Registration Dossier

Administrative data

Description of key information

Repeat dose dermal toxicity data is available which provides a LOAEL of 70mg/kg bw/day, and an OECD 422 study is available for an analogous substance and suitable for read across.  

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
160 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
70 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Additional information

The oral repeat dose toxicity of an analog substance was evaluated with rats at doses as high as 160 mg/kg/day for up to 52 consecutive days in accordance with OECD 422. Substance-related toxicity was limited to morbundity, adverse clinical signs, and epithelial hyperplasia, hyperkeratosis, and inflammation of the stomach. The NOAEL for systemic toxicity was 160 mg/kg/day. The NOEL for portal of entry irritation and related secondary effects parental toxicity was 40 mg/kg/day. 

Repeated dermal applications (uncovered) of up to 2 ml/kg bw of a solution containing 0, 5 or 25% test material, equivalent to about 0, 70 or 350 mg/kg bw/day (after adjusting for exposure on 5/7 days per week), were made to the clipped skin of rabbits (10/sex/group) for around 28 days (6 hours/day, 5 days/week). This resulted in weight loss, haematology and clinical chemistry effects, organ weight changes and local irritancy at both test doses, while the high-dose males also showed evidence of testicular toxicity (including reduced absolute testis weight and tissue changes). A LOAEL of 70mg/kg bw/day was established.

Justification for classification or non-classification

In accordance to Directive 67/548/EEC and the EU CLP (Regulation (EC) No. 1272/2008) classification of this substance is not required for prolonged exposure.

While there are effects in this study which result from treatment, and these do occur at a level which could indicate Cat 2 STOT-RE classification, it is known that these are secondary to the repeated irritation which occurred on application in this study. This irritation induced significant stress in the animals, which in turn induced a sympathetic nervous system response and an increase in adrenal medulla activity – resulting in the increase in adrenal weights noted. The hormonal changes induced increases in temperature (basal metabolic rate) which is in turn known to induce hypospermatogenesis and hence accounts for the testes effects noted. This hypothesis has been proven by means of control studies such as one carried out using sodium hydroxide to induce pyrogenicity and testicular effects, and another included in the IUCLID dataset as supporting carried out on this material, again demonstrating the effects on temperature and testes. The increase in temperature is also considered a factor in the blood cell changes observed. These secondary effects require continued application to occur, and this sort of exposure is not going to occur in situations relevant to human exposure – the irritation will result in a cessation of exposure before the systemic effects could occur. Hence in accordance to Directive 67/548/EEC and the EU CLP (Regulation (EC) No. 1272/2008) this material is not classified for repeat exposure toxicity. This decision is further supported by the lack of systemic toxicity observed in the oral studies using similar materials.