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Effects on fertility

Additional information

No two-generation reproduction toxicity study is available on potassium tetrafluoroaluminate. However, Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i. e., applying alternative methods such as in vitro tests, QSARs, grouping and read-across.

For the structural analogue of potassium tetrafluoroaluminate, cryolite, a two-generation toxicity study is available.

In this two-generation reproduction study, Sprague-Dawley rats (30 per group) were administered cryolite in the diet at dose levels of 0, 200, 600, or 1800 ppm (representing 0, 14, 42, and 128 mg/kg/day for males and 0, 16, 49, and 149 mg/kg/day for females, respectively, during premating) (Pharmaco LSR, Inc., 1994). Compound-related systemic toxicity was observed in a dose related manner among both sexes and generations at all dose levels as evidenced by clinical signs of dental fluorosis. Whitening of the upper and/or lower incisors was observed in most treated animals of both generations. Bevelled anterior edge of the lower incisor was observed in 67% of animals from both generations at 1800 ppm. Mottled appearance of the lower incisor was noted at dose levels ≥ 600 ppm in 6%-40% of F1 animals; however, this sign was not dose related.

Reproductive toxicity was observed at 1800 ppm as evidenced by significantly decreased pup body weights during lactation days 7, 14, and 21 (82%-88% of control in F1 offspring) and days 4, 7, 14, and 21 (74%-89%) of control in F2 offspring). Gross findings were also observed in pups of both generations at 1800 ppm by the time of weaning. They were manifested as pale kidneys, pale livers and enlarged hearts and were considered to be compound related. No effects were observed on parental reproductive performance.

From this study a NOAEL for fertility of >1800 ppm / >128 mg cryolite/kg bw/day can be derived. As there is no indication for fertility risks, a quantitative assessment for effects on fertility is not necessary.

Besides dental fluorosis and teeth whitening, no other compound-related systemically toxic effects could be revealed from this study with daily dosages of up to and including 128 mg cryolite/kg bw/day.

Based on the observed decreased mean body weights during lactation for both the F1 and F2 litters and an increased incidence of F1 and F2 animals with pale/white livers and/or kidneys and enlarged hearts at weaning at 1800 ppm, a NOAEL for developmental toxicity of 600 ppm / 42 mg cryolite/kg bw/day is derived from this study (see also section on developmental toxicity). After applying a correction for molecular weight, a NOAEL of 28.4 mg/kg bw/day is calculated for potassium tetrafluoroaluminate. For parental toxicity, the highest dose level of 128 mg/kg bw/day (equal to 86.6 mg/kg bw/day for potassium tetrafluoroaluminate after applying a correction for molecular weight) is considered to be a NOAEL.

Based on the available data (repeated dose toxicity studies with another read-across candidate, multiconstituent aluminium potassium fluoride, in which no systemic effects were observed and the two-generation study with cryolite), there is no indication for fertility risks caused by potassium tetrafluoroaluminate. Therefore, a quantitative assessment is not considered necessary for this endpoint.


Short description of key information:
There is no indication for fertility risks caused by potassium tetrafluoroaluminate based on the results of the two-generation study with the structural analogue cryolite.

Effects on developmental toxicity

Description of key information
No developmental toxicity study is available for potassium tetrafluoroaluminate. During the two-generation study (with rats) with the structural analogue cryolite, effects on postnatal growth evidenced by significantly decreased pup body weights during lactation as well as pathologic gross findings in several organs of the pups resulted from dose levels without any significant parental toxicity. Because these effects occurred without any significant sign for parental toxicity it is considered indicative for a specific toxic potential of cryolite (and thus potassium tetrafluoroaluminate ) adverse to postnatal development. The NOAEL for these effects is 42 mg cryolite/kg bw/day. Applying a correction for molecular weight, a NOAEL of 28.4 mg/kg bw/day is calculated for potassium tetrafluoroaluminate.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
28.4 mg/kg bw/day
Additional information

No developmental toxicity study is available on potassium tetrafluoroaluminate. However, Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i. e., applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For the structural analogue of pure KAlF4, cryolite, a developmental toxicity study is available.

Cryolite was investigated for prenatal developmental toxicity in rats, mice and rabbits with the oral route of administration. While in the studies with rats and with rabbits no evidence of prenatal developmental toxicity was observed, some indications of bent ribs and bent limb bones were reported in the mice study.

Cryolite was administered by gavage in the developmental toxicity study to female CD-1 mice (25/group) at dose levels of 0, 30, 100 or 300 mg/kg bw/day once daily from gestation days 6 through 15 (WIL Research Laboratories, 1991). There was increased mortality at 300 mg/kg bw/day. The glandular portion of the stomach was red beginning at 100 mg/kg bw/day. In addition, females in the 300 mg/kg bw/day group exhibited dark red contents of the stomach.

Fetuses at 300 mg/kg bw/day exhibited bent ribs and bent limb bones.

The study reveals severe maternal toxicity in terms of mortality and signs of toxicity in the gastrointestinal tract induced at dosages of 100 mg cryolite/kg bw/day leading to derivation of a NOAEL for maternal toxicity of 30 mg cryolite/kg bw/day.

Based on the observation of skeletal anomalies at the dose level of 300 mg cryolite/kg bw/day also a NOAEL for developmental toxicity of 100 mg cryolite/kg bw/day can be derived from the study. As these anomalies were only reported at dose levels showing severe maternal toxicity, the effects are not considered to be indicative for a substance specific teratogenic potential of cryolite.

During the two-generation study with cryolite in rats (Pharmaco LSR, Inc., 1994), effects on postnatal growth evidenced by significantly decreased pup body weights during lactation as well as pathologic gross findings in several organs (kidney, liver, heart) of the pups resulted from dose levels without any parental toxicity. Because these effects occurred without any significant sign for parental toxicity it is considered to be indicative for a specific toxic potential of cryolite adverse to postnatal development. The respective NOAEL for these effects in this study was 42 mg cryolite/kg bw/day.

 

As systemic toxicity of both cryolite and potassium tetrafluoroaluminate is primarily governed by accumulation of the fluoride formed upon hydrolysis of fluoroaluminate moieties, the same type of effects on reproduction and development as observed for cryolite can also be expected for potassium tetrafluoroaluminate. However, as the solubility of potassium tetrafluoroaluminate is ca. 4 times higher than that of cryolite, a higher absorption by oral route can be expected for the former substance. Consequently, the same type of effects can be expected to occur in case of potassium tetrafluoroaluminate at lower dose levels in comparison to cryolite. Based on the available toxicokinetic studies, the absorption of cryolite has been shown to correspond to at least 60% in humans and 85% in rats. As a maximal absorption of potassium tetrafluoroaluminate cannot exceed 100%, an application of a safety factor 2 is considered to be sufficient (and a worst-case approach) to account for the difference in solubility between the two substances. Regarding the risk assessment, the observed effects on development are considered to be less critical in comparison to the effects observed upon repeated exposure in quantitative terms. A DNEL of 0.11 mg/m3 has been derived for potassium tetrafluoroaluminate for local effects by repeated exposure, while the DNEL for developmental toxicity is 1.7 mg/m3 using route to route extrapolation based on the NOAEL of 28.4 mg /kg bw/day for potassium tetrafluoroaluminate (derived by read-across from cryolite and corrected for molecular weight) and applying a safety factor 2 to account for the difference in solubility between cryolite and potassium tetrafluoroaluminate ((28.4 mg/kg bw/day / 2) / 0.38 m3/kg bw * (85/100) * 6.7 m3/10 m3/ (2.5 × 5) = 1.7 mg/m3).

Justification for classification or non-classification

In accordance to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for effects on fertility.

 

No developmental toxicity study is available for potassium tetrafluoroaluminate. During the two-generation study (with rats) with the structural analogue cryolite, the critical adverse effects that had been revealed were impairment of postnatal growth evidenced by significantly decreased pup body weights during lactation as well as gross pathological changes in several organs (kidney, liver, heart) of the pups (not statistically significantly increased) observed at dose levels of 128 mg/kg bw/day without any significant maternal toxicity. No effects were observed that could indicate that pups under lactation were already affected in utero (normal weight at birth and absence of visual defects). From the data that are available it could be concluded that the observed effects in the pups were due to the lactation itself. The effects may have been caused by reduced amount of milk available to the pups or the altered nutritional composition of the milk or by the presence of fluoride in the milk. Therefore, cryolite is proposed to be classified with R64 in accordance to Directive 67/548/EEC and H362 (May cause harm to breast-fed children) under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008).

The same classification should be applied for potassium tetrafluoroaluminate.

Additional information