300 mg/m3, no macroscopic nor microscopic changes were observed in the rat testes (see §7.2.2).
Furthermore, TFA did not induce any effect on the fertility of male rats both in vivo and in vitro studies using testes target cells such as Sertoli cells (Weight of evidence approach).
Particular concern regarding the female reproductive system should be highlighted. However, it is scientifically unjustified to perform a reproduction study to detect any effects on the reproduction at doses recommended by the guidelines since strong corrosive effects of TFA, and therefore TFAH, would be observed. Moreover, it would be unlikely for effects to occur at low doses where corrosivity is not already observed in the animals.

Effects on developmental toxicity

Description of key information
The trifluoroacetic acid (TFA), as relevant substance for TFAH,  is a strong corrosive substance. Therefore, it is scientifically unjustified to perform a developmental study at doses recommended by the guidelines since strong corrosive effects would be observed. Moreover, effects would be unlikely detected at low doses where no corrosivity may occur in the animals.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
150 mg/kg bw/day
Additional information

In a developmental toxicity study (Saillenfait, 1996), Trifluoroacetic acid (TFA), considered as relevant for TFAH (see 7.1), 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 occured approximately on gestation day 21. Then, the pups were examined until day 49 postnatal (PND 49). Mothers and pups were examined for the body weight and the only liver and kidney weight. In addition, the urine and serum analysis were performed in both the dams and the pups to examine the hepatic and the renal biochemistry and/or function. Hence, the hepatotoxicity and the nephrotoxicity were assessed by the measure of different biochemical parameters. Moreover, the creatinine clearance was calculated as a measure of the rate of glomerular filtration.

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

No meaningful differences in the kidney weights, serum and urinary indicators, renal damage were observed between the control and the TFA dosed dams. The statistically significant reductions of GGT excretion in the 75 and 150 mg/kg bw groups were considered by the authors to be biological variations and unrelated to the dosing.

The length of gestation, the litter size and the offspring survival in the first 3 days were not adversely affected by the TFA dosing at both levels. Slight but non-significant decreases in pup weights were observed in both TFA-dosed groups on postnatal day (PND) 1 and 3. External examination of the pups did not reveal any malformation.

The prenatal exposure to TFA induced slight but transient changes in the neonatal rat liver without being predictive of any developmental effect in rat and therefore in human as no external malformations were observed.

The trifluoroacetic acid (TFA) is corrosive based on the pH (0.45) and the alkali reserve (35 g NaOH/g substance). Therefore, it is scientifically unjustified to perform a new developmental study at doses recommended by the guidelines since strong corrosive effects would be observed. Moreover, effects would be unlikely detected at low doses where no corrosivity may occur in the animals. Hence, considering both the available supporting study (Saillenfait, reliability 2) and the TFA corrosivity there is no concern for the reprotoxicity for the TFA.

Finally, considering the corrosive classification of TFAH, together with its uses both as intermediate, the industrial risk management measures conduct to an absence of TFAH (and therefore of TFA) human exposure at the workplace. In accordance with column 2 of REACH Annex IX, teratogenicity study (required in section 8.7.2) does not need to be conducted if there is no or no significant human exposure.

Toxicity to reproduction: other studies

Additional information

In an in vitro study performed in compliance with GLP (William, 1997), the intrinsic potential of trifluoroacetic acid (TFA), as relevant substance for TFAH (see § 7.1), to alter the function and/or integrity of the principal cell types of the testis, was determined. The 2,2,2, trifluoroethanol and its metabolite, trifluoroacetaldehyde (TFAld) were also included in the study. Isolated Leydig cell cultures (LCC), Sertoli cell only cultures (SCOC) and Sertoli-germ cell co-cultures (SGCC) were obtained from the testis of Sprague Dawley rat.

Several positive controls (ketoconazole, 1,3 -dinitrobenzene, methoxyacetic acid) were used to validate the study.

Various cell parameters including LCC and SGCC culture protein content, LDH activity, LCC medium culture secreted testosterone, LDH-X (specific isoenzyme of LDH of spermatocyte in pachytene stage) in SGGC culture medium, SGCC medium culture lactate and pyruvate concentrations were measured. Moreover, the morphological cell appearance was analysed in order to evaluate the potential adverse effect of TFE on reproductive system cells.

The TFA affected also Leydig cell function by inhibiting testosterone output but only in the presence of hormone at 5 hours. The no observed-effect level (NOEL) for this effect was less than 1 mM TFA. The results were the same for TFE. However, TFAld induced marked effects on the Leydig cell as decreased testotesterone production, on the SCOC and SCCC as altered morphology, decreased lactate and pyruvate production in SCOC, increased cell loss and LDHX leakage in SGCC. To resume, TFA showed only a small effect on Leydig cell function and essentially no effect on Sertoli cells.

This study doesn't satisfy the requirements for a reproduction toxicity study but this study is scientifically acceptable as it was well conducted and focused on the target cells of the testis.

 

Justification for classification or non-classification

Harmonised classification:

No harmonized classification is available according to the Regulation (EC) No 1272/2008 including ATP1.

Self classification:

Based on the available data, no self-classification for toxicity to the reproduction is proposed for Trifluoroacetic anhydride according to the Directive 67/548/EEC and the CLP Regulation.


 

Additional information

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