Registration Dossier

Administrative data

Description of key information

The administration of the structural analogue by oral gavage to male and female rats at doses of 40, 120 and 360 mg/kg body weight over a period of 90 days did not produce adverse systemic effects in this study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
360 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The oral repeated dose toxicity of the structural analogue, Cyclohexyl salicylate, over a period of 90 days was studied under GLP in accordance with OECD TG 408 with some restrictions. The nominal test concentrations were 0 (vehicle control), 40, 120 and 360 mg/kg bw/day. In addition to the ten male and female rats per study group that were sacrificed at the end of the 90 -day treatment period, additional five male and female animals were used for investigation during a 29-day recovery period without oral treatment. The administration of test substance by oral gavage to male and female rats at doses of 40, 120 and 360 mg/kg body weight over a period of 90 days did not produce adverse systemic effects in this study.

The oral repeated dose toxicity of the substance Cyclohexyl salicylate was studied over a period of 28 days under GLP in a study in accordance with EU Method B.7 in male and female Sprague-Dawley rats.

The administration of test substance by oral gavage to male and female rats at doses of 40, 100 and 250/500 mg/kg body weight over a period of 28 days did not produce adverse systemic effects in this study. The only relevant finding in this study was an increase in the GPT levels in the animals of the high-dose group, where an increase of 29% in males and 19% in females was seen compared to the controls. The histological examination of liver slides provided no explanation for this increase as no tissue damage could be seen. The high dose of 500 mg/kg may be the limit of systemic tolerance of the test substance starting to induce enzyme activity.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The Target Substance and Source Substance have been characterised using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling, it can be seen that the two substances share structural similarities and also ‘mechanistic action’ similarities which are both general and endpoint specific.
Two repeat dose oral toxicity studies (28-days and 90-days) on the structural analogue, Cyclohexyl salicylate (Source Substance), were determined to be suitable to read across to the registration substance, Benzyl salicylate (Target Substance).
For classification and labelling purposes this indicates that the structural analogue is relatively harmless and would not, in itself, be classified in accordance with Regulation (EC) No 1272/2008 (CLP). The registration substance is considered to have similar properties by analogy and is therefore not classified in accordance with CLP.

Justification for classification or non-classification

The structural analogue, Cyclohexyl salicylate, produced no significant adverse effects that are relevant for human health at concentrations of up to 360 mg/kg bw in a 90-day repeated dose (oral) toxicity study and at concentrations of 500 mg/kg bw in a 28-day repeated dose (oral) toxicity study. No other adverse effects were observed.

To address toxicological endpoints as part of the REACH registration of Benzyl Salicylate (Target Substance) it is proposed to read-across to Cyclohexyl Salicylate (Source Substance).

The use of read-across works within the spirit of REACH and the stated aim of the legislation to reduce animal testing where possible.

The main hydrolysis product of all the salicylate substances is salicylic acid (Belsito et al, 2007). The alcohols and acids that are formed as metabolites of salicylates are without significant toxicity. The hydrolysed side chains are metabolized by common and well characterized metabolic pathways. These primary alcohols (butanol, pentanol, hexanol, octanol, and propanol) and their corresponding aldehydes and acids have also been evaluated by JECFA (2001) who found them to have no safety concerns based on their current levels as food flavours.

 

The reproductive and developmental toxicity data on salicylates demonstrate that, under conditions of sufficient exposure, there is a pattern of embryotoxicity and teratogenesis that is similar to those caused by salicylic acid at comparable doses (Belsito et al).

The Target Substance and Source Substance have been characterised using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling, it can be seen that the two substances share structural similarities and also ‘mechanistic action’ similarities which are both general and endpoint specific.

For classification and labelling purposes this indicates that the structural analogue is relatively harmless and would not, in itself, be classified in accordance with Regulation (EC) No 1272/2008 (CLP). The registration substance is considered to have similar properties and is therefore not classified in accordance with CLP.