Registration Dossier

Administrative data

Description of key information

Oral: LD50 > 20 000 mg/kg bw 
Inhalation: LC50 > 5.7 mg/L
Dermal: LD50 > 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) 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 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 - 17 Jun 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
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 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

IN-LIFE DATES: From: To:
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
- Frequency of observations and weighing:
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 day2 after exposure, no further signs of adverse toxicity were observed until the end of the 14 day observation period.
Key result
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:
Hunched posture was shown by all animals on Day 2 after exposure. No clinical signs were noted during exposure.
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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) 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 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:
12 - 26 Feb 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The test substance was applied using an occlusive dressing.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
occlusive dressing
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
occlusive dressing
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar Crl:(WI)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 292 ± 13 g (mean ± SD, males); 199 ± 9 (mean ± SD, females)
- Fasting period before study: no
- Housing: animls were individually housed in labelled polycarbonate cages containing purified sawdust as bedding material (Woody SPF, supplied by B.M.I., Helmond, the Netherlands)
- Diet: standard pelleted laboratory animal diet (Carfil Quality BVBA, Oud-Turnhout, Belgium), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 50
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 12 Feb 1998 To: 26 Feb 1998
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: the test substance was applied to an area of approximately 25 cm² for males and 18 cm² for females, using a gauze patch measuring 5x 5 cm and 3.5 x 5 cm, respectively
- % coverage: approximately 10% of total body surface
- Type of wrap if used: the gauze patch was fixed to aluminium foil and held in place with Coban elastic bandage (with drops of petrolatum). A piece of Micropore tape was used for additional fixation of the dressings in females only.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test substance was removed using a tissue moistened with tap water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw (10 mL/kg bw)
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
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; clinical signs were observed at periodic intervals during the dosing day and once daily for the rest of the study period; the body weight was measured on Day 1 (pre-administration), 8 and 15
- Necropsy of survivors performed: yes, the animals were examined for macroscopic abnormalities
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:
Red staining of the neck fur (score 1 of 3) was observed in 1/5 females on Day 8-13. This is an effect that is frequently seen in rats under stressful conditions and is therefore not considered to be toxicologically relevant. No other clinical signs were noted in any animals during the study period.
Body weight:
The body weight gains were within the normal ranges in males and females during the whole study period.
Gross pathology:
The necropsy and histopathological examination did not revealed any substance-related findings.

Table 1: mortality and clinical signs

Dose
[mg/kg bw]

Toxicological results*

Duration of clinical signs

Time of death

Mortality (%)

Males

2000

0/0/5

- 

-

0

Females

2000

0/1/5

Day 8-13 

-

0

Overall 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                               

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) 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 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 Isohexadecyl 12 -[(1 -oxooctadecyl)oxy]octadecanoate (CAS 97338-28-8) are not available. The assessment of acute toxicity was therefore based on studies conducted with analogue (source) 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 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 analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Acute oral toxicity

CAS 90052-75-8

The acute oral toxicity of 2-octyldodecyl 12-[(1-oxooctadecyl)oxy]octadecanoate was assessed in a study that was performed according a protocol similar to OECD guideline 401 and under GLP conditions (key, 1983). 5 Sprague-Dawley rats/sex were administered 20 g/kg bw test substance via the oral route. There was no mortality during the 15-day study period. 5/5 males and 5/5 females had diarrhoea 1 - 4 h after administration, while 1/5 females had soft stool on Day 2 only. On Day 2, 2/5 females had apparent urinary incontinence, one of these females also showed decreased activity. 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 acute oral LD50 value is considered to be > 20 g/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 h. 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 inhalation LC50 value is considered to be > 5.7 mg/L.  

Acute dermal toxicity

CAS 93803-87-3

An acute dermal toxicity study was performed with 2-octyldodecyl isooctadecanoate following a protocol similar to OECD guideline 402 and in compliance with GLP (key, 1998). In a limit test 2000 mg/kg bw of the undiluted test substance was applied to the shaved skin of 5 rats/sex for 24 h under occlusive conditions. After the exposure period, residual test substance was removed and the animals were observed for a period of 14 days. No mortality occurred. Red staining of the fur was observed in 1/5 females on Day 8 – 13. As this is a known sign of stress in rats, it is not considered to be a toxicologically relevant effect. Male and female rats showed the expected gain in body weight throughout the study. The necropsy and histopathological examination did not reveal any substance-related findings. Based on these results, the dermal LD50 value for male and female rats is > 2000 mg/kg bw.

Overall conclusion for acute toxicity

The reliable data available for the source 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, Isohexadecyl 12 -[(1 -oxooctadecyl)oxy]octadecanoate is not expected 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 Isohexadecyl 12-[(1-oxooctadecyl)oxy]octadecanoate, data will be generated from information on 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.