Registration Dossier

Administrative data

Description of key information

NOAEL (oral; sub-chronic; rat) = 125 mg/kg bw/day

NOAEC (inhalation; chronic; rat) = 0.13 mg/L air (corresponding to 1000 ppm, analytical concentration)

NOAEL (dermal; sub-acute; rat) = 20 mL/kg bw/day

Key value for chemical safety assessment

Toxic effect type:
concentration-driven

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
0.13 mg/m³
Study duration:
chronic
Experimental exposure time per week (hours/week):
30
Species:
rat

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

No experimental data on the repeated dose toxicity of the substance was available, therefore, repeated dose toxicity of the substance was evaluated using a variety of experimental studies performed on the structural analogues of the substance, and using a weight of evidence approach. Greater weight was given to studies performed according to principles of GLP, performed according to (or equivalent/similar to) OECD guidelines, performed on the recommended lab animal (appropriate strains of rat) and performed on structural analogues with greater structural similarity. Justification for the use of a read-across approach is detailed in Section 13 of this Registration Dossier.

Repeated Dose Toxicity: Oral

Several relevant studies were considered in order to assess the oral repeated dose toxicity. The most relevant of these are two GLP, OECD studies on rats performed on the two primary metabolites of the substance. The first of these is a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, performed on SC11 according to the OECD Guideline 422. This study provided a sub-acute NOAEL of 250 mg/kg bw/day among rats. The second of these studies was performed on SC09 and according to a method similar to the OECD Guideline 408. This study provided a sub-chronic NOAEL of 125 mg/kg bw/day among rats. Rapid and complete hydrolysis of the substance occurs in aqueous medium, rendering both SC09 and SC11, therefore, data on these two substances is sufficient to evaluate this endpoint. Based on these values, the NOAEL for the substance can be considered the lower of these two chemicals: 125 mg/kg bw/day.

An increasing trend in toxicity was observed with decreasing ester length. Specifically, the structural analogues with methanol, ethanol and octanol esters in place of the butanol esters rendered NOAEL values of 50, 30-150 and 300 mg/kg/d, respectively, in line with the predicted NOAEL range of 125-250 mg/kg bw/day for the substance. This was further supported by a battery of tests on rats performed by the National Toxicology Program, but without GLP or an OECD guideline, provided a sub-acute NOAEL of 250 mg/kg bw/day and a sub-chronic NOAEL of 50 mg/kg bw/day (females) and 100 mg/kg bw/day (males).

Based on this supporting evidence, a sub-chronic NOAEL value of 125 mg/kg bw/day is accepted for use of this substance.

Repeated Dose Toxicity: Inhalation

Few inhalation repeated dose toxicity studies performed on structural analogues were available. Of these, a study on a primary metabolite of the substance (SC09) was awarded a reliability value of 4, and is therefore not considered in the evaluation of inhalation repeated dose toxicity. Two experimental studies performed on rats and according to methods equivalent/similar to OECD guidelines were identified, both performed on the more sensitive structural analogue with methanol esters in place of the butanol esters. One of these studies is a sub-acute study (OECD Guideline 412) and the other is a chronic study (OECD Guideline 453); the resulting NOAEL values are 6.63 mg/L (equivalent to 5010 ppm, analytical measurement) and 0.13 mg/L (equivalent to 100 ppm), respectively. The only other inhalation study considered for the evaluation of repeated dose toxicity was performed on a test animal not usually used (monkey) and not according to an OECD Guideline, and was therefore not considered in the calculation of NOAEL for the substance.

Due to the wide range of values obtained for the repeated dose toxicity of the substance via inhalation, the more conservative chronic NOAEC value of 0.13 mg/L is applied in order to consider a worst-case scenario approach. In any case, it should be noted that this value was not used in the DNEL calculation as it is considered too conservative and not representative of the true toxicity of the substance.

Repeated Dose Toxicity: Dermal

One experimental study on a structural analogue was identified in order to assess the dermal repeated dose toxicity of the substance. A sub-chronic NOAEL value of 20 mL/kg bw/day was set in this study. However it should be noted that this study was perfored (i) not according to principles of GLP, (ii) not according to an OECD Guideline, (iii) on rabbits, (iv) with poor documentation, (v) as a limit test, and (vi) on a primary metabolite of the substance. Therefore, caution should be exercised in the application of a NOAEL for dermal repeated dose toxicity using this study.

Justification for classification or non-classification

According to the CLP Regulation (EC) No. 1272/2008, substances are classified as specific target organ toxicants following repeated exposure, and are placed in one of two categories, depending on the nature and severity of the effect(s) observed. Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure, are classified in Category 1 for target organ toxicity (repeat exposure). Classification in Category 1 is applicable when significant toxic effects are observed in a 90-day repeated-dose animal study at low concentrations (< 10 mg/kg bw/day in oral studies, and < 20 mg/kg bw/day in dermal studies) (CLP Regulation (EC) No. 1272/2008: Annex 1, Part 3, Table 3.9.2).

Substances which can be presumed to have the potential to be harmful to human health following repeated exposure, based on evidence from animal studies, are classified in Category 2. Classification in Category 2 is applicable when significant toxic effects are observed in a 90-day repeated-dose animal study at generally moderate exposure concentrations (10 to 100 mg/kg bw/day in oral studies, and 20 to 200 mg/kg bw/day in dermal studies) (CLP Regulation (EC) No. 1272/2008: Annex 1, Part 3, Table 3.9.3).

Equivalent guidance values for an equivalent 28-day study period raises the concentration values for classification by three-fold: classification in category 1 is applicable at low concentrations (< 30 mg/kg bw/day in oral studies; < 60 mg/kg bw/day in dermal studies) and in Category 2 at generally moderate concentrations (30 to 300 mg/kg bw/day in oral studies, 60 to 600 mg/kg bw/day in dermal studies).

Based on the sub-chronic, oral NOAEL value of 125 mg/kg bw/day in rats, no classification of the test item is warranted for specific target organ toxicity – repeated exposure according to the CLP Regulation (EC) No. 1272/2008.