Fatty acids, C8-10, C8-10-alkyl esters

Endpoint summary

Description of key information

Oral (read-across): LD50 > 4300 mg/kg bw 
Inhalation (read-across): LC50 > 5.7 mg/L
Dermal (read-across): LD50 > 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given. Test substance purity not specified.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

analytical purity/composition of test substance not specified, limited documentation, no necropsy

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 180 g (mean body weight)

Route of administration:

oral: unspecified

Doses:

1000 and 5000 mg/kg bw

No. of animals per sex per dose:

10

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: prior application and 48 h, 1 week, 2 weeks after application
- Necropsy of survivors performed: no

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured during the observation period.

Clinical signs:

other: No overt signs of toxicity were observed up to the end of the observation period.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008

Conclusions:

CLP: not classified

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given. Test substance purity not specified.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

only basic data given; lack of details on test substance; observation time not given

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

mouse

Strain:

NMRI

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 21 g

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Doses:

5 mL/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

> 4 300 mg/kg bw

Based on:

test mat.

Remarks on result:

other: converted from 5 mL/kg bw based on a density of 0.87 g/mL

Mortality:

No mortality occurred during the study period.

Clinical signs:

other: Significant absence of reactions.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008

Conclusions:

CLP: not classified

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

12 - 18 Mar 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given. Test substance purity not specified.

Principles of method if other than guideline:

To determine the LD50 of the test substance, 5000 mg/kg bw was administered to 5 female mice orally. The mice were observed for mortality and signs of toxicity for 6 days after dosing. The body weights were recorded on day 0 prior to dosing and on day 6.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

mouse

Strain:

other: NMRI EOPS

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 19-20 g
- Fasting period before study: 4 h

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 6 mL/kg bw

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 6 days
- Frequency of observations and weighing: the animals were observed for mortality and signs of toxicity daily; the body weight was recorded on day 0 prior to dosing and on day 6
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, mortality, body weight

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

No mortality occurred during the study period.

Clinical signs:

other: No signs of toxicity were observed.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.

Conclusions:

CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details). The selected studies are sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 Jun - 17 Jun 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Version / remarks:

adopted in 2009

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Crl:WI (Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 9 weeks old
- Weight at study initiation: max. ± 20% of the sex mean
- Housing: Before exposure-Group housing of maximally 5 animals per sex per cage in labeled Makrolon cages (type IV; height 18cm.) containing sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, UK). After exposure - Group housing as described above, maximally 3 animals per sex per cage.
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF Spezialdiäteb GmbH, Soest, Germany), ad libitum except during exposure to the test substance.
- Water: tap-water, ad libitum except during exposure to the test substance.
- Acclimation period: 5 days before the start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3
- Humidity (%): 40-70
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: The design of the exposure chamber is based on the flow past nose-pnly inhalation chamber (Am.Ind.Hyg Assoc.J. 44(12): 923-928, 1983). The chamber consists of animal sections with eight animal ports each. Each animal port has its own atmosphere inlet and exhaust outlet.

- Method of holding animals in test chamber: Animals are placed in restraining tubes, which is then connected to the exposure chamber.

- Source and rate of air: The theoretical air flow was at least 1L/min.

- System of generating aerosols: An aerosol was generated by nebulization of the test substance by means of a nebulizer (type 950,
Hospitak Inc., Lindenhurst, NY, USA). The primary aerosol was diluted with pressurized air before it entered the exposure chamber. The mean total airflow was 16 L/min. From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.

- Method of conditioning air: The direction of the flow of the test atmosphere guarantees a freshly generated atmosphere for each individual animal.

- Temperature, humidity, pressure in air chamber: The temperature of the atmosphere was between 20.0 and 20.7 °C and relative humidity was between 28 and 30%. These conditions were considered appropriate for the relatively short 4 hours exposure duration.

TEST ATMOSPHERE
- Brief description of analytical method used: Samples were drawn through a glass fiber filter (type APFC04700, Millipore, Billerica, MA, USA). The collected amount of test substance in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter (type G 1.6, Actaris Meterfabriek B.V., Dordrecht, The Netherlands).
- Samples taken from breathing zone: yes

VEHICLE
- The test substance was used as delivered by the sponsor

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The MMAD was 2.5 µm (GSD 2.4) and 2.6 µm (GSD 2.3).

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: Target concentrations were based on the cut off concentration values specified in the UN and EC classification guidelines.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetrically

Duration of exposure:

4 h

Concentrations:

The mean actual concentration was 5.7 ± 0.4 mg/L. The nominal concentration was 15.4 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 37%. Data obtained from the opacity monitor showed that the aerosol was sufficiently stable.

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
Mortality/Viability: twice daily
Clinical signs: twice on the day of dosing (1 and 3 hours after exposure); daily thereafter until day 15
Body weight: recorded on day1 (pre-exposure), 2, 4, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
All animals were sacrificed at the end of the observation period by an intraperitoneal injection with Euthasol® (AST Farma BV, Oudewater, The Netherlands).

Statistics:

No statistical analysis was performed (the method used was not intended to calculate a LC50 value).

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.7 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: No mortalities occured. Apart from hunched position observed in all on day 2 after exposure, no further signs of adverse toxicity were observed until the end of the 14 day observation period.

Remarks:

Source CAS 26399-02-0

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 15.4 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortalities occured during the 14-day observation period.

Clinical signs:

other:

Body weight:

Body weight gain in males and females were within the range expected for rats of this strain and age used in this type of study.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008

Conclusions:

CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 1) study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details). The selected study is thus 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.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19 May - 2 Jun 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The test substance was applied with an occlusive dressing.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

the test substance was applied with an occlusive dressing

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

yes

Remarks:

the test substance was applied with an occlusive dressing

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

the test substance was applied with an occlusive dressing

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No. 8147, November 2000; including the most recent partial revisions

Deviations:

yes

Remarks:

the test substance was applied with an occlusive dressing

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar Crl:WI (Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 10 weeks
- Weight at study initiation: 269-284 g (males), 181-194 g (females)
- Housing: animals were housed individually in labelled Makrolon cages (MIII type, height 18 cm) containing sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd.), Surrey, UK). During the acclimation period the animals were housed in groups in Macrolon cages (MIV type).
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6-21.2
- Humidity (%): 39-62
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: the back of the animals; approximately 25 cm² for males and 18 cm² for females
- % coverage: 10
- Type of wrap if used: the test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D) covered with aluminium foil and Coben elastic bandage, respectively. A piece of Micropore tape was used to fix the bandage in females only.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the skin was cleaned using tap water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Constant volume or concentration used: yes, the dose volume was calculated as dose level (g/kg) / density (g/mL)

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

other: an untreated, adjacent skin area served as the control

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were observed twice daily for mortality; the body weight was recorded on Day 1 (prior to dosing), 8 and 15.
- Necropsy of survivors performed: yes, on Day 15 the animals were subjected to necropsy and all gross macroscopical abnormalities were recorded
- Other examinations performed: clinical signs were observed at periodic intervals on the day of dosing (day 1) and once daily thereafter, until sacrifice. The time of onset, degree and duration were recorded and the symptoms graded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1)

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There was no mortality during the study period (see Table 1).

Clinical signs:

other: Piloerection was observed from 4 h - day 2 after dosing in 2/5 males (see Table 2). Chromodacryorrhoea (excessive secretion of a reddish-brown liquid from the eyes) (grade 1) was observed in 3/5 males 2-4 hours after dosing. No systemic clinical signs of

Gross pathology:

The necropsy and histopathological examination did not reveal substance-related findings.

Other findings:

- Other observations: On the treated skin area, erythema was observed for up to 4 days during Day 3-7 in 4/5 females. Scales or scabs (grade 1) were noted on the treated skin area in 5/5 females and 3/5 males for up to 9 days during Day 7-15 of the observation period.

Table 1: Mortality and clinical signs

Dose [mg/kg bw]	Toxicological results*	Duration of clinical signs	Time of death	Mortality (%)
Males
2000	0/5/5	4 h – day 2	Day 1-3	0
Females
2000	0/0/5	-	Day 1	0
LD50 > 2000 mg/kg bw

* first number = number of dead animals                                 

second number = number of animals with systemic clinical signs         

  third number = number of animals used                 Table 2: Clinical signs, systemic/local

Effect*	Max grade	Male No./duration (hours or day after dosing)					Female No./duration (hours or day after dosing)
		1	2	3	4	5	6	7	8	9	10
Systemic
Piloerection	1	4 h - 2 d				4 h - 2 d
Chromoda-cryorrhoea	3		2 - 4 h	2 - 4 h	4 h
Local
Erythema, focal	4						7 d		7 d	3 – 7 d	7 d
Scales	3			8 – 10 d	7 – 15 d		7 – 8 d, 14 d	8 – 11 d	7 – 9 d	7 – 8 d	7 – 9 d
Scabs	3		7 - 11 d		9 - 15 d		8 – 13 d

* all grade 1

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008

Conclusions:

CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 1) study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details). The selected study is thus 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.

Additional information

Justification for read-across

Data on the acute oral, inhalation and dermal toxicity of Fatty acids, C8-10, C8-10 alkyl esters (CAS 129677-93-6) are not available. The assessment of acute toxicity was therefore based on studies conducted with analogue substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with 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 analogue read-across approach is provided in the technical dossier (see IUCLID Section 13) and within Chapter 5.1 of the CSR.

Acute oral toxicity

CAS 2306-88-9

The acute oral toxicity of octyl octanoate (CAS 2306-88-9) was assessed in a study comparable to OECD guideline 401 (Key, 1981). Administration of 1000 and 5000 mg/kg bw to 10 rats/sex/dose via the oral route did not cause mortality and no clinical signs were recorded during the 6-day observation period. There were no effects on body weight. Therefore, the acute oral LD50 in the rat was found to be > 5000 mg/kg bw.

CAS 95912-86-0

In a non-guideline study, 5 female mice were administered 5000 mg/kg bw fatty acids, C8-10, C12-18 alkyl esters (CAS 95912-86-0) via the oral route (Supporting, 1991). The study report contained limited information. No mortality occurred and no clinical signs were recorded during the 6-day observation period. There were no effects on body weight. The oral LD50 is considered to be > 5000 mg/kg bw.

CAS 34316-64-8

In an acute oral toxicity study performed similar to OECD guideline 401, 5 male Swiss mice were administered 5 mLhexyl laurate/kg bw (equivalent to 4300 mg/kg bw, based on a density of 0.87 g/mL) via the oral route (Supporting, 1987). The study report contained very limited data. The summary indicated that no mortality occurred during the observation period (of unknown length), and that no clinical signs were noted in the animals. Therefore, the oral LD50 value for female Swiss mice is > 4300 mg/kg bw.

 

Acute inhalation toxicity

CAS 26399-02-0

The acute inhalation toxicity of 2-ethylhexyl oleate (CAS 26399-02-0) was assessed in a study performed according to OECD guideline 436 (Key, 2010). 3 rats/sex were administered 5.7 ± 0.4 mg/L (actual concentration) of the test substance as an aerosol via nose-only exposure for 4 hours. The nominal concentration was 15.4 mg/L and the MMAD was 2.5-2.6 µm. No mortality occurred. The animals had a hunched posture on Day 2; no further clinical signs were observed during the 14-day observation period. The body weight gain was within the range that is normal for this strain and study type. No findings were reported during the macroscopic examination. The LC50 is considered to be > 5.7 mg/L.  

Acute dermal toxicity

CAS 3687-46-5

An acute dermal toxicity study (limit test) was performed with decyl oleate (CAS 3687-46-5) according to OECD guideline 402 (Key, 2010). 2000 mg/kg bw of the test substance was applied to the skin of 5 Wistar rats/sex under an occlusive dressing for 24 hours. No mortality occurred. Clinical signs were observed in all males on Day 1 and/or 2; as piloerection (2/5 males) or chromodacryorrhoea (3/5 males). No clinical signs were noted in females. The body weight increases were within the range expected for rats used in this type of study and no treatment-related findings were reported during the necropsy and histopathological examination. Erythema (grade 1) was observed on the treated skin for up to 4 days during Day 3-7 in 3/5 during the first week in 45 females. Scales or scabs (grade 1) were noted on the treated skin area in 5/5 females and 3/5 males for up to 9 days during Day 7-15 of the observation period. The LD50 is considered to be > 2000 mg/kg bw.

Overall conclusion for acute toxicity

The reliable data available for the read-across analogue substances indicate a very low level of acute toxicity following the oral, inhalation and dermal route, as LD50 and LC50 values were greater than the currently applied limit values. Therefore, as the available data did not identify any hazard for acute toxicity, Fatty acids, C8-10, C8-10 alkyl esters is not considered to be hazardous following acute exposure.

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 analogue concept is applied to Fatty acids, C8-10, C8-10 alkyl esters (CAS 129677-93-6), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the analogue read-across approach, the available data on acute toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.