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Description of key information

Only limited animal data on repeated dose application are available for Quaternary ammonium compounds, C12-14,

even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS). The assessment of the endpoint repeated dose toxicity is based on read across to an oral (dietary) repeated dose toxicity study in rats according to OECD 408 with the chemically closely related compound SS0772.01 (i.e. C8-C10 alkyl dimethyl hydroxyethyl ammonium chloride) which is used here as surrogate substance (For Read across justification refer to IUCLID section 13 Assessment reports). The use as surrogate is justified as it is seen as a worst case, i. e. based on the shorter chain length, its lower molecular weight and thus its higher chemical reactivity. However, with HYEQS as relevant test substance an OECD 422 study is available which allows an evaluation of repeated oral dosing in males and females for 29 days and at least 53 days, respectively. Based on the absence of any toxicological relevant effects observed with the analogue compound SS0772.01 a clear no observed effect level (NOEL) at 50 mg/kg bw/day was established. Only minor effects not considered being adverse were revealed at the next higher dose of 75 mg/kg bw/day which was considered to be a NOAEL. Taking a conservative approach the NOEL of 50 mg/kg bw/day will be used for the CSA.
With regard to dermal toxicity, repeated dermal treatment for at least 12 weeks with the C13-C15 analogue substance E3333.01 revealed local signs of irritation but no effects attributable to direct systemic toxicity. A NO(A)EL regarding systemic effects was therefore not established. Under the conditions of the study the NO(A)EC for dermal local toxicity (irritation) was determined to be 0.02% w/v.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Only limited animal data on repeated dose application are available for Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS). Read across is made to a 13 week repeated oral dose (dietary) study in rats with the analogue and chemically closely related compound SS0772.01 (i.e. C8-C10 alkyl dimethyl hydroxyethyl ammonium chloride), which was used as surrogate here (For read across justification refer to IUCLID section 13 Assessmetn reports). The test substance was administered with the food at dose levels of 0 (vehicle only), 15, 50 or 75 mg/kg bw/day. In this study mildly lower cholesterol values for females given 75 mg/kg/day, and increased incidences of positive urine occult blood and amorphous phosphate crystalluria in urine sediment for males given 75 mg/kg/day were detected. These findings were of uncertain relationship to administration of the test substance and they were not considered to be adverse. There were no other effects observed in this study attributed to administration of the test substance. Based herupon a NOAEL of 75 mg/kg bw/day and a NOEL of 50 mg/kg bw/day was established by the study results.

These results are supported by findings of an OECD 422 screening study with the test item under evaluation HYEQS, where male and female rats were treated daily by oral gavage with doses of 0, 15, 30 and 60 mg/kg bw/day for about 29 and 53 days, respectively. No adverse systemic findings are described for males and females. However, gross pathological findings in the nonglandular part of the stomach in all animals of the 60 mg/kg bw/day and some animals of the 30 mg/kg bw/day dose were histopathological identified as multifocal/diffuse epithelial hyperplasia, mostly in combination with epithelial hyperkeratosis and in some animals with submucosal inflammatory edema. These findings are considered as direct consequence of the repetitive direct irritation of the gastric mucosa by the test item. Minor epithelial alteration/hyperplasia seen in the trachea of some animals of the 30 mg/kg bw/day and 60 mg/kg bw/day dose without dose relationship are also considered a consequence of the corrosive purpose of the test item under evaluation (see also section "Effects on fertility", chapter 5.9.1. in CSR and chapter 7.8.1 in IUCLID).

Repeated treatment of rabbit skin for at least 12 weeks with concentrations of 0, 0.02, 0.2 and 2.0 % w/v of the C13-C15 analogue substance Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS), resulted in no systemic effects. All animals in the 2.0 % w/v group were killed and necropsied in week three owing to the severity of the skin reactions. During weeks 1 and 2 several animals from this dose group were noted to be not eating. All animals in the 2.0 % w/v group showed marked skin reaction from day 2. Erythema, oedema, and atonia were noted. The severity of the skin irritation increased. During week 2 fissuring was noted. From day 8, dosing was ceased for various animals in the 2.0 % w/v group (at different stages) due to the condition of the treated skin, including peeling and bleeding. No clinical signs were observed in any of the other dose groups. All animals in the 2.0 % w/v group, except one, lost weight over the period they were dosed. Mean body weight of the 0.2 and 0.02 % w/v group were comparable to controls throughout the study. There were no apparent effects on hematology or clinical chemistry parameters. In the 0.2% and 2.0% w/v groups there was a dose-related dermatitis.  At necropsy this appeared as thickening of the skin with fissuring and in 2.0% group animals was accompanied by sloughing of the superficial layers. In addition, minor hyaline droplet accumulation in the kidney was observed in one female from the 0.2% group and all animals in the 2.0% w/v group. This was interpreted as being secondary to dermal irritation and not a direct toxic effect on the kidney. A NO(A)EL was not determined.

Justification for classification or non-classification

The available results on HYEQS indicate a classification according to DSD as harmful (Xn) with the designation of R48/22 (danger of serios damage to health by prolonged exposure if swallowed), respectively STOT RE Cat 2 (signal word "Warning" with hazard statement H373) according to CLP. This classification is based on the established NOEL of 50 mg/kg bw/day derived from a 90 day subchronic oral (dietary) toxicity study and is supported by local irritative findings of HYEQS in the gastro-intestinal tract in an OECD 422 screening study due to the corrosive properties of the test item.