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

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 adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for grouping of substances and read-across

The Short Chain Alcohol Esters (SCAE C2-C8) category covers esters from a fatty acid (C8-C29) and a C2-C8 alcohol (ethanol, isopropanol, butanol, isobutanol, pentanol, iso-pentanol, hexanol, 2-ethylhexanol or octanol). This category includes both well-defined mono-constituent substances as well as related UVCB substances with varying fatty acid chain lengths.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

 

Overview of repeated dose toxicity

CAS No.

NOAEL [mg/kg bw/day]

Oral

Dermal

111-62-6 (b)

5500 (m,f) (90-day)

-

91051-05-7 (b)

RA: 111-62-6

RA: 110-27-0

RA: 163961-32-8

RA: 63393-93-1

10233-13-3 (b)

RA: 111-62-6

RA: 110-27-0

RA: 163961-32-8

RA: 63393-93-1

110-27-0 (b)

1000 (m,f) (28-day)

RA: 63393-93-1

142-91-6 (b)

RA: 111-62-6

RA: 110-27-0

RA: 163961-32-8

RA: 63393-93-1

68171-33-5 (a)

RA: 111-62-6

RA: 110-27-0

RA: 163961-32-8

RA: 63393-93-1

112-11-8 (a)

RA: 111-62-6

RA: 110-27-0

RA: 163961-32-8

RA: 63393-93-1

91031-58-2 (a)

RA: 111-62-6

RA: 110-27-0

RA: 163961-32-8

RA: 63393-93-1

63393-93-1 (a)

RA: 111-62-6

RA: 110-27-0

RA: 163961-32-8

100 (f) (90-day)

123-95-5 (b)

6000 (m) (2-year)

-

67762-63-4 (b)

RA: 135800-37-2

RA: 91031-48-0

RA: 163961-32-8

RA: 123-95-5

 

85408-76-0 (a)

RA: 123-95-5

RA: 163961-32-8

RA: 63393-93-1

84988-74-9 (a)

RA: 123-95-5

RA: 163961-32-8

RA: 63393-93-1

163961-32-8 (b)

1000 (m,f) (90-day)

-

85865-69-6 (a)

RA: 110-27-0

RA: 123-95-5

RA: 163961-32-8

RA: 91031-48-0

RA: 63393-93-1

84988-79-4 (a)

RA: 123-95-5

RA: 163961-32-8

RA: 63393-93-1

6309-51-9 (a)

RA: 110-27-0

RA: 163961-32-8

RA: 34316-64-8

RA: 20292-08-4

RA: 135800-37-2

RA: 63393-93-1

1365095-43-7 (a)

RA: 110-27-0

RA: 163961-32-8

RA: 34316-64-8

RA: 20292-08-4

RA: 135800-37-2

RA: 63393-93-1

34316-64-8 (a)

800 (m,f) (90-day)

RA: 63393-93-1

2306-88-9 (a)

RA: 110-27-0

RA: 163961-32-8

RA: 34316-64-8

RA: 20292-08-4

RA: 135800-37-2

RA: 63393-93-1

59587-44-9 (a)

RA: 91031-48-0

RA: 135800-37-2

RA: 163961-32-8

RA: 34316-64-8

RA: 63393-93-1

20292-08-4 (a)

1000 (m,f) (28-day)

RA: 63393-93-1

649747-80-8 (a)

RA: 110-27-0

RA: 163961-32-8

RA: 34316-64-8

RA: 20292-08-4

RA: 135800-37-2

RA: 63393-93-1

135800-37-2 (b)

1000 (m,f) (28-day)

RA: 63393-93-1

29806-73-3 (a)

RA: 123-95-5

RA: 34316-64-8

RA: 135800-37-2

RA: 91031-48-0

RA: 63393-93-1

22047-49-0 (a)

RA: 123-95-5

RA: 34316-64-8

RA: 135800-37-2

RA: 91031-48-0

RA: 63393-93-1

92044-87-6 (a)

RA: 110-27-0

RA: 163961-32-8

RA: 34316-64-8

RA: 20292-08-4

RA: 135800-37-2

RA: 63393-93-1

91031-48-0 (b)

1000 (m,f) (28-day)

RA: 63393-93-1

85049-37-2 (b)

RA: 135800-37-2

RA: 91031-48-0

RA: 123-95-5

RA: 163961-32-8

RA: 63393-93-1

93572-14-6 (a)

RA: 135800-37-2

RA: 91031-48-0

RA: 123-95-5

RA: 163961-32-8

RA: 63393-93-1

26399-02-0 (b)

RA: 91031-48-0

RA: 135800-37-2

RA: 123-95-5

RA: 163961-32-8

RA: 63393-93-1

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh, or not subject to the REACh Phase-in registration deadline of 31 May 2013, are indicated in normal font.

For all category members registered under REACh a full data set for each endpoint is provided. For substances not subject to the current REACh Phase-in registration, lack of data for a given endpoint is indicated by "--".

 

Repeated dose, oral/dermal - Isopropyl esters 

CAS 110-27-0

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

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 dose levels 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 histopathological 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.

 

CAS 63393-93-1

dermal, 90-day NOAEL for rats: >100 mg/kg bw/day (active ingredient)

A 90-day dermal toxicity study with Fatty Acids, Lanolin, Isopropyl Esters (CAS# 63393-93-1) was performed comparable to OECD Guideline 411 (CTFA, 1977). Groups of 15 female COBS CD (BR) rats were once daily (5 days/week) exposed to a 5%-formulation of the substance at 100 mg/kg bw for 90 days (65 applications in total). Animals were observed for clinical sings, body weight, dermal irritation, haematology, clinical chemistry, organ weights, gross necropsy and histopathological examinations.

Overall there were no adverse effects found after dermal application of the test substance for 90 days. All groups (control and treated group) exhibited slight to moderate erythema and drying of the skin intermittently throughout the study. Higher body weights of control animals, as well as increase in kidney weights for the dose group were not considered adverse, since body weights adapted after 14 days and there was no histopathological evidence found to support changes in kidney weights. Therefore a 90-day dermal NOAEL of > 100 mg/kg bw/day was found for fatty acids, lanolin, isopropyl esters in female rats.

Repeated dose, oral - Hexyl esters

CAS 34316-64-8

oral, 90-day NOAEL for rats: 800 mg/kg bw/day

A 90-day oral feeding toxicity study with Hexyl Laurate (CAS# 34316-64-8) was performed according to OECD Guideline 408 (Potokar, 1973). Groups of 10 male and female Wistar rats were continuously exposed to the substance at 10000 ppm in the diet via an automatic feeding system (approximately 800 mg/kg bw/d) for 90 days. Control animals received liquefied margarine. Animals were observed for clinical sings, body weight, food consumption, food efficiency, water consumption, haematology, clinical chemistry, urinalysis, organ weights, gross necropsy and histopathological examinations.

Overall there were no adverse effects found after feeding of the animals with the test substance for 16 weeks. Changes in the liver and lung observed frequently occur in untreated ageing animals of both sexes and therefore, are not considered as adverse effects. Therefore a 90-day oral NOAEL of 800 mg/kg bw/d was found for Hexyl Laurate in male and female rats.

  

CAS 20292-08-4

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

A repeated dose 28-day oral toxicity study was performed with 2-Ethylhexyl Laurate (CAS# 20292-08-4) equivalent to OECD Guideline 407 (Henkel, 1981). Groups of male and female Sprague-Dawley rats received daily oral gavage doses of the test substance at dose levels of 0, 100, 300 and 1000 mg/kg/d. Based on the study results, the 28 day oral NOAEL for male and female Sprague-Dawley rats was found to be 1000 mg/kg bw/day.

Repeated dose, oral - 2-Ethylhexyl esters

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 NOEL was determined at 1000 mg/kg bw/d in male and female rats.

 

Repeated dose, oral– Read Across Substances

CAS 111-62-6

oral 90 -day NOAEL for rats: 5500 mg/kg bw/day

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 and under GLP. 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 faeces, 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 corresponds to approximately 5500 mg/kg bw/d when administered by daily feeding to rats for 91-days.

 

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 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.

 

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/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 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.

 

Conclusion for subchronic repeated dose toxicity, oral/dermal

In summary, subacute and subchronic administration of several substances of the SCAE C2-C8 category consistently showed no adverse systemic effects resulting in NOAELs of 1000 mg/kg bw/day and higher

There are no data available on the repeated dose toxicity after inhalation of the category members.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

 

 

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met.

Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint".

Since the group concept is applied to the members of the SCAE C2-C8 category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, 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.