Fatty acids, C18-unsatd, dimers, hydrogenated, diisopropyl esters

Endpoint summary

Description of key information

Oral LD50 (OECD 423), rat > 2500 mg/kg bw (RA 68440-06-2)
Inhalation LC50 (OECD 436), rat > 5.3 mg/L air (RA CAS 68334-05-4)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

06 May - 10 Jun 2015

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study, tested with the source substance Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2). In accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (Dec 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

(2001)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

(2008)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

THE DEPARTMENT OF HEALTH OF THE GOVERNMENT OF THE UNITED KINGDOM

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: RccHan(TM):WIST

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK
- Age at study initiation: 8 – 12 weeks
- Weight at study initiation: 151 – 194 g
- Fasting period before study: overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing
- Housing: The animals were housed in groups of three in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet: 2014C Teklad Global Rodent diet (Harlan Laboratories UK Ltd., Oxon, UK), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/mL
- Amount of vehicle (if gavage): 2.23 and 10 mL/kg bw
- Justification for choice of vehicle: Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION: For the purpose of the 2000 mg/kg bw dose level the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level. For the purpose of the 300 mg/kg bw dose level the test item was freshly prepared, as required, as a solution in arachis oil BP. The test item was formulated within 2 hours of being applied to the test system.

CLASS METHOD
- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test item, 300 mg/kg bw was chosen as the starting dose.

Doses:

300 and 2000 mg/kg bw

No. of animals per sex per dose:

3 females (300 mg/kg bw)
6 females (2000 mg/kg bw)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours after dosing subsequently once daily for 14 days. Individual body weights were recorded prior to dosing and 7 and 14 days after treatment.
- Necropsy of survivors performed: yes
- Other examinations performed: External examination and opening of the abdominal thoracic cavities for examination of major organs.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortalities or clinical signs of toxicity observed

Mortality:

No mortalities were observed during the study.

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period in animals treated at a dose level of 300 mg/kg bw. Hunched posture was noted during the day of dosing in all animals treated at a dose level of 2000 mg/kg bw. All animals treated at a

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

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 and fromhydrolysis products. Read-across is justified either based on structural similarity or common precursors/breakdown products.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

23 Apr - 07 Mai 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study, tested with the source substance Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4). In accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (Dec 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.”

Qualifier:

according to guideline

Guideline:

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

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: approximately 12 weeks old
- Weight at study initiation: max. ± 20% of the sex mean
- Housing: before exposure: Group housing of five animals per sex per cage in labelled Makrolon cages (type IV; 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, United Kingdom); after exposure: Group housing of maximally three animals per sex per cage as described above, except that a paper sheet was introduced into the cage covering the bedding and cage enrichment to prevent suffocation in case of bad health condition. At the end of the Day of exposure the paper sheet was removed.
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) except during exposure to the test substance, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0 (actual range: 19.8 – 21.4)
- Humidity (%): 40 - 70 (actual range: 37 - 60)
- Air changes (per hr): 15
- 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-only inhalation chamber (Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983).
- Method of holding animals in test chamber: animal ports
- System of generating particulates/aerosols: An aerosol was generated by nebulization of the test substance by means of a nebulizer (type 950, Hospitak Inc., Lindenhurst, NY, USA)
- Method of particle size determination: Amounts of test substance collected were measured gravimetrically. Subsequently the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD) were determined
- Treatment of exhaust air: From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.


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
- Concentration of test material in vehicle (if applicable): Since the substance was too viscous to be aerosolized, an acetone : test substance formulation (1 : 3 v/v) was prepared.
- Justification of choice of vehicle:Acetone (Acetone p.a.: Merck, Darmstadt) was selected as suitable vehicle based on trial formulation results.

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (GSD) were determined twice. The MMAD was 3.0 µm and 3.3 µm respectively and the GSD was 1.9 and 2.0 respectively.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: The target concentration was based on the hazard categories for dust and mists specified in the Globally Harmonized System of Classification of Chemicals (GHS), United Nations, New York and Geneva, 2003.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetrically

Duration of exposure:

4 h

Concentrations:

The mean actual concentration was 5.3 ± 0.5 mg/L. The nominal concentration was 9.0 mg/L. The concentration was stable. The generation efficiency (ratio of actual and nominal concentration) was 59%.

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 during exposure: Three times during exposure for mortality, behavioural signs of distress and effects on respiration. Clinical signs after exposure: Twice (at 1 and at 3 hours after exposure) on the day of dosing (day 1) and once daily thereafter, until day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded: 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); Body weights Days 1 (pre-administration), 2, 4, 8 and 15.
- Necropsy of survivors performed: yes

Statistics:

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

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.3 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality occured during the observation period.

Clinical signs:

other: No clinical signs were noted during or after exposure.

Body weight:

Body weight gain in males and females was 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.

The inhalatory 4h-LC50 value of Fatty acids, C18-unsaturated, dimers, 2-ethylhexyl esters in Wistar rats was established to exceed 5 mg/L.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: 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 origin, common precursors and breakdown products of hydrolysis and consistent trends in the toxicological profile.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for grouping of substances and read-across

There are only limited data available on acute toxicity of Fatty acids, C18-unsatd., dimers, hydrogenated, diisopropyl esters (CAS 103213-20-3). In order to fulfil the standard information requirements set out in Annex VII and VIII, 8.5, 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 acute toxicity:

CAS	Chemical name	Molecular weight	Acute toxicity Oral	Acute toxicity Inhalation	Acute toxicity Dermal
103213-20-3 (a)	Fatty acids, C18-unsatd., dimers, hydrogenated, diisopropyl esters	645	RA: CAS 68440-06-2   Experimental result: LD50 > 5000 mg/kg bw (rat, RL4)	RA: CAS 68334-05-4	Experimental result: LD50 > 5000 mg/kg bw (rat, RL4)
68440-06-2 (b)	Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters	789	Experimental result: LD50 > 2500 mg/kg bw (rat)	--	--
68334-05-4 (b)	Fatty acids, C18-unsaturated, dimers, 2-ethylhexyl esters	673	--	Experimental result: LC50 > 5.3 mg/L (rat)	--

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Fatty acids, C18-unsatd., dimers, hydrogenated, diisopropyl esters (CAS 103213-20-3). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

No reliable data on acute toxicity is available with Fatty acids, C18-unsatd., dimers, hydrogenated, diisopropyl esters (CAS 103213-20-3). Therefore, read across from the structurally analogues Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2) and Fatty acids, C18-unsaturated, dimers, 2-ethylhexyl esters (CAS 68334-05-4) was applied.

Acute oral toxicity

Beside a non-reliable acute oral toxicity study (CIR, 2003; RL4) indicating no toxicity in rats no further data on acute oral toxicity are available with Fatty acids, C18-unsatd., dimers, hydrogenated, diisopropyl esters (CAS 103213-20-3). Therefore, read across from the structurally analogue Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2) was applied.

CAS 68440-06-2

A reliable acute oral toxicity study with Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2) is available and was performed according to OECD TG 423 and in compliance with GLP (Bradshaw, 2015). In this acute toxic class method three female fasted Wistar rats were administered one dose of 300 mg/kg bw of the test substance (CAS 68440-06-2) whereas another six females received one dose of 2000 mg/kg bw of the test substance in a stepwise procedure via oral gavage. The animals were observed for 14 days after administration. The acute oral LD50 value for females was calculated to be greater than 2500 mg/kg bw. No mortalities were observed during the study and no signs of systemic toxicity were noted during the observation period in animals treated at a dose level of 300 mg/kg bw. Hunched posture was noted during the day of dosing in all animals treated at a dose level of 2000 mg/kg bw. All animals treated at a dose level of 2000 mg/kg bw appeared normal 1 day after dosing. No abnormalities were noted at necropsy. Based on the study results and according to EU classification criteria, the test substance is not to be classified.

Acute inhalation toxicity

CAS 68334-05-4

A reliable acute inhalation toxicity study was performed with Fatty acids, C18-unsaturated, dimers, 2-ethylhexyl esters (CAS 68334-05-4) according to OECD TG 436 and in compliance with GLP (Huygevoort, 2010). In this acute toxic class method three Crl:WI(Han) rats of each sex were exposed to an aerosol with an analytical concentration of 5.3 mg/L of the test substance for 4 hours via nose-only inhalation in an nose-only inhalation exposure chamber. No mortalities or any abnormal clinical signs were reported during the exposure or within the 14 days observation period. Additionally body weight gain in males and females was within the range expected for rats of this strain and age used in this type of study and no abnormalities were found at macroscopic post mortem examination of the animals. The acute inhalation LC50 value was calculated to be greater than 5.3 mg/L.Based on the results of the study and according to EU classification criteria, the test substance is not to be classified.

 

Acute dermal toxicity

Beside a non-reliable acute dermal toxicity study (CIR, 2003; RL4) indicating no toxicity in rats no further data on acute dermal toxicity are available with Fatty acids, C18-unsatd., dimers, hydrogenated, diisopropyl esters (CAS 103213-20-3). Based on the low water solubility (< 0.05 mg/L at 20 °C, pH = 6.3 - 6.7) and the high molecular weight (>600) dermal penetration is considered very low thus, the dermal route is not considered to be a relevant route of exposure.

Justification for selection of acute toxicity – oral endpoint
Hazard assessment is conducted by means of read-across from structural analogues/surrogates. 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.

Justification for selection of acute toxicity – inhalation 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.

Justification for classification or non-classification

The available data on acute toxicity of Fatty acids, C18-unsatd., dimers, hydrogenated, diisopropyl esters do not meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.