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Description of key information

All available subacute and subchronic oral repeated dose toxicity studies resulted in NOAELs of 1000 mg/kg bw/d or greater. 
Studies on oral subacute repeated dose toxicity were available for the following category members (CAS#): 110-27-0, 135800-37-2 and 91031-48-0.
Studies on oral subchronic repeated dose toxicity were available for the following category members (CAS#): 111-62-6, 163961-32-8 and for the metabolite 2-ethylhexanol (104-76-7).

Key value for chemical safety assessment

Additional information

Ethyl ester - Repeated dose toxicity:

oral 90 -day NOAEL for rats: 6000 mg/kg bw/d

 

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 equivalent to OECD Guideline 408. 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 0, 3.3, 6.7, and 10% by weight (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 feces, ophthalmic examinations, haematology, clinical chemistry, urinalysis, organ weights, histopathology, or male and female reproductive assessments). The 90-day oral NOAEL was determined to be 10% ethyl oleate, which refers to approximately 6000 mg/kg bw/d when administered by daily feeding to rats for 91-days.

 

Isopropyl ester - Repeated dose toxicity:

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

 

A repeated dose 28-day oral toxicity study was performed with isopropyl myristate (CAS# 110-27-0) equivalent to OECD Guideline 407 (Gloxhuber, 1982). Groups of 10 male and female Wistar rats received daily oral gavage doses of the test substance at concentrations of 0, 100, 500 and 1000 mg/kg/d in olive oil. Concurrent negative control animals received the vehicle alone. Clinical observations, body weight changes, haematology, clinical chemistry, organ weight measurements as well as gross and histopathologic examinations revealed no treatment-related abnormalities or adverse effects. Based on the study results, the 28 day oral NOAEL for male and female Wistar rats was found to be 1000 mg/kg bw/d.

 

Butyl ester - Repeated dose toxicity:

oral 90 -day NOAEL for rats: 1000 mg/kg bw/d; 2 -year NOAEL for rats: 6000 mg/kg bw/d

 

A 90 day oral gavage toxicity study was performed with Fatty acids, C16-18 and C18-unsatd., branched and linear, Butyl esters (CAS# 163961-32-8) was performed according to OECD Guideline 408 (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/day. 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 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/day showed increased liver weight accompanied in 1000 mg/kg/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. Therefore an 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.

A 2-year feeding study was performed with butyl stearate (CAS# 123-95-5) similar to OECD Guideline 452 (Smith, 1953, summarized by Elder, 1985). 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. 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.

 

2-Ethylhexyl ester - Repeated dose toxicity:

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

 

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 (Fitzgerald, 1991). Groups of 5 male and female Sprague-Dawley rats received daily oral gavage doses of the test substance in corn oil at concentrations 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.

 

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 (Pittermann, 1992). Groups of 10 male and female Sprague-Dawley rats received daily oral gavage doses of the test substance in peanut oil at concentrations 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 NOEL was determined at 1000 mg/kg bw/d in male and female rats.

 

2 -Ethylhexanol - Repeated dose toxicity:

oral 90 -day NOAEL for rats: 125 mg/kg bw/d, 90 -day inhalation NOAEC (vapour) for rats: 638.4 mg/m3

 

A subchronic oral gavage study on the toxicologically most critical metabolite 2 -ethylhexanol (CAS# 104 -76 -7) was available: Groups of 10 male and female rats received daily oral gavage doses of 0, 25, 125, 250, and 500 mg/kg 2-ethylhexanol (CAS# 104-76-7) for 90 days on 5 consecutive days per week (Astill, 1996). In this study a subchronic NOAEL of 125 mg/kg bw/d could be identified for 2 -ethylhexanol. At higher doses pathologic changes in the liver histology and organ weights, increase of reticulocytes and decrease of serum ALAT were observed.

The MW of 2 -ethylhexanol (CAS# 104 -76 -6) is 130.23.

For the 2 -ethylhexyl members of the category this would refer to the following equimolar subchronic NAELs:

- CAS# 26399 -02 -0 (MW 394.7, molar ratio factor of 3.03): 378.75 mg/kg bw/d

- CAS# 135800 -37 -2 (smallest MW 256.4, molar ratio factor of 1.97): 246.25 mg/kg bw/d

- CAS# 91031 -48 -0 (smallest MW 368.64, molar ratio factor of 2.83): 353.84 mg/kg bw/d

- CAS# 85049 -37 -2 (smallest MW 368.64, molar ratio factor of 2.83): 353.84 mg/kg bw/d

These equimolar NAELs were not taken into consideration for the calculation of DNELs for 2 -ethylhexyl esters members of the category for the following reason: Application of a default factor 3 (from subacute to subchronic) on the subacute (28 -day) NOAEL of 1000 mg/kg bw/d results in similar values as above. Thus, DNEL calculations for 2 -ethylhexyl esters members of the category were based on the two available subacute (28 -day) oral repeated dose toxicity studies.

A 90-day subchronic inhalation toxicity study was performed on Wistar rats with 2-ethylhexan-1-ol (CAS# 104-76-7) in accordance to OECD guideline 413 (Klimisch, 1998). 10 males and 10 females per group were exposed to 2-ethylhexanol vapours at concentrations of 15, 40 and 120 ppm (the latter corresponding to the vapour saturation at 20ºC) 6 hours/day on working days for 90 days. The respective controls inhaled clean air under the same conditions. No substance-related adverse effects were observed for body weight, body weight gain, mortality, organ weights, ophthalmoscopy, clinical biochemistry and haematological parameters including clotting time. There were no findings related to the treatment with 2-ethylhexanol either at necropsy or at histological examination. The highest concentration tested under these conditions (120 ppm, equivalent to 638.4 mg/m3) was found to be the NOAEC for male and female rats.

The 90 -day vapour inhalation study with 2 -ethylhexanol was not taken into consideration for derivation of inhalation DNEL, as the inhalation exposure to a vapour of 2 -ethylhexanol should not be directly compared with an inhalation exposure to an aerosol (droplets) of fatty acid 2 -ethylhexyl esters. Therefore the route to route extrapolation from oral studies was judged to be more adequate.

Justification for classification or non-classification

The available studies within the Category were judged to be sufficient for risk assessment, considering the similarity of toxicological characteristics upon systemic uptake of the category members. Accounting for animal welfare, further animal testings would not be reasonable.

According to DSD (67/548/EEC) and CLP (1272/2008/EC) classification criteria for repeated dose toxicity, no classification is required.