Isobutyl laurate

Endpoint summary

Description of key information

Oral (WoE): LD50 (OECD 401), rat >2000 mg/kg bw (RA CAS 110-27-0); LD50 (OECD 401), mouse >5000 mg/kg bw (RA CAS 646-13-9)
Inhalation LC50 (OECD 436), rat >5.3 mg/L air (RA CAS 10233-13-3)
Dermal LD50 (OECD 402), rat >2000 mg/kg bw (RA CAS 163961-32-8)

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. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in the toxicological profile. Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole 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:

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

Adequacy of study:

key study

Study period:

28 Apr - 12 May 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study, tested with the source substance Isopropyl laurate (CAS 10233-13-3). 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 - 63)
- 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.
- Temperature, humidity, pressure in air chamber: The temperature of the atmosphere was between 20.8 and 21.2 °C and relative humidity was between 23 and 25%. These conditions were considered appropriate for this 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 undiluted.

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The MMAD and GSD were determined twice, MMAD was 4.0 µm (GSD 2.4) and 5.2 µm (GSD 1.9).

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 ± 0.3 mg/L. The nominal concentration was 7.1 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 75%. 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 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 occurred.

Clinical signs:

other: Hunched posture was observed in all animals 1 and 3 hours after exposure. No clinical signs were noted during 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 observed 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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 2 due to read-across) study from a reference substance 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

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Study period:

17 Sep - 01 Oct 2003

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP guideline study with acceptable restrictions (analytical purity of test substance not specified).

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

analytical purity of test substance not specified

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

yes

Remarks:

analytical purity of test substance not specified

GLP compliance:

yes (incl. QA statement)

Remarks:

The Department of Health of the Government of the United Kingdom

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, UK
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: at least 200 g (± 20%)
- Fasting period before study: No
- Housing: individually in solid floor polypropylene cages during treatment and in groups of 5 thereafter
- Diet: ad libitum (Certified Mouse and Rat Diets, Code 5LF2, International Product Supplies Limited, UK)
- 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

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back and flanks
- % coverage: 10
- Type of wrap if used: surgical gauze fixed with self-adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing: cotton wool moisted with distilled water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: 2.26 mL/kg bw
- Constant volume or concentration used: yes

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 4 times on day of treatmentand subsequently once daily
- Necropsy of survivors performed: yes
- Other examinations performed: body weight on days 7 and 14.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortalities observed at the highest dose tested

Mortality:

No mortality occurred during the study period.

Clinical signs:

other: No signs of systemic toxicity and no signs of dermal irritation were observed up to the end of the observation period.

Gross pathology:

Necropsy revealed no substance-related findings.

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 an adequate, reliable (Klimisch score 2 due to read-across) study from a reference substance 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.

Additional information

Justification for grouping of substances and read-across

There are only limited data available on acute toxicity of isobutyl laurate (CAS 37811-72-6). 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 [g/mol]	Acute toxicity Oral	Acute toxicity Inhalation	Acute toxicity Dermal
37811-72-6 (a)	Isobutyl laurate	256.42	WoE: RA: CAS 110-27-0 RA: CAS 646-13-9	RA: CAS 10233-13-3	RA: CAS 163961-32-8
110-27-0 (b)	Isopropyl myristate	270.45	Experimental result: LD50 >2000 mg/kg bw (rat)	--	--
646-13-9 (b)	Isobutyl stearate	340.58	Experimental result: LD50 >5000 mg/kg bw (mouse)	--	--
10233-13-3 (b)	Isopropyl laurate	242.40	Experimental result: LD50 >5000 mg/kg bw (mouse, females)	Experimental result: LC50 >5.3 mg/L air (rat)	--
163961-32-8 (b)	Fatty acids, C16-18 and C18 unsatd. branched and linear, butyl esters	312.53-340.58	Experimental result: LD50 >2000 mg/kg bw (rat)	--	Experimental result: LD50 >2000 mg/kg bw (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 isobutyl laurate (CAS 37811-72-6). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

No data on acute toxicity is available with isobutyl laurate (CAS 37811-72-6). Therefore, read across from the structurally analogue substances isopropyl myristate (CAS 110-27-0), isopropyl stearate (CAS 646-13-9), isopropyl laurate (CAS 10233-13-3) and fatty acids, C16-18 and C18 unsatd. branched and linear, butyl esters (CAS 163961-32-8) was applied.

 

Acute oral toxicity

CAS 110-27-0

A reliable acute oral toxicity study with isopropyl myristate (CAS 110-27-0) is available and was performed according to OECD TG 401 and in compliance with GLP (Reijnders, 1988). In this limit test five fasted Wistar rats of each sex were administered a single dose of 2000 mg/kg bw of the test substance (CAS 110-27-0) via oral gavage. The animals were observed for 14 days after administration. No mortalities occurred and no clinical signs of toxicity were recorded during the entire study period. There were no remarkable changes or differences in body weights during the study period. Gross pathology revealed no abnormalities at necropsy. The acute oral LD50 value for males/females was calculated to be greater than 2000 mg/kg bw.

CAS 646-13-9

A reliable acute oral toxicity study with isobutyl stearate (CAS 646-13-9) is available and was performed according to OECD TG 401 (Dufour, 1993). In this limit test five fasted NMRI mice of each sex were administered a single dose of 5000 mg/kg bw of the test substance (CAS 646-13-9) via oral gavage. The animals were observed for 14 days after administration. No mortalities occurred and no clinical signs of toxicity were recorded during the entire study period. There were no remarkable changes or differences in body weights during the study period. Gross pathology revealed no abnormalities at necropsy. The acute oral LD50 value for males/females was calculated to be greater than 5000 mg/kg bw.

Taken together, the available data on acute oral toxicity from structural analogue substances do not indicate any systemic toxicity. Therefore, according to EU classification criteria, the target substance isobutyl laurate (CAS 37811-72-6) is not to be classified.

 

Acute inhalation toxicity

CAS 10233-13-3

A reliable acute inhalation toxicity study was performed with isopropyl laurate (CAS 10233-13-3) according to OECD TG 436 and in compliance with GLP (van Huygevoort, 2010). In this study following the acute toxic class method three Crl:WI(Han) rats of each sex were exposed to an aerosol with an analytical concentration of 5.3 ± 0.3 mg/L of the test substance (CAS 10233-13-3) for 4 hours 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.

Therefore, according to EU classification criteria, the target substance isobutyl laurate (CAS 37811-72-6) is not to be classified.

 

Acute dermal toxicity

CAS 163961-32-8

A reliable acute dermal toxicity study was performed with fatty acids, C16-18 and C18 unsatd. branched and linear, butyl esters (CAS 163961-32-8) according to OECD TG 402 and in compliance with GLP (Sanders, 2004). In this limit test five Sprague-Dawley rats of each sex were exposed to a single dose of 2000 mg/kg bw of the test substance (CAS 163961-32-8) for 24 h via semi-occlusive dressing and observed for 14 days post-application. No mortalities occurred during the entire study period. No signs of systemic toxicity and no dermal irritation were observed up to the end of the observation period. Body weight gain was normal except for one female which showed a body weight loss in the first week but expected body weight gain during the second week. No abnormalities were detected at necropsy at the end of the 14-day observation period. The acute dermal LD50 value was calculated to be greater than 2000 mg/kg bw.

Therefore, according to EU classification criteria, the target substance isobutyl laurate (CAS 37811-72-6) is not to be classified.

Justification for selection of acute toxicity – oral 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 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 selection of acute toxicity – dermal 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.

References:

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.

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 isobutyl laurate (CAS 37811-72-6), data will be generated from data for 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.