Fatty acids, C16-18 and C18-unsatd., Me esters, epoxidized, reaction products with ethylene glycol

Endpoint summary

Description of key information

No repeated dose toxicity data on the substance itself is available. Therefore, the sub-chronic toxicity study on the structural analogue with CAS# 151661-88-0 was used. Based on these observations the NOAEL was determined to be 1000 mg/kg bw/day in male and female rat. However, since a developmental toxicity study is available for the substance itself, in which the NOAEL for maternal toxicity was determined to be 200 mg/kg bw/day, this value is adapted as starting point for hazard assessment, as a conservative approach.

To further improve the toxicological data available for this substance and to further imperove the read-across hypothesis, an OECD 422 for substance itself is ordered. This study can then be used as bridging study and further support the read-across hypothesis. Additionally, a subchronic study is ordered for a read-across substance (CAS 85586-35-2) to improve the available data on subchronic toxicity based on the agreed testing strategy.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

Please refer to chapter 13 for the read-across justification.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

90 days

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No toxic effects at highest dose tested

Remarks on result:

other: Read-across from 151661-88-0, sub-chronic

Dose descriptor:

NOAEL

Remarks:

28 days

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Remarks on result:

other: Read-across from Oleic methyl ester, epoxidized, reaction products with glycerol (OEG), sub-acute

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

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

No data on repeated dose toxicity of the substance itself are available. Therefore, investigations on repeated dose toxicity of the structural analogous substances with CAS# 151661-88-0 and Oleic methyl ester, epoxidized, reaction products with glycerol (OEG) were used. Since a developmental toxicity study is available for the substance itself, in which the NOAEL for maternal toxicity was determined to be 200 mg/kg bw/day, this value is adapted as starting point for hazard assessment, as a conservative approach.

90-day repeated dose toxicity (CAS 151661-88-0)

The substance was tested for systemic toxicity at repeated doses of 0 (group 1), 100 (group 2), 300 (group 3) and 1000 (group 4) mg/kg body weight/ day. The compound was administered daily by gavage over a period of 90 days. 10 male and 10 female rats were used for each dose. In addition to the groups 1 and 4, 5 male and 5 female animals were used to determine the reversibility of passible compound- related findings (recovery groups). All doses applied were tolerated without lethality. No compound- related symptoms were observed. The mean food consumption in all treated groups was comparable to the control. The increase in food consumption in the female group 4 at the beginning of the week 4 up to the end resulted from food wasting by the animals. The mean water intake of all groups was comparable to the control. The total body weight gain of all groups showed no deviation and was comparable to the control. The intermediate and the final haematological examinations revealed a decrease of the Haematocrit value (HCT) in the male groups 2 - 4. The decrease of the HCT seems to be compound- and partially dose-related. Additionally the intermediate analysis showed slightly reduced (Red Blood Cell count) RBC- value for the male group 4. The observed deviation of the is considered to be incidental/ because the diagnosed values are within the limits of the historical control. In addition to this, there are no corresponding deviations of the RBC- or MCV- values to prove the biological relevance of this findings. All other findings were considered to be spontaneous and therefore not related to the treatment. The biochemical examinations revealed some compound and dose independent findings. The examination of the eyes by slit lamp microscope showed no compound- related effects. The absolute and relative organ weights in all groups showed no deviations and were comparable to the control. The macroscopical examination of the organs displayed some observations like discolouration of the thymus, deformation of the spleen, cyst of the kidney, hydronephrosis, atrophy of the testes, hydrometra and necrosis of the fatty tissue which were considered to be spontaneous. Compound-related macroscopical effects were not observed. The male and female animals of the recovery group 4 (recovery period 33 days) showed no macroscopical compound- related alterations. The microscopical examination revealed no compound- related effects. In the male and female animals of all groups (including the recovery group 1 and 4 ) the livers, the heart and the mandibulary lymph node showed effects which were due to a bacteriosis of unknown etiology. The observed germinal hyperplasia of the mandibulary lymph node can be interpreted as a consequence of this bacteriosis. Possible target organs have not been diagnosed. The liver and the heart of the recovery groups 1 and 4 were examined in order to prove the persistence of the bacteriosis. According to the described study, a daily administration of the test item up to 1000 mg/kg bw/day is not cumulative- systemic toxic to rats. Based on these observations the NOAEL was determined to be 1000 mg/kg bw/day for males and females (Henkel 1991).

28-day repeated dose toxicity (Oleic methyl ester, epoxidized, reaction products with glycerol (OEG))

The substance was tested for systemic toxicity at dosages of 100, 500 and 1000 mg/kg body weight/day, administered by gavage for 28 days. 10 male and 10 female rats were used for each dose. The low, middle and high dose was tolerated in all animals without administration related lethality. The only symptom was salivation in few animals of the high dose group. There were some variations in food, water consumption and body weight gain in dosage groups to be without compound and dose related relevance. Haematologically, compound related, decreased haematocrit and erythrocyte values were observed in male animals in the high dose group. In female animals the same findings occurred in the middle dose group. A slight significant increase in GPT-levels in males of the high dose and a significant increase of GPT-values in female animals of the high dose were measured. Eye examination revealed no compound related findings. The relative liver weights were significantly increased in male animals of the high dose. A slight increase of the relative liver weights was seen in female animals of the high dose. These findings were considered to be compound related. Pathologically-anatomically examination revealed in all animals no evidence of compound related damage of inner organs. Microscopic examination in animals of high dose level revealed degenerative alterations in kidneys which were reversible in the recovery group. It was concluded by the study director that a daily administration of 1000 mg/ kg bw/ day is for rats a cumulative toxic level with liver and kidney as target organs. A NOAEL of 100 mg/kg bw/day was suggested as non-cumulative toxic level for rats (BASF 1987).

However, it is arguable whether the effects observed in the study are sufficient to conclude on a NOAEL of 100 mg/kg bw/day. According to a recent publication by Hall et al., the variation of liver weights without histological evidence or distinct alterations in clinical chemistry is not considered to be an adverse effect. Hall et al. reach the conclusion that only a 2-3-fold increase in ALT (GPT) or a biologically significant change in other biomarkers is considered to be an adverse effect. In the study at hand, the only remarkable alteration in liver parameters was an ALT increase in the highest dose group of males and females, but it was less than 2-fold. Regarding the observed degradations in the kidney, they were not accompanied with relevant biochemical changes (urea, creatinine, sodium, potassium) and were reversible in the recovery group. The absence of adverse effects in the 90-day study further supports the argumentation that the alterations found in the 28-day study were temporary and rather a non-adverse adaptation than an evidence for a toxicological action (Henkel 1987).

Reference

Hall et al. (2012), Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes – conclusions from the third international ESTP workshop, Toxicol Pathol, 40(7), 971-94

Justification for classification or non-classification

Based on the available data, classification for repeated dose toxicity is not warranted in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.