Registration Dossier

Administrative data

Description of key information

Methyl benzoate could not be classified as specific target organ toxic compound, since one key and two supporting studies show the potential toxicity above the guidance values (specific target organ toxicity - repeated exposure).

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
557 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
One reliable key and two unreliable supporting studies are available. The key study is performed with benzoic acid, therefore is a read-across study to Methyl Benzoate. One of the supporting studies is performed with Methyl benzoate and the other is read-across study with Sodium benzoate.

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

- Repeated dose toxicity, oral:

In the key study (Kieckebusch & Lang, 1960), concentrations of 0.5 and 1 % of Benzoic acid (read-across compound, see section 13) in the diet were administered in 4-generations of rats (the two first generations: lifelong, 3rd generation: 16 weeks and 4th generation: until breeding). The study was conducted before the publication of GLP and OECD guidelines, but is considered as reliable with restrictions. The provided information on methods, testing conditions and results is sufficient to use the study results for the chemical hazard assessment. No adverse signs directly attributable to exposure to the tested compound were observed in treated animals. No differences in the average body weight, organ weight and food intake between treated and control groups were observed. It was concluded that the NOEL of benzoic acid is at 1 % (corresponding to 500 mg/kg bw /day or 557 mg methyl benzoate/kg bw/day).

The repeated dose toxicity of the substance methyl benzoate is characterised on the basis of valid and reliable studies with the read-across substances benzoic acid and sodium benzoate. It has to be considered that the enzyme-driven hydrolysis of methyl benzoate in organisms releases methanol, which is not released from benzoic acid or sodium benzoate. The toxicity of the metabolite methanol has to be addressed, as it may contribute to the repeated dose toxicity of methyl benzoate. Please refer to section 5.11 for a discussion.

In a supporting study (Kravets-Bekker & Ivanova, 1970), methyl benzoate was administered to rats by oral gavage for 45 days. The substance is deemed to not show a classifiable target organ specific toxicity in the study at dose levels of 0, 111 and 500 mg/kg bw/day methyl benzoate. The results observed at 111 mg/kg/day, are equivocal, since an observed increase of erythrocytes and reticulocytes at the same time is not scientifically justified. In addition, the percentage of reticulocytes in blood (8.3 to 23.6 %) are not comparable with available literature data on typical values for the percentage of reticulocytes in rats, where reticulocyte count (% RBC) ranges from 0.3 to 2.5 (e.g. Derelanko & Hollinger, 2002). It may be speculated that the increase of leucocytes and a decrease of phagocitic index as well as reduced activity of cholinesterase in whole blood may be adverse effects occurring at 500 mg/kg/day, which thus may define the LOAEL in this supporting study. However, due to the limitations of the study and the sub-standard in reporting the findings of this supporting study were not taken into account in the chemical hazard assessment.

A chronic drinking water study in mice (Toth, 1984) was conducted with sodium benzoate (additional read-across substance, see section 13). However, the reliability of the study is limited. One experimental group of 50 female and 50 male mice was treated with 2 % sodium benzoate dissolved in the drinking water. The untreated control group consisted of 100 female and 100 male mice. The average daily intake of sodium benzoate was 119.2 mg for female and 124.0 for male over the study period. The treatment had no effect on the survival of treated animals when compared with untreated controls. Based on an average body weight of animals of 40 g, the NOAEL was calculated to be 2980 mg/kg bw (2815 mg/kg bw methyl benzoate) for females and 3100 mg/kg bw (2929 mg/kg bw methyl benzoate) for males.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The reliable 4-generation study with life long exposure to Benzoic acid in two first generations allowed to establish an adequate NOEL.

Justification for classification or non-classification

- Repeated dose toxicity, oral:

Based on the above stated assessment of the specific target organ toxicity potential after repeated oral exposure of Methyl benzoate, the compound does not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

-Repeated dose toxicity, dermal:

As no data of the specific target organ toxicity potential after repeated dermal exposure of Methyl benzoate is available a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

 

-Repeated dose toxicity, inhalation:

As no data of the specific target organ toxicity potential after repeated dermal exposure of Methyl benzoate is available a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.