Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane

Endpoint summary

Description of key information

Oral (EU Method B.1), rat: LD50 > 2000 mg/kg bw
Inhalation (OECD 403), rat: LC50 > 5.3 mg/L air (based on read-across from 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:

experimental study

Adequacy of study:

key study

Study period:

24 Jul - 16 Aug 2012

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)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

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:

yes

Species:

rat

Strain:

other: Wistar (RccHanTM: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: 146-166 g (first group) and 157-163 g (second group)
- Fasting period before study: animals were fasted overnight immediately before the day of dosing and for approx. 3 to 4 h after dosing.
- Housing: animals were housed in groups of 3 in suspended solid-floor polypropylene cages furnished with woodflakes and environmental enrichment items.
- Diet: 2014C Teklad Global Diet (Harlan Laboratories UK Ltd., Oxon, UK), ad libitum
- Water: drinking water, ad libitum
- Acclimation period: at least 5 days

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

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 2.18 mL/kg

CLASS METHOD
- Rationale for the selection of the starting dose: based on available information on the toxicity of the test item, 2000 mg/kg bw was chosen as the starting dose.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 per group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed for mortalities and overt signs of toxicity 30 min, 1, 2 and 4 h after dosing and subsequently once daily during the 14-day observation period.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

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 mortalities were observed during the study period.

Clinical signs:

other: No signs of systemic toxicity were noted during the 14-day observation period.

Gross pathology:

At gross pathology, no abnormalities were found.

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 1) and consistent studies, 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 similar functional groups and similar precursors/breakdown products (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., dimers, mixed esters with oleic acid and trimethylolpropane (CAS 147256-33-5). 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	147256-33-5 (a)	68334-05-4 (b)
Chemical Name	Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane	Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (ESIS: NLP)
MW	624.97 1115.78 1606.58 677.05; 1219.92; 1762.80	673.10
Acute toxicity oral	Experimental result: LD50 > 2000 mg/kg bw	--
Acute toxicity inhalation	RA: CAS 68334-05-4	LC50 > 5.3 mg/L air
Acute toxicity dermal	Waiving	--

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

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 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, mixed esters with oleic acid and trimethylolpropane (CAS 147256-33-5).

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

 

Acute toxicity

Oral

CAS 147256-33-5

The acute toxicity via the oral route of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane has been investigated in two studies in rats (CAS 147256-33-5).

A GLP-conform acute oral toxicity study with Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane was performed in female Wistar (RccHanTM:WIST) rats according to the acute toxic class method described in OECD guideline 423 (Sanders, 2012). In two sequential steps, the undiluted test substance was administered to the each 3 animals at a dose level of 2000 mg/kg bw (limit test) via oral gavage. In both treatment steps, no mortalities and no clinical signs of toxicity were observed up to the end of the 14-day study period. All animals showed the expected gains in body weight and no abnormalities were observed at necropsy. Based on these results, the experimental oral LD50 in rats was greater than 2000 mg/kg bw. According to OECD guideline 423, an oral LD50 cut-off greater than 5000 mg/kg bw was derived.

In a further study, the acute oral toxicity of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane was investigated in Wistar rats according to EU Method B.1 and in compliance with GLP (Potokar, 1989). The test substance in vehicle (arachis oil) was administered by oral gavage to groups of 5 animals per sex at a limit dose of 2000 mg/kg bw. No mortalities and no clinical signs were observed up to the end of the 14-day observation period. Body weights were not affected by treatment with the test substance. Gross pathology revealed a filled bladder in 2 males and hydrometra (left) in 1 female. However, these findings were not related to treatment. Based on the results, the oral LD50 value for male and female rats was greater than 2000 mg/kg bw.

In summary, the oral LD50 of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane was greater than 2000 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 assumed to be greater than 5.3 mg/L air (5300 mg/m³).

Dermal

This information is not available.

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., dimers, mixed esters with oleic acid and trimethylolpropane 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, two studies are available addressing the acute oral toxicity of Fatty acids C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane (CAS 147256-33-5) resulting in an oral LD50 > 2000 mg/kg bw. For acute inhalation toxicity, one study is available with the analogue substance Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4), showing an LC50 value greater than 5.3 mg/L air. Taking into account the MW (above 500), the high log Pow value (>5.7) and the poor water solubility (< 1 mg/L) dermal absorption rate is expected to be very low, thus acute dermal toxicity is not anticipated.

Therefore, the available data indicate no hazard for acute oral, dermal and inhalation toxicity of Fatty acids C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane.

Justification for classification or non-classification

Based on the results of the target and structurally similar substances, 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.