Tetraethylammonium heptadecafluorooctanesulphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Several other sudies were conducted. The main focus of this studies were influenced of exposure duration, mecahnistic, underlying pathophysiological mechanism, biochemical and toxicokinetik parameters,  or stress.

Effect on fertility: via oral route

Dose descriptor:

NOAEL

0.4 mg/kg bw/day

Additional information

In the 2 -generation study, the NOAEL and LOAEL for both the F0 generation male and female parents are 0.1 mg/kg/day and 0.4 mg/kg/day, respectively, based on reductions in body weight gain and food consumption. The NOAEL for the F1 generation parental males could not be established since treatment-related reductions in absolute food consumption values were reported at the lowest dose tested, 0.1 mg/kg/day. The NOAEL and LOAEL for the F1 generation parental females are 0.1 mg/kg/day and 0.4 mg/kg/day, respectively, based on significant reductions in body weights and food consumption. The NOAEL and LOAEL for the F1 generation offspring are 0.4 mg/kg/day and 1.6 mg/kg/day, respectively, based on significant reductions in the number of implantation sites, litter size, pup viability, pup body weight and survival. The NOAEL and LOAEL for the F2 generation offspring are 0.1 mg/kg/day and 0.4 mg/kg/day, respectively, based on significant reductions in mean pup body weight. In the cross fostering study, the limited data appear to indicate that reduced pup survival is mainly a result of in utero exposure to PFOS and that post-natal exposure via milk in conjunction with in utero exposure may also contribute to reduced pup survival. In contrast, exposure during lactation alone, through milk from exposed dams, does not appear to have any adverse affect on pup viability. Additionally, analysis of PFOS concentration showed that PFOS was observed in the sera of F0 female rats exposed during the in-life phase of the study. Additionally, PFOS was observed in sera samples taken from F1 generation pups from female rats exposed to the test substance, and in F1 generation pups exposed via lactation, but not exposed in utero.

In the 1 -generation study, the LOAEL for maternal toxicity was 1.0 mg/kg/day and the NOAEL was 0.1 mg/kg/day. Developmental toxicity was evident at doses of 2.5 mg/kg/day and above. The number of corpora lutea, resorptions, live/dead fetuses, litter size and sex ratio were comparable among treated and control groups. Mean fetal body weight (male, female and sexes combined) was significantly reduced in the 2.5 and 3.75 mg/kg/day groups. There was also a significant reduction in the ossification of the sternum (litter averages) in the 2.5 and 3.75 mg/kg/day groups, and a significant reduction in the ossification of the hyoid (litter averages), metacarpals (litter averages) and pubis (litter and fetal averages) in the 3.75 mg/kg/day group. The LOAEL for developmental toxicity was 2.5 mg/kg/day and the NOAEL was 1.0 mg/kg/day.

Read-across justification

- Group: The perfluorooctane sulfonate anion (PFOS) does not have a specific CAS number. The acid and salts have the following CAS numbers: acid (1763-23-1), ammonium (NH4 +) salt (29081-56-9), potassium (K+) salt (2795-39-3), tetraethylammonium (C2H5)4N+) salt (56773-42-3).

For the registration of tetraethylammonium perfluorooctanesulfonate (CAS 56773-42-3) the data on perfluorooctane sulfonate anion (PFOS) as well as the respective salts were taken into consideration and a read across approach was used due to the following reasons:

- Justification: REACH regulation EC 1907/2006 and ECHA guidance document R.6 state that substances whose physico-chemical, toxicological and ecotoxicological properties are likely to be similar, or follow a regular pattern as a result of structural similarity, may be considered as a group / category of substances. Properties of PFOS are mainly determined by the length of the fluorinated tail and not by the nature of the functional group. PFOS and its salts are dissociated in aqueous media, substituted amines and the corresponding sulfonyl fluorid are hydrolysed in aqueous media to PFOS. Therefore these compounds are members of a large family of perfluoroalkyl sulfonate substances. According to OECD, 2002, (ENV/JM/RD(2002)17/FINAL) “perfluorinated compounds represent a very unique chemistry”, at least substances with equal numbers of perfluorinated carbon atoms and functional groups.

Thus, in accordance with OECD, 2002, grouping and read-across based on the length of the perfluorinated carbon structure with a sulfonate moiety is in principle possible. The criterion of structural similarity is fulfilled and all substances may be regarded as group with respect to chemical behaviour. This judgement is in line with and confirmed by the existing classification of perfluoroalkyl sulfonates in Europe: according Annex VI to Regulation (EC) No 1272/2008 for classification and labeling several perfluoroalkyl sulfonates are considered as a group/category and therefore identical hazard class/category codes, and hazard statement codes applies. The following substances/CAS number are mentioned explicitly in the regulation: perfluorooctane sulfonic acid/1763-23-1, potassium perfluorooctanesulfonate/ 2795-39-3, diethanolamine perfluorooctane sulfonate/70225-14-8, ammonium perfluorooctane sulfonate/29081-56-9, lithium perfluoroocane sulfonate/29457-72-5.

This approach also apply to tetraethylammonium perfluorooctanesulfonate, as the evaluation of the toxicological data of tetraethylammonium perfluorooctanesulfonate substantiate the membership of the substance to the group and the same hazard class and statement codes are valid.

Therefore based on the available data as well as on earlier judgements by e.g. OECD and within the EU classification a read across approach is justified.

Short description of key information:
A two-generation reproductive toxicity study, designed to test for the toxic effects of PFOS on reproductive function in adult animals and on developmental and reproductive effects in the offspring, was conducted in Sprague-Dawley rats. Five groups of 35 rats per sex per dose group were administered PFOS by gavage at doses of 0, 0.1, 0.4, 1.6, and 3.2 mg/kg/day for six weeks prior to and during mating. Treatment in male rats continued until one day before sacrifice (approximately 22 days total); female rats were treated throughout gestation, parturition, and lactation.
Based on the results of the two-generation reproductive toxicity study in which significant reductions in pup viability were observed at 1.6 and 3.2 mg/kg/day, a cross-fostering study was conducted as a means of determining whether the effects observed in pups were a result of in utero exposure to PFOS or as a result of exposure during lactation; thus the potential for a distinction to be made between prenatal and postnatal effects following continuous maternal treatment.
In an 1-generation study, timed-pregnant New Zealand White rabbits, 22 per group, were given doses of 0, 0.1, 1.0, 2.5 or 3.75 mg/kg/day PFOS in 0.5% Tween-80 by gavage on gestation days 7-20.

Effects on developmental toxicity

Description of key information

Serveral studies in rats, mice and rabbits were conducted.
In the key-study, the maternal and developmental toxicities of perfluorooctane sulfonate (PFOS, C8F17SO3 -) were evaluated in the rat and mouse. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mglkg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1,5, 10, 15, and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehiele (1 ml/kg for rats and 10 ml/kg for mice). Rats were euthanized on GD 21 and mice on GD 18. PFOS levels in maternal serum and in maternal and fetal livers were determined.
In a further study, ten pregnant ICR mice per group were given I, 10 or 20 mg/kg PFOS daily by gavage from gestational day (GD) 0 to the end of the study. Five dams per group were sacrificed on GD 18 for prenatal evaluation, the others were left to give birth. Additional studies were conducted for histopathological examination of lungs and heads of fetuses and neonates at birth.
Rabbit developmental toxicology studies were conducted on two perfluoronated compounds perfluorooctanesulfonate (PFOS) and 2-(N-ethyl perf1uoro- octanesulfonamido)-ethyl alcohol (N-EtFOSE). Dosages of 0, 0.1, 1.0, 2.5 and 3.75 mg/kg/day in 0.5% Tween 80 were used for both studies

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

0.3 mg/kg bw/day

Additional information

In the key-study, maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately fourfold higher than serum. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects, including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium, were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively.

In the study by Yahia et al. (2008) PFOS treatment (20 mg/kg) reduced the maternal weight gain and feed intake but increased the water intake. The liver weight increased in a dose-dependent manner accompanied by hepatic hypertrophy at 20 mg/kg. PFOS reduced the fetal body weight in a dosedependent manner and caused a bilateral enlargement in the neck region in all fetuses at 20 mg/kg and mild enlargement in some fetuses at 10 mg/kg, in addition to skeletal malformations. ALOAEL of 1 mg/kg bw/d was determined for developmental toxicity.

Although no compound related deaths occurred in the rabbit study, maternal toxicity (reduced body weight gain and feed consumption values) was present at the higher dosage levels of both studies. On the basis of these data, the matemal no observable- effect-level (NOEL) of N-EtFOSE and PFOS was 0.1 mg/kglday (the 1.0 mg/kglday and higher dosages caused statistically significant reductions

in body weight gains or weight losses and the 2.5 and 3.75 mg/kg/day dosages also significantly reduced absolute and relative feed consumption va1ues), The developmental NOEL was 1.0 mglkglday for both compounds.

In the other studies a no observed adverse effect level (NOAEL) cound not be determined. Effects on maternal or developmental toxicity were higher than in the discussed studies.

Toxicity to reproduction: other studies

Additional information

the other studies (special investigations) are not relevant for the chemical safety assessment

Justification for classification or non-classification

Due to the teratogenic effects of PFOS including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium

a classification as Repr. Cat. 2; R61 May cause harm to the unborn child (GHS: Repr. 1B; H360: May damage fertility or the unborn child) seems adequate.

Data from a crossfostering study to a 2-generation study indicate that exposure to PFOS in litters can occur both in utero and via milk from treated dams. Therefore a classification as R 64 (May cause harm to breastfed babies), GHS: H362: May cause harm to breast-fed children ist suggested.

This classification complies with Annex VI to Regulation (EC) No 1272/2008 for classification and labeling of several perfluoroalkyl sulfonates (perfluorooctane sulfonic acid/1763-23-1, potassium perfluorooctanesulfonate/ 2795-39-3, diethanolamine perfluorooctane sulfonate/70225-14-8, ammonium perfluorooctane sulfonate/29081-56-9, lithium perfluoroocane sulfonate/29457-72-5).