Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
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.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

There are no data available for the reproduction toxicity of Fatty acids, soya, 2 -ethylhexyl esters (CAS 93572 -14 -6). In order to fulfil the standard information requirements set out in Annex IX, 8.7, 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,

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

Overview Reproductive toxicity:

CAS #

Reproductive Toxicity

111-62-6

NOAEL: 5500 mg/kg bw/day

123-95-5

NOAEL: 6000 mg/kg bw/day

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).

CAS 111-62-6

NOAEL (fertility) = 6000 mg/kg bw/day, OECD 408

A 90-day oral feeding study (Bookstaff, 2004) was performed with Ethyl Oleate (CAS# 111-62-6) according to the 1993 FDA draft "Redbook II" guidelines (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food). The study was performed equivalently to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) with additional assessment of oestrus cycle and sperm parameters. The purpose of the study was to determine the safety of Ethyl Oleate (EO) in a 91-day feeding study in Sprague-Dawley rats. EO was mixed into AIN-93G purified diet at levels of approx. 0, 1900, 3800 and 6000 mg/kg bw/day. All diets were calorie- and fat-matched using high oleic safflower oil (HOSO) as the control fat. There were 20 male and 20 female rats per group. EO in the diet was well tolerated and there were no toxicologically significant findings in any of the measured parameters (clinical observations, body weight gains, appearance of the faeces, ophthalmic examinations, haematology, clinical chemistry, urinalysis, organ weights, histopathology, or male and female reproductive assessments). Based on the absence of abnormalities concerning oestrus cyclus, sperm characterization and histopathologic evaluation of oestrus cycle in females, sperm characterization in males and histologic examinations (incl. epididymides, mammary gland, ovaries, prostate, seminal vesicles, testes, thyroid with parathyroid, uterus with uterine horns and Vagina) the subchronic 90-day oral NOAEL for fertility in rats for Ethyl Oleate was found to be approx. 5500 mg/kg bw/d.

 

CAS 123-95-5 

NOAEL (parental fertility) = 6000 mg/kg bw/day, OECD 421

NOAEL (offspring development) = 6000 mg/kg bw/day, OECD 421

A reproduction/developmental toxicity screening test was performed with Butyl Stearate (CAS# 123-95-5) similar to OECD Guideline 421 (Smith, 1953). 20 male and female Sprague-Dawley rats received Butyl Stearate at a concentration of 6.25% in the diet, corresponding to approx. 6000 mg/kg bw/day for a period of 10 weeks. Negative control animals (12 males and females) were fed with the concurrent basal diet. After 10 weeks animals were mated. Successfully mated pregnant females were housed individually in breeding cages. The date of parturition and the number and sex of pups in each litter were recorded. Litters were weaned 21 days postpartum and the weights of the weanlings determined. From each of the three groups of weanlings (those receiving the test material and the controls), 24 males and 24 females were chosen at random and for the next 21 days, these young were fed the same 6.25% diet as had been ingested by their parents. Diet intake and body weights were recorded daily; 21 days after weaning, the rats were sacrificed and necropsies were performed.

Based on reproduction, fertility index, litter size, survival index/viability index of offspring and necropsy at day 21 after weaning the NOAEL for parental fertility as well as for offspring development was found to be 6000 mg/kg bw/d.

 

Conclusion for reproduction toxicity

Two studies are available investigating the reproduction toxicity using analogue based read-across. A reproduction/developmental toxicity screening test was performed with Butyl Stearate (CAS 123-95-5) similar to OECD Guideline 421. 20 male and female Sprague-Dawley rats received Butyl Stearate at a concentration of 6.25% in the diet, corresponding to approx. 6000 mg/kg bw/day for a period of 10 weeks. Based on reproduction, fertility index, litter size, survival index/viability index of offspring and necropsy at day 21 after weaning the NOAEL for parental fertility as well as for offspring development was found to be 6000 mg/kg bw/day.

Moreover, a 90-day oral feeding study is available with Ethyl Oleate (CAS 111-62-6) according to the 1993 FDA draft "Redbook II" guidelines (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food). The study was performed equivalently to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) with additional assessment of oestrus cycle and sperm parameters. Ethyl Oleate in the diet was well tolerated and there were no toxicologically significant findings in any of the measured parameters. Based on the absence of abnormalities concerning oestrus cyclus, sperm characterization and histopathologic evaluation of oestrus cycle in females, sperm characterization in males and histologic examinations (incl. epididymides, mammary gland, ovaries, prostate, seminal vesicles, testes, thyroid with parathyroid, uterus with uterine horns and Vagina) the subchronic 90-day oral NOAEL for fertility in rats for Ethyl Oleate was found to be approx. 5500 mg/kg bw/day. Thus, no hazard for reproduction toxicity was identified.


Justification for selection of Effect on fertility via oral route:
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).

Effects on developmental toxicity

Description of key information
Oral (OECD 414, analogue approach), rat: NOAEL >= 1000 mg/kg bw/day;
Oral (OECD 414, analogue approach), rat: NOAEL >= 1000 mg/kg bw/day
Effect on developmental toxicity: via oral route
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.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

There are no data available for the developmental toxicity of Fatty acids, soya, 2 -ethylhexyl esters (CAS 93572 -14 -6). In order to fulfil the standard information requirements set out in Annex IX, 8.7, 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,

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

Overview Developmental toxicity: 

CAS #

Developmental Toxicity

22047-49-0

NOAEL: 1000 mg/kg bw/day

91031-48-0

NOAEL: 1000 mg/kg bw/day

CAS 22047-49-0

NOAEL (maternal toxicity) = 1000 mg/kg bw/day, OECD 414

NOAEL (embryo-/fetotoxicity and teratogenicity) = 1000 mg/kg bw/day, OECD 414

The developmental toxicity of 2-Ethylhexyl Stearate (CAS 22047-49-0) was investigated according to OECD Guideline 414 and GLP conditions (Aulmann, 2000). Groups of 24 female Sprague-Dawley rats received daily oral gavage doses of the test substance in arachidis oil at dose levels of 0, 100, 300 and 1000 mg/kg bw/d during gestational days 6 to 15. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/d. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed no differences to control and no indication for teratogenic effects. Therefore, the NOAEL for embryo-/fetotoxicity and teratogenicity in rats for 2-Ethylhexyl Stearate was found to be 1000 mg/kg bw/day.

 

CAS 91031-48-0

NOAEL (maternal toxicity) = 1000 mg/kg bw/day, OECD 414

NOAEL (embryo-/fetotoxicity and teratogenicity) = 1000 mg/kg bw/day, OECD 414

A Prenatal Developmental Toxicity Study was performed with Fatty Acids, C16-18, 2-Ethylhexyl Esters (CAS 91031-48-0) according to OECD Guideline 414 (Pittermann, 1994). Groups of 24 female Sprague-Dawley rats received daily oral gavage doses of the test substance in arachidis oil at dose levels of 0, 100, 300 and 1000 mg/kg bw/day during gestational days 6 to 15. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed no differences to control and no indication for teratogenic effects. Therefore, the NOAEL for embryo-/foetotoxicity and teratogenicity in rats for Fatty Acids C16-18, 2-Ethylhexyl Esters was found to be 1000 mg/kg bw/day.

 

 

Conclusion for developmental toxicity

Two developmental toxicity studies are available using analogue based read-across. The studies from the structural analogue substances 2-ethylhexyl stearate (CAS 22047-49-0) and Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) did not show treatment-related effects up to the highest tested dose level. Thus, no hazard for developmental toxicity was identified.

Moreover, according to Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 2, ”reproductive toxicity studies do not need to be conducted if the substance is of low toxicological activity and it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure”. In accordance with the general rules set out in Regulation (EC) No 1907/2006, Annex XI, section 1.2, a weight of evidence approach considering “several independent sources of information”, available toxicity data demonstrate that Fatty acids, soya, 2-ethylhexyl esters (CAS 93572-14-6) exhibit no or only low toxicological potency. As determined in the toxicokinetic assessment, only a moderate to low potential for absorption is considered for the Fatty acids, soya, 2-ethylhexyl esters (CAS 93572-14-6).


Justification for selection of Effect on developmental toxicity: via oral route:
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 the structurally similar substances, the available data on toxicity to reproduction 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.