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Diss Factsheets

Administrative data

Description of key information

Oral (OECD 423), rat: LD50 > 5000 mg/kg bw/day
Inhalation (OECD 436), rat: LC50 > 5.3 mg/mL (based on read-across from CAS 68334-05-4)
Dermal: no study available

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
29 Apr - 13 May 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
(adopted in 1996)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain as cited in study report: Wistar strain Crl:(WI) BR (outbred, SPF-Quality)
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: approx. 8 weeks old
- Mean weight at study initiation: 267 g (males); 177 g (females)
- Fasting period before study: yes (overnight)
- Housing: 3 per cage in polycarbonate cages
- Diet: standard pelleted laboratory animal diet (Carfil Quality BVBA, Out-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): approx. 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Animals were fasted overnight prior to dosing until approx. 3-4 hours after administration of the test substance.
Doses:
2000 mg/kg bw (2.15 mL/kg bw)
(Dose volume calculated as follows: dose level (g/kg) : densitiy (0.93 g/mL))
No. of animals per sex per dose:
- Group 1: 3 males
- Group 2: 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations: daily
- Frequency of weighing: day 1 (pre-administration), day 8 and day 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
No statistical analysis was performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 experimental
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 cut-off according to OECD 423
Mortality:
No mortality occurred.
Clinical signs:
No clinical signs were observed during the study period.
Body weight:
The body weight gain was considered to be similar to that expected of normal untreated animals of the same age and strain.
Mean values (day 1; day 8; day 15):
- Group 1: 267 g; 326 g; 363 g
- Group 2: 177 g; 206 g; 223 g
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
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 VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
23 Apr - 07 May 2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", 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)
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, 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 functional groups, common precursors/breakdown products and similarities in physicochemical, ecotoxicological and toxicological properties (refer to 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

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

There are no data available for the acute inhalation toxicity of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (CAS 173832-46-7). In order 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, 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

173832-46-7 (a)

68334-05-4 (b)

Chemical Name

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

Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (ESIS: NLP)

Molecular weight

973.62
1085.84
1184.02

673.10

Acute toxicity oral

Experimental result:
LD50 > 2000 mg/kg bw

--

Acute toxicity inhalation

RA: CAS 68334-05-4

Experimental result:
LC50 > 5.3 mg/L air

Acute toxicity dermal

Waiving

--

(a) Category members subjected to the REACh  Phase-in registration deadline of 31 May 2013 are indicated in bold font.

Lack of data for a given endpoint is indicated by “--“.

(b) Surrogate substances are indicated in normal font and are precursors/breakdown products of the target substance (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described for the present analogue approach.

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 Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters (CAS 173832-46-7).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Acute toxicity

Oral

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.

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 air (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 air (5300 mg/m³).

Dermal

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., trimers, 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.

Conclusion for acute toxicity

In summary, one study is available investigating the acute oral toxicity of Fatty acids, C18 unsatd., trimers, 2-ethylhexyl esters resulting in an oral LD50 value greater than 5000 mg/kg bw. For acute inhalation toxicity, one study is available for the surrogate substance Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters showing a LC50 value greater than 5.3 mg/L air of the test aerosol. 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., trimers, 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., trimers, 2-ethylhexyl esters and thus no hazard for acute oral, inhalative and dermal toxicity was identified.


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

Justification for selection of acute toxicity – inhalation endpoint
Hazard assessment is conducted by means of read-across from a structural surrogate. 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 selection of acute toxicity – dermal endpoint
According to REGULATION (EC) No 1907/2006, Annex VIII, Section 8.5.3, Column 2, testing by the dermal route is appropriate if: the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin. 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., trimers, 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.

Justification for classification or non-classification

Based on the results of the target and the surrogate substance, the available data on acute oral, inhalation and dermal 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.

There are no data available on acute dermal toxicity.