Registration Dossier

Administrative data

Description of key information

NOAEL (28 days, rat): 1000 mg/kg bw/day
NOAEL (90 days, rat): 800 mg/kg bw/day

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:
The available information comprises adequate and reliable studies (Klimisch score 2) from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group, common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to 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

Additional information

Justification for grouping of substances and read-across

There are no data available for the repeated dose toxicity of Fatty acids, C8-10, octyl esters (CAS 91031-98-0). In order to fulfil the standard information requirements set out in Regulation (EC) No 1907/2006, Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, a 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.

Overview of repeated dose toxicity

CAS

NOAEL [mg/kg bw/day]

Oral

91031-98-0 Target substance

RA: 34316-64-8

RA: 163961-32-8

RA: 135800-37-2

RA: 91031-48-0

34316-64-8

800 (m,f) (16 weeks)

163961-32-8

1000 (m,f) (90 day)

135800-37-2

1000 (m,f) (28 day)

91031-48-0

1000 (m,f) (28 day)

 

The above mentioned substances are 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, C16-18 and C18-unsatd., ethyl esters (CAS 85049-36-1).

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

CAS 34316-64-8

Oral subchronic (16 weeks) NOAEL for rats: 800 mg/kg bw/day

An oral feeding study (Potokar, 1973) was performed with dodecanoic acid, hexyl ester (CAS 34316-64-8) similar to OECD Guideline 408 in male and female Wistar rats. Approximately 800 mg/kg bw (equivalent to 10 000 ppm) were administered via diet daily for 16 weeks. In each dose group, 10 male and 10 female rats per included. 10 control animals received liquefied margarine in the food. No clinical signs and mortality were detected. The body weights increased steadily and were comparable to the body weights of the control animals. No deviations in comparison with the control animals were seen regarding hematology, clinical chemistry and urinalysis. The organ weights were within the normal range. Under macroscopic examination, dissection revealed some small, limited pneumonic foci in some of the experimental animals and also in some of the controls. Apart from this, there were no findings of note in the macroscopic examinations. In the histopathological examinations, the Kupffer cells in the liver were more adipose in some of the experimental animals than among the controls. The liver cells also showed an increased eosinophilia of certain cells in some of the experimental animals. The remaining organs showed the customary histological pictures for adult rats, consisting of bronchiolitis, slight alterations in the lung structure, varying activity of the thyroid glands, haemosiderosis of the spleen, milky albumen in the uriniferous tubules, slight inflammation of the bowel and occasionally marked sinus catarrh of the mesenteric lymph nodes. The described changes in the liver and lung frequently occur in untreated ageing animals of both sexes and therefore, are not considered as adverse. The subchronic oral NOAEL was determined to be 800 mg/kg bw/day when administered by daily feeding to rats for 16 weeks.

CAS 163961-32-8

Oral 90 days NOAEL for rats: 1000 mg/kg bw/day

An oral 90 days study (McRae, 2004) was performed with Fatty acids, C16-18 and C18 unsatd. branched and linear, butyl esters (CAS 163961-32-8) according to OECD Guideline 408 in male and female Sprague-Dawley rats. 5, 50 and 1000 mg/kg bw in arachis oil were administered via gavage (4 mL/kg bw) daily for 90 days. There were 10 male and 10 female rats per group. 10 control animals received the concurrent vehicle. There were no clinical signs and mortality. No adverse effects on body weight gains were detected. No adverse effect on dietary intake or food efficiency was seen. Daily visual inspections of water bottles revealed no overt intergroup differences. No treatment-related ocular effects were detected and there were also no hematological findings. At 1000 mg/kg bw 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 bw/day showed increased liver weight accompanied in 1000 mg/kg bw/day 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. The oral 90 days NOAEL was therefore determined to be 1000 mg/kg bw/day when administered oral via gavage to rats for 90 days.

CAS135800-37-2

Oral 28 days NOAEL for rats: 1000 mg/kg bw/day

An oral 28 days study (Fitzgerald, 1991) was performed with Fatty acids, C8-16, 2-ethylhexyl esters(CAS 135800-37-2) according to OECD Guideline 407 in male and female Sprague-Dawley rats. 100, 300 and 1000 mg/kg bw in corn oil were administered via gavage (4 mL/kg bw) daily(5 days per week) for 28 days. There were 5 male and 5 female rats per group.5 control animals received the concurrent vehicle. Fatty acids, C8-16, 2-ethylhexyl esterswere well tolerated and there were no toxicologically significant findings in any of the measured parameters (clinical manifestation, neurotoxicity, haematology and clinical chemistry, necropsy, organ weights, body weights, food consumption and histopathological findings). The oral 28 days NOAEL was therefore determined to be 1000 mg/kg bw/day when administered oral via gavage to rats for 28 days.

CAS91031-48-0

Oral 28 days NOAEL for rats: 1000 mg/kg bw/day

An oral 28 days study (Pittermann, 1992) was performed withFatty acids, C16-18, 2-ethylhexyl esters(CAS 91031-48-0) similar to OECD Guideline 407, in male and female Sprague-Dawley rats. 100, 500 and 1000 mg/kg bw in peanut oil were administered via gavage (5 mL/kg bw) daily (5 days per week) for 28 days. There were 10 male and 5 female rats per group.10 control animals received the concurrent vehicle. Fatty acids, C16-18, 2-ethylhexyl esters were well tolerated and there were no toxicologically significant findings in any of the measured parameters (clinical signs, food consumption, water intake, body weight gain, hematological and clinical chemistry, ophthalmoscopic examination, absolute and relative organ weights as well as macroscopical and histological examinations) c). The NOAEL was therefore determined to be 1000 mg/kg bw/day when administered oral via gavage to rats for 28 days.

 

Conclusion:

Two oral subchronic toxicity studies conducted with the structurally related substances dodecanoic acid, hexyl ester (CAS 34316-64-8) and Fatty acids, C16-18 and C18 unsatd. branched and linear, butyl esters (CAS 163961-32-8) showed no signs of overt toxicity. The NOAELs were found to be 800 and 1000 mg/kg bw for dodecanoic acid, hexyl ester (CAS 34316-64-8) and Fatty acids, C16-18 and C18 unsatd. branched and linear, butyl esters (CAS 163961-32-8), respectively based on the result from this study.

Two oral 28 days studies with the structure related substances Fatty acids, C8-16, 2-ethylhexyl esters(CAS 135800-37-2) andFatty acids, C16-18, 2-ethylhexyl esters(CAS 91031-48-0) did also not show signs of overt toxicity. The NOAELs were found to be 1000 mg/kg bw for both Fatty acids, C8-16, 2-ethylhexyl esters(CAS 135800-37-2) andFatty acids, C16-18, 2-ethylhexyl esters(CAS 91031-48-0) based on the result from this study. Based on these data, Fatty acids, C8-10, octyl esters are not considered to exhibit hazardous properties after short or long-term exposure.


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 and are therefore conclusive but not sufficient for classification.