Registration Dossier

Administrative data

Description of key information

Based on a weight of evidence approach, all available subacute and subchronic repeated dose toxicity studies resulted in NOAELs of 1000 mg/kg bw/day or greater. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, 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

Additional information

There are no data available for the repeated dose toxicity of Fatty acids, soya, 2 -ethylhexyl esters (CAS 93572 -14 -6). In order to fulfil the standard information requirements set out in Annex VIII and IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity,

the substance listed below are selected as reference substances for hazard assessment.

Overview of repeated dose toxicity

CAS

NOAEL [mg/kg bw/day]

Oral

93572 -14 -6 Target substance

RA: CAS 91031-48-0

RA: CAS 135800-37-2

RA: CAS 163961-32-8

RA: CAS 123 -95 -5

91031-48-0

1000 (m,f) (28-day)

135800-37-2

1000 (m,f) (28-day)

163961-32-8

1000 (m,f) (90-day)

123 -95 -5

6000 (m) (2 -years)

The above mentioned substance is considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Fatty acids, soya, 2-ethylhexyl esters (CAS 93572-14-6).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion:

CAS 91031-48-0

oral 28 -day NOAEL for rats: 1000 mg/kg bw/day

A repeated dose 28-day oral toxicity study was performed with Fatty acids, C16-18, 2-Ethylhexyl Esters (CAS# 91031-48-0) according to 87/302/EWG, Annex, Part B and GLP (Pittermann, 1992). Groups of 10 male and female Sprague-Dawley rats received daily oral gavage doses of the test substance in peanut oil at dose levels of 0, 100, 500 and 1000 mg/kg bw/d over a period of 28 days. Concurrent negative control animals received the vehicle alone. In addition 5 male and 5 female animals were used to determine the reversibility of possible compound-related findings (recovery group).

All doses applied were tolerated without lethality. No compound-related effects were observed based on clinical signs, food consumption, water intake, body weight gain, haematological and clinical chemistry examinations, ophthalmoscopic examination, absolute and relative organ weights as well as macroscopical and histological examinations. Therefore, the 28 day oral NOAEL was determined at 1000 mg/kg bw/d in male and female rats.

CAS 135800 -37 -2

oral 28 -day NOAEL for rats: 1000 mg/kg bw/day

The oral toxicity after daily oral administration for 28 consecutive days of Fatty Acids, C8-16, 2-Ethylhexyl Esters (CAS# 135800-37-2) was tested according to OECD Guideline 407 and GLP (Fitzgerald, 1991). Groups of 5 male and female Sprague-Dawley rats received daily oral gavage doses of the test substance in corn oil at dose levels of 0, 100, 300 and 1000 mg/kg bw/d. Concurrent negative control animals received the vehicle alone.

Based on clinical observations, neurological observations, examinations of various blood parameters (haematology and clinical chemistry), necropsy observations, organ weights, body weights, food consumption and histopathological findings, the 28d oral NOAEL for male and female rats was found to be 1000 mg/kg bw/d.

CAS 163961-32-8

oral 90 -day NOAEL for rats: 1000 mg/kg bw/day

A 90-day oral gavage toxicity study with Fatty acids, C16-18 and C18-unsatd., branched and linear, Butyl Esters (CAS# 163961-32-8) was performed according to OECD Guideline 408 and GLP (McRae, 2004). Groups of 10 male and female Sprague-Dawley rats received daily oral gavage doses of the test substance in arachis oil at concentrations of 0, 5, 50 and 1000 mg/kg/d. Animals were observed for clinical sings, body weight, food consumption, food efficiency, water consumption, ophthalmoscopic examination, haematology, clinical chemistry, neurobehavioral examination, organ weights, gross necropsy and histopathological examinations.

At 1000 mg/kg bw/d slightly elevated plasma cholesterol and creatinine levels were detected for males and a marginal effect on hepatocyte size was observed histopathologically in females. Males and females treated with 1000 mg/kg/d showed increased liver weight accompanied in 1000 mg/kg/d males only by an increase in spleen weight and in females only by increases in adrenal and kidney weight. No such effects were detected among animals from the remaining treatment groups. These effects were considered to be adaptive responses and not adverse effects. Therefore a 90-day oral NOAEL of 1000 mg/kg bw/d was found for fatty acids, C16-18 and C18-unsatd., branched and linear, Butyl Esters in male and female rats.

CAS 123-95-5

2 -year NOAEL for rats: 6000 mg/kg bw/day

A 2-year feeding study was performed with Butyl Stearate (CAS# 123-95-5) similarly to OECD Guideline 452 (Smith, 1953). Groups of 16 male Sprague-Dawley rats received daily doses of 0, 0.01, 0.05, 0.25, 1.25 and 6.25% in the diet but only the two highest doses (approximately 2500 and 6000 mg/kg bw/d) were considered for reporting. Control animals received plain diet. Based on absence of abnormalities in clinical signs, mortality, body weight, food consumption, haematology, clinical chemistry, gross pathology, organ weights and histopathology, the chronic NOAEL was found to be 6000 mg/kg bw /d.

Conclusion for Repeated Dose Toxicity

In summary, two 28-day studies conducted with the structure related substances 2-ethylhexyl stearate (CAS 91031-48-0) and 2-ethyl-hexylester with fatty acids C8-C14 (CAS 135800-37-2) showed no signs of overt toxicity. The 90-day study conducted with Fatty acids, C16-18 and C18 unsatd. Branched and linear, butyl esters (CAS 163961-32-8) and a 2-year study conducted with butyl stearate (CAS 123-95-5) did not show any sign of overt toxicity as well.

In conclusion, since the effects observed are not considered to be systemic and relevant for humans, the NOAEL was found to exceed 1000 mg/kg bw/d for all substances based on the result from the repeated dose toxicity studies.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from structural analogues. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from structurally similar substances, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.