Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
180 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
One-generation reproduction toxicity study in Wistar rats treated orally with structural analogue, Cyclohexyl salicylate, according to OECD Guideline 415.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

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).

Further, the reproductive and developmental toxicity of alcohol products that are formed upon hydrolysis of salicylates was evaluated by the Maximum workplace concentration (Maximale Arbeitsplatzkonzentration, a.k.a. MAK) commission and concluded that 2- ethyl hexanol, methanol, ethanol, butyl alcohol, Octanol and isobutyl alcohol show no reproductive/developmental potential when used at levels ranging from 200–8000 ml/m3 for inhalation studies and 130–300 mg/kg for dietary studies.

In a one-generation reproduction toxicity study in Wistar rats were treated orally with structural analogue, Cyclohexyl salicylate, according to OECD Guideline 415.

Potential adverse effects of the test substance, Cyclohexyl salicylate, on the reproduction of male and female rats and on their offspring resulting from daily oral administration to the parent animals during gametogenesis, mating, gestation and lactation up to day 21 post partum was studied in a one-generation study under GLP in accordance with OECD TG 415 as of May 1983. Four groups of 24 female and 24 male rats each were used in the study. The substance was dissolved in corn oil and administered to parent animals by oral gavage daily at a constant volume of 5 mL/kg body weight at doses of 0 (vehicle control), 60, 180 and 540 mg/kg bw in these groups. Evaluation of indices of mating performance and fertility (mating index and performance, fertility index and conception rate) showed no difference between the treated groups and the control group. Examination of male reproductive organs revealed no differences between treated groups and controls. During necropsy of males and females no distinctly treatment related findings were noted. However, liver weights were significantly increased in the high dose group. In addition, a distinct lobular pattern of the liver seemed to be increased in females of the high dose group. A number of findings were noted in female parent animals of the high dose group at the end of gestation, particularly at the day of delivery. These findings comprised reduced activity, shutting of eyes, respiratory disorders and increased amount of blood in the bedding during delivery and were interpreted as signs of dystocia. Additionally, two pre-terminal deaths occurred shortly before or during delivery in the high dose group. High dose females showed significantly decreased body weight gain during gestation, especially in the last week of gestation. No females showed signs of abortion or premature delivery throughout pregnancy. Evaluation of gestation index, gestation length and number of implantations provided no evidence of a treatment related effect. A slight effect on pre-birth loss was found in the high dose group receiving 540 mg/kg bw/day. It was concluded that the NOAEL for reproductive effects was 180 mg/kg bw/day in female rats and 540 mg/kg bw/day in male rats. The NOAEL for developmental effects in the pups was 180 mg/kg bw/day.

To address toxicological endpoints as part of the REACH registration of Benzyl Salicylate it is proposed to read-across to Cyclohexyl salicylate.

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 target substance and the source substances have been characterised using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling, it can be seen that these 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 analogues are relatively harmless and would not 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.


Short description of key information:
NOAEL for reproductive effects was 180 mg/kg bw/day in female rats and 540 mg/kg bw/day in male rats. The NOAEL for developmental effects in the pups was 180 mg/kg bw/day.

Justification for selection of Effect on fertility via oral route:
In a one-generation reproduction toxicity study in rats the NOAEL for reproductive effects was 180 mg/kg bw/day in female rats and 540 mg/kg bw/day in male rats.

Effects on developmental toxicity

Description of key information
NOAEL for developmental effects in the pups was 180 mg/kg bw/day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
180 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
One-generation reproduction toxicity study in Wistar rats treated orally with structural analogue, Cyclohexyl salicylate, according to OECD Guideline 415
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a one-generation reproduction toxicity study in Wistar rats were treated orally with structural analogue, Cyclohexyl salicylate, according to OECD Guideline 415.

The litter size was significantly reduced in the high dose group from birth to day 21 post partum, whereby the sex ratio did not show any important differences. Pup loss at birth was slightly increased in the high dose group. Cumulative pup loss was significantly increased in this group from day 4 post partum, also becoming evident as an increased number of litters with 4 or more pup losses during pre-weaning development. Treatment-related retardation in pinna unfolding, upper incisor eruption, eye opening and onset of the auditory startle reflex was observed in pups of the high dose group. Mean group body weights of the pups at birth were significantly reduced in the high dose group. Necropsy of pups on day 21 post partum gave a higher number of litters with pups showing a truncated coniform heart in the high dose group. Additionally, the weights of heart, liver and brain seemed to be affected in the pups of the high dose group. It was concluded that the NOAEL for reproductive effects was 180 mg/kg bw/day in female rats and 540 mg/kg bw/day in male rats. The NOAEL for developmental effects in the pups was 180 mg/kg bw/day.

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 Substances).

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 Target Substance and Source Substances have been characterised using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling, it can be seen that these 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 analogues are relatively harmless and would not 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.


Justification for selection of Effect on developmental toxicity: via oral route:
In a one-generation reproduction toxicity study in rats the NOAEL for developmental effects in the pups was 180 mg/kg bw/day.

Justification for classification or non-classification

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 Substances).

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 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 these 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 analogues are relatively harmless and would not 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.