Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Oral (read-across, similar to OECD 408) NOAEL m/f rat ≥1000 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Source: CAS 151661-88-0
Key result
Critical effects observed:
no

The 90-day repeated oral dose toxicity study with the source substance Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol (CAS 151661-88-0) was selected as key result for reasons of structural similarity and data reliability. Additionally in vivo sub-chronic (90-day) oral toxicity data from the source substance 2-hydroxypropyl stearate (CAS 1323-39-3) showed an NOAEL of 5657 mg/kg bw/day in male rats and of 7355 mg/kg bw/day in female rats.

Conclusions:
The read-across approach is justified in the analogue justification. The target and source substances are considered unlikely to differ in their repeated dose toxicity potential. The oral repeated dose toxicity of the target substance is estimated based on adequate and reliable sub-chronic (90 day) toxicity studies with structural analogue source substances conducted in rats. The NOAEL for sub-chronic (90 day) systemic toxicity was found to be 1000 mg/kg bw/day. Therefore, a NOAEL for repeated dose toxicity after oral exposure of 1000 mg/kg bw/day is considered for the target substance Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises adequate and reliable (Klimisch score ≤2) studies from source substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

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

Mode of Action Analysis / Human Relevance Framework

Not applicable.

Additional information

There are no data on the repeated dose toxicity of Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9). The assessment was therefore based on studies conducted with analogue substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Repeated dose toxicity, oral, sub-chronic

CAS 151661-88-0

A repeated dose 90-day oral toxicity study was conducted similar to OECD guideline 408 and under GLP conditions (key study, 1992) with Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol (CAS 151661-88-0). 10 rats/sex/dose and 5 satellite control and high-dose rats/sex were administered 0 (vehicle control), 100, 300 and 1000 mg/kg bw/day, 5 days per week by oral gavage for a period of 94 days.

Rats were observed daily for mortality/morbidity and any clinical signs were recorded daily. The body weight, and feed consumption and water consumption were measured weekly; haematology and clinical chemistry parameters were assessed in week 6 and at study termination. And Opthalmoscopic examination, gross pathology, histopathology examinations were performed, and organ weights were determined at study termination. No treatment-related effects were observed on any of the listed parameters. Based on the absence of treatment-related effects, the NOAEL for sub-chronic (90-day) systemic toxicity for male and female rats was 1000 mg/kg bw/day.

CAS 1323-39-3

A repeated dose 90-day oral toxicity study was performed similar to OECD guideline 408 (supporting study, 1967) with Stearic acid, monoester with propane-1,2-diol (CAS 1323-39-3). Twenty four rats per sex and per dose were administered 1.5, 3.36, and 7.52% of the test substance (nominal) in diet (w/w). As calculated from the reported mean body weights and feed consumption the highest dose was equivalent to 5657 mg/kg bw/day for male and 7355 mg/kg bw/day for female rats. The total fat additive in the diet was equal to 7.52% for all treatment groups, meaning that the low-and mid-dose group were administered 6.02 and 4.16% mono-and diglyceride, respectively. The concurrent control group was fed an isocaloric diet containing 7.52% mono-and di-glyceride. The treatment period was 13 weeks.

Rats were observed daily for mortality/morbidity and any clinical signs were recorded daily. The body weight and feed consumption were measured weekly; water consumption was measured daily; haematology and clinical chemistry parameters were assessed in week 1 and 13; and urine was collected during week 1 and 12. A gross pathology and histopathology examination was performed after sacrifice, and organ weights were determined after sacrifice at study termination. All of the 192 test animals survived until termination of the study and were sacrificed. A very high incidence of demonstrable lung involvement was observed upon necropsy. 163/192 rats showed gross lung pathology. These findings, mainly diffuse congestion and consolidation, were not related to treatment or sex but reflected a general condition of the entire group of rats. Limited, scattered incidental gross findings were observed in groups of rats, male and female, fed the control or the test substance diets. Statistically significantly higher body weights were found in males of the 1.5% and 3.36% groups during weeks 6 and 7; statistically significant increased water consumption was seen in male rats fed 1.5% and 7.52% for Week 4 and in female rats fed 7.52% for Week 1. The white blood cell count for female rats fed 7.52% was higher than that for the control group at Week 13. Urine analyses showed no finding in incidence or concentration considered to be dose-related or to be outside a normal control range except for the few scattered statistically significant differences listed: the urine specific gravity of male rate fed 7.52% was lower than that of the control group at Week 1 (p < 0.05). The urine values for female rats fed 1.5% and 7.52% were significantly lower than that of the control group at Week 12 (p < 0.05). Qualitative values for urinary sugar, acetone, albumin and microscopic examination of centrifuged urine, for occult blood, crystals and epithelial cells were made. Scattered incidences of qualitative urinary sugar and albumin show no relation to diet, period of sampling or to sex. No urinary acetone was observed at any time. Occult blood was demonstrated at a minimum level in only four rats (one control male, one low- and high-dose male and one female high-dose); all other urine samples were free of red blood cells. Occasional epithelial cells at a minimum level appear unrelated to diet, sampling period or to sex. Occasional uric acid, urate, phosphate, and oxalate crystals were seen in the urine sediment but these appeared in incidence and concentration to be unrelated to any diet, period of sample or sex and were considered to be within a normal control range. Male rats fed 1.5% of the test material in the diet had a lower gonads to body weight ratio (p < 0.05) than did the control group, which was considered to be incidental and not dose related since no pattern of response was seen at other levels or in the other sex. All effects were judged to be of no toxicological relevance. Therefore, the NOAEL for sub-chronic (90-day) systemic toxicity for male and female Sprague Dawley rats was above 5000 mg/kg bw/day.

 

Overall conclusion for repeated dose toxicity

The data for the source substances showed that no treatment-related effects were observed up to and including the recommended limit values. Therefore, as the available data did not identify any hazard for repeated dose toxicity, Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) is not considered to be hazardous following repeated exposure.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the analogue read-across approach, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification.