2-ethylhexyl nonanoate

Endpoint summary

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

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

disregarded due to major methodological deficiencies

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Insufficient for assessment (only a 5% formulation tested, test substance purity not specified, limited documentation, no ophthalmoscopic and neurobehavioural examination).

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

only a 5% formulation tested, test substance purity not specified, limited documentation, no ophthalmoscopic and neurobehavioural examination

GLP compliance:

no

Limit test:

yes

Species:

rat

Strain:

other: COBS CD (BR)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, In., Wilmington, Massachusetts
- Housing: Animals were individually housed in wire-mesh, stainless steel cages
- Diet: Teklad Mouse and Rat Died, ad libitum
- Water: tap water, ad libitum

Type of coverage:

not specified

Vehicle:

other: 5% isopropyl lanolate and 3% glycol stearate in a liquid foundation

Details on exposure:

TEST SITE
- Time intervals for shavings or clipplings: Each rat was clipped weekly to remove dorsal hair.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks (animals received 65 applications in total)

Frequency of treatment:

once daily, 5 days a week

Remarks:

Doses / Concentrations:
100 mg/kg bw
Basis:
nominal per unit body weight

No. of animals per sex per dose:

15

Control animals:

yes

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily

BODY WEIGHT: Yes
- Time schedule for examinations: initially and weekly thereafter and on the day of necropsy

HAEMATOLOGY: Yes
- Time schedule for collection of blood: One week prior to the termination of the study, animals were fasted over night (16 hours).
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- How many animals: 15 animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: One week prior to the termination of the study, animals were fasted over night (16 hours).
- Animals fasted: Yes
- How many animals: 15 animals

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, at the end of the test, all animals were dissected, with a macroscopic assessment of the internal organs, these being weighed and preserved for histological investigations. The following organs were analyzed: thymus, trachea, esophagus, stomach, pancreas, small intestine, large intestine, ovary and bladder.

ORGAN WEIGHTS: Yes, brain, lung, heart, liver, spleen, kidney, adrenals and uterus

HISTOPATHOLOGY: Yes, tissues were subjected to histopathologic examination by A.A. Stein, M.D., Microscopy for Biological Research, Ltd., Albany, New York. The following organs were analyzed: bone marrow, liver, spleen, kidney, skin, brain, heart, lung and uterus.

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

non adverse

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

non adverse

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

non adverse

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
All animals survived for the duration of the study.
External appearance of the skin at sites of application of the test substance was not different from that of control. All groups exhibited slight to moderate erythema and drying intermittently throughout the study.
During the period of application and at the end of the test, all animals were free from other symptoms.

BODY WEIGHT AND WEIGHT GAIN
The dose group exhibited higher body weights compared to the control group. After 14 days no significant differences were observed. Therefore, this finding was not believed to be compound-related.

HAEMATOLOGY
No deviations in comparison with the control animals.

CLINICAL CHEMISTRY
No deviations in comparison with the control animals.

ORGAN WEIGHTS
The kidney weight for the dose group was higher compared to the control value. The histopathology showed no deviations in comparison with the control anaimals. Therefore, this observation was not believed to be compound-related. All other organ weights were within the normal range.

GROSS PATHOLOGY
No deviations in comparison with the control animals.

HISTOPATHOLOGY: NON-NEOPLASTIC
No deviations in comparison with the control animals.

Dose descriptor:

NOAEL

Effect level:

> 100 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

female

Basis for effect level:

other: clinical observations, body weight gains, hematology, clinical chemistry, organ weights, histopathology

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 2) study from reference substance with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in toxicological profile (refer to endpoint discussion for further details). The selected study is 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: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There are no data available for the repeated dose toxicity of 2 -ethylhexyl nonanoate (CAS 59587 -44 -9). 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.

Overview of repeated dose toxicity

CAS	NOAEL [mg/kg bw/day]
	Oral	Dermal
59587-44-9 Target substance	RA: 91031-48-0 RA: 135800-37-2 RA: 163961-32-8	63393-93-1
91031-48-0	1000 (m,f) (28-day)	--
135800-37-2	1000 (m,f) (28-day)	--
163961-32-8	1000 (m,f) (90-day)	--
63393-93-1	--	100 (f) (90-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 2-ethylhexyl nonanoate (CAS 59587-44-9).

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 NOEL 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/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.

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.

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. Two 90-day studies conducted with Fatty acids, C16-18 and C18 unsatd. Branched and linear, butyl esters (CAS 163961-32-8) showed no signs of overt toxicity.

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 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 selection of repeated dose toxicity dermal - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance 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.