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Administrative data

Description of key information

WoE:
Inhalation aerosol: LC50 rat > 5300 mg/m³
Read across substance Fatty acids, C18-unsatd., dimers (CAS: 61788-89-4): oral LD50 rat > 5000mg/kg bw
Read across substance Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (CAS: 173832-46-7): oral LD50 rat > 2000mg/kg bw
Read across substance 2-ethylhexanol (CAS No. 104-76-7): oral LD50 rat > 2000 mg/kg bw and inhal LC50 rat > 1.46 mg/L (highest attainable aerosol concentration)

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 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:
experimental study
Adequacy of study:
key study
Study period:
23 Apr - 07 May 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP 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: approximately 12 weeks
- Mean weight at study initiation: 349 g (males); 229 g (females)
- 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, ad libitum except during exposure to the test substance.
- 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: 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
- 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
- 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:
9 mg/L (nominal concentration)
5.3 ± 0.5 mg/L (mean actual concentration)
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. 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 occurred during the study period.
Clinical signs:
other: No clinical signs of toxicity were observed up to the end of the observation period.
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:
Necropsy and histopathological examination revealed no substance-related findings.

The inhalatory 4-h LC50value 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 an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

There are no data available the toxicity to reproduction of Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4). In order to fulfil the standard information requirements set out in Annex X, 8.7, 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 and/or common chemical precursors or similar hydrolysis/breakdown products (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 and/or common chemical precursors or similar hydrolysis/breakdown products.

The read-across is either based structural similarity or on the metabolism of Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4), in particular on the fact that the substance undergoes enzymatic ester hydrolysis resulting in the formation of Fatty acids, C18-unsatd., dimers and 2-ethylhexanol. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of acute toxicity

CAS

Chemical name

Molecular weight

Acute toxicity – oral

Acute toxicity – inhalation

Acute toxicity – dermal

68334-05-4 (a)

Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters

673.12

RA: CAS 104-76-7

RA: CAS 61788-89-4

RA: CAS 173832-46-7

Experimental result:
LC50 > 5.3 mg/L air

--

61788-89-4

Fatty acids, C18-

unsatd., dimers

560.89

Experimental result:
LD50>5000 mg/kg bw

--

--

104-76-7 (b)

2-ethylhexanol

130.23

Secondary source: LD50>2000 mg/kg bw

--

--

173832-46-7

Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters

973.62
1085.84
1184.02

Experimental result:
LD50>2000 mg/kg bw

--

--

(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 structural similarity and common chemical precursors and common hydrolysis/breakdown products. The available endpoint information is used to predict the same endpoints for Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Acute toxicity - oral

CAS 61788-89-4

The acute oral toxicity of Fatty acids, C18 unsatd., dimers was studied in 5 male and 5 female Wistar rats according to OECD guideline 401 and under the requirements of GLP (Thouin, 1986). The animals received the test substance at a limit dose of 5000 mg/kg bw/day via oral gavage. No animals died and no clinical signs were observed up to the end of the 14-day observation period. The body weight gain was considered to be similar to that expected of normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals.

Based on these results, the oral LD50 value for Fatty acids, C18 unsatd., dimers was > 2000 mg/kg bw.

CAS 173832-46-7

The acute oral toxicity of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters was studied in 3 male and 3 female Wistar rats according to the acute toxic class method (OECD guideline 423) and under the requirements of GLP (Pels Rijcken, 1997). In two sequential steps, each 3 animals (step 1: males; step 2: females) received the test substance at a limit dose of 2000 mg/kg bw/day via oral gavage. During both treatment steps, no animals died and no clinical signs were observed up to the end of the 14-day observation period. The body weight gain was considered to be similar to that expected of normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals.

Based on these results, the oral LD50 value for Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters was > 2000 mg/kg bw. In accordance with OECD guideline 423, the oral LD50 cut-off of the test substance may be considered to be > 5000 mg/kg bw.

CAS 104-76-7

Secondary source data reported a LD50 >2000 mg/kg bw in rats and mice (Rowe and McCollister, 1982). No further details are available.

Acute toxicity - inhalation

CAS 68334-05-4

The acute inhalation toxicity of Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters was investigated in a GLP-compliant study according to the acute toxic class method described in OECD guideline 436 (Huygevoort, 2010). One group of 3 Crl:WI(Han) rats per sex were exposed to an analytical atmosphere concentration of the test aerosol of 5.3 mg/L (5300 mg/m³) for 4 h using a nose only exposure system. No mortality and no clinical signs of toxicity were observed up to the end of the 14-day observation period. The body weight gain in males and females was within the range expected for rats of this strain. Gross pathology and histopathological examination did not reveal any substance-related changes.

Based on these results, the LC50 value for Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters was > 5.3 mg/L (5300 mg/m³).

 

Acute toxicity - dermal

No studies are available for the dermal route of exposure. Overall, the calculated low dermal absorption potential, the low water solubility, the molecular weight (>100), and the fact that the substance is not irritating to skin implies that dermal uptake of Fatty acids, C18 unsatd., dimers, 2-ethylhexyl esters in humans is considered as very limited. Studies on the acute oral and inhalation toxicity are available. With respect to the animal welfare, the conduct of an acute dermal toxicity study would be scientifically unjustified.

Conclusions for acute toxicity

For acute inhalation toxicity, one study is available for the target substance Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters showing a LC50 value greater than 5.3 mg/L air of the test aerosol. Acute oral toxicity studies performed with a structural analogue and the hydrolysis products resulted in LD50>2000 mg/kg bw. Taking into account the MW (above 500), the high log Pow value (> 10) and poor water solubility (<1 mg/L) the dermal absorption rate for Fatty acids, C18 unsatd., dimers, 2-ethylhexyl esters is expected to be low, thus acute dermal toxicity is not anticipated.

Therefore, the available data indicate a very low level of acute toxicity for Fatty acids, C18 unsatd., dimers, 2-ethylhexyl esters and thus no hazard for acute oral, inhalative and dermal toxicity was identified.


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 (refer to the endpoint discussion for further details).

Justification for selection of acute toxicity – inhalation endpoint
There is only one study available.

Justification for classification or non-classification

Based on read-across from structurally similar substances and hydrolysis products, the available data on acute oral and inhalation 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. No data are available for acute dermal toxicity.