Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
concentration-driven

Effects on fertility

Description of key information

NOAEL (fertility) = 500 mg/kg bw/day

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1.3 mg/m³
Study duration:
subchronic
Experimental exposure time per week (hours/week):
140
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No experimental data on the effects on fertility of the substance were available, therefore, toxicity to fertility was evaluated using a variety of experimental studies performed on structural analogues, and using a weight of evidence approach. Greater weight was given to studies performed according to the principles of GLP, performed according to relevant OECD Guidelines, performed on the recommended test species (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.

Several relevant studies were considered in order to assess the toxicity of the substance to fertility. The most relevant of these are two non-GLP, non-OECD studies on rats performed a primary metabolite of the substance; the third is a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (GLP; OECD Guideline 422) performed on the other primary metabolite of the substance.

An experimental study on the first primary metabolite of the substance (SC09) was not performed according to an OECD guideline, however, is comparable to an OECD Guideline 416 Prenatal Developmental Toxicity Study via the inhalation route. In this study, although developmental toxicity and general toxicity was observed at 2000 ppm, no toxicity to fertility was observed at this dose and the NOAEL for fertility was subsequently set at 2000 ppm. However, a supporing study on a structural analogue of a primary metabolite of the substance demonstrates a more sensitive NOAEL for sub-chronic inhalation toxicity of 1.3 mg/L, therefore, using a worst-case scenario approach, this NOAEL value is shared also for this substance.

The second experimental study on this substance was a drinking water study performed according to a method comparable to the OECD Guideline 415 (a One-Generation Reproduction Toxicity Study): no toxicity to fertility (or developmental or general toxicity) was observed up to the highest dose administered of 5000 mg/kg bw/day in either male or female rats following an 8-week pre-mating period, a mating period, and a 20-day gestion period. An experimental study on the other primary metabolite of the substance (SC11) was a GLP, OECD study (OECD Guideline 422: Combined Repeated Dose Toxicity Study with the  Reproduction/Developmental Toxicity Screening Test). In this study, no impact on fertility parameters was observed (or general/developmental toxicity), up to the highest dose of 500 mg/kg bw/day. 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, no toxicity to fertility occurs at oral doses of at least 800 mg/kg bw/day, therefore, the lower NOAEL of 500 mg/kg bw/day is considered relevant also for this substance.

An increasing trend in toxicity is observed with decreasing ester length (also observed in acute oral toxicity and repeated dose oral toxicity). Specifically, the structural analogues with methanol and octanol esters in place of the butanol esters rendered NOAEL (fertility, oral) values of 90 and 800 mg/kg/d, respectively. As the predicted NOAEL value of 500 mg/kg bw/day for this substance falls between these two values, this NOAEL value is accepted.

Effects on developmental toxicity

Description of key information

NOAEL (foetal developmental toxicity) = 250 mg/kg bw/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1.33 mg/m³
Study duration:
subacute
Experimental exposure time per week (hours/week):
159
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No experimental data on the effects on foetal development of the substance were available, therefore, developmental toxicity was evaluated using a variety of experimental studies performed on structural analogues, and using a weight of evidence approach. Greater weight was given to studies performed according to the principles of GLP, performed according to relevant OECD Guidelines, performed on the recommended test species (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.

Several relevant studies were considered in order to assess the developmental toxicity of the substance. The most relevant of these are two non-GLP, non-OECD studies on rats performed a primary metabolite of the substance; and a third study performed on the other primary metabolite of the substance, which is a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (GLP; OECD Guideline 422).

An experimental study on the first primary metabolite of the substance (SC09) was not performed according to an OECD guideline, however, is comparable to an OECD Guideline 416 Prenatal Developmental Toxicity Study via the inhalation route. In this study, the NOAEL for developmental toxicity was considered to be 750 ppm. However, a supporing study on a structural analogue of a primary metabolite of the substance demonstrates a more sensitive NOAEL for deveopmental toxicity via the inhalation route of 1.33 mg/L, therefore, using a worst-case scenario approach, this NOAEL value is shared also for this substance.

The second experimental study on this substance was a drinking water study performed according to a method comparable to the OECD Guideline 414 (a Prenatal Developmental Toxicity Study): the NOAEL for foetal development was set at 300 mg/kg bw/day in the absence of maternal/general toxicity at this dose and up to 5000 mg/kg bw/day. An experimental study on the other primary metabolite of the substance (SC11) was a GLP, OECD study (OECD Guideline 422: Combined Repeated Dose Toxicity Study with the  Reproduction/Developmental Toxicity Screening Test). In this study, toxicity to foetal development was observed at 500 mg/kg bw/day in the absence of maternal toxicity at this dose, therefore, the NOAEL for development was set at the next dose of 250 mg/kg bw/day. 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, no toxicity to fertility occurs at oral doses of at least 250 mg/kg bw/day, therefore, as both metabolites are expected to be present following ingestion, the lower NOAEL of 250 mg/kg bw/day is considered relevant for this substance.

An increasing trend in toxicity is observed with decreasing ester length (also observed in acute oral toxicity and repeated dose oral toxicity). Specifically, the structural analogues with methanol and octanol esters in place of the butanol esters rendered NOAEL (development, oral) values of 90 and 800 mg/kg bw/day, respectively. As the predicted NOAEL value of 250 mg/kg bw/day for this substance falls between these two values, this NOAEL value is accepted.

Justification for classification or non-classification

According to CLP Regulation (EC) No 1272/2008, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring. For the purpose of classification for reproductive toxicity, substances may be allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately.

-Category 1: Known or presumed human reproductive toxicant. Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

-Category 2: Suspected human reproductive toxicant. Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1.

Based on the evaluation using the available data on reproductive toxicity, effects on fertility and development were not observed at oral doses exceeding 500 and 250 mg/kg bw/day, respectively, or at inhalation concentrations of 1.33 mg/L. However, evidence for effects on fertility and development on animals are implicated at higher doses. Therefore, the substance is considered a suspected human reproductive toxicant and should be classified in Category 2 for reproductive toxicity, according to CLP Regulation (EC) No 1272/2008.