Isobutyl laurate

Endpoint summary

Description of key information

Repeated dose toxicity, oral (OECD 407), rat: NOAEL =1000 mg/kg bw/day (RA CAS 110-27-0)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (limited details on test substance purity, lack of urine analysis, neurology and ophthalmoscopy.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

limited details on test substance purity, no urine analysis, no neurology, no ophthalmoscopy performed

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Zentralinstitut für Versuchstierzucht, Hannover, Germany
- Age at study initiation: no data
- Weight at study initiation: mean ca. 150 g (females); ca. 195 g (males)
- Fasting period before study: no data
- Housing: 2-3 males per cage
- Diet: Altromin rat diet No. 1424 DK, ad libitum
- Water: yes, ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): ca. 50
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/23

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared freshly every day.
Dosing volume was 5 mL/kg bw.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily, 5 days per week

Remarks:

Doses / Concentrations:
100, 500 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for selecting satellite groups:
5 additional animals per sex were for analysis of possible post-exposure reversibility of intoxication symptoms

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: No

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: no data
- How many animals: all
- Parameters checked: Hct, Hb, erythrocyte count, leucocyte count, MCV, thromocyte count, differential leucocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination
- Animals fasted: Yes, ether
- How many animals: all
- Parameters checked: Urea, Sodium, Potassium, Glucose, Calcium, ASAT, ALAT, gamma-Glutamyltransferase, Chloride, total protein, total cholesterol, anorganic phosphorus, AP

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

ORGAN WEIGHTS:
Thyroid gland, thymus, adrenal glands, spleen, heart, kidneys, brain, testes, liver

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all animals
HISTOPATHOLOGY: Yes, ca. 33 organs of 5 male and 5 female animals of the highest dose group and of the control group were analyzed. Additionally all non-glandulary stomachs from all animals - including those of the recovery group 14 days after the last application - were histopathologically analyzed.
Histologically analyzed organs:
Eye, tongue, salivary gland, trachea, lung, Aorta thoracica, heart, maxillary and mesenterial lymph nodes, thymus, liver, spleen, pancreas, kidney, non-glandular stomach, glandular stomach, small and large intestine, urinary bladder, testes, epididymides, seminal vesicle, prostate, uterus, ovaries, thyroid gland, parathyroid gland, cerebellum, brain stem, cerebrum (hippocampus), sceletal muscle, peripher nerv, skin

Statistics:

t-test, U-test.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

not treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No deaths occured and no signs of systemic toxicity were observed in any animals.

BODY WEIGHT AND WEIGHT GAIN
Control and test animals showed similar gain in body weight.

HAEMATOLOGY
No significant treatment-related changes observed.

CLINICAL CHEMISTRY
No significant treatment-related changes observed.

GROSS PATHOLOGY
No treatment related abnormalities observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
Hyperplastic changes were found in the non-glandular stomach of treated and control animals. Manifest mucosal hyperplasia was found in animals of the highest dose group. In few cases the mucosal hyperplasia was found combined with a submucosal inflammatory oedema. In the recovery group these findings were not present in the non-glandular stomach, indicating the reversibility of the changes. The changes were judged to be induced by the olive oil used as vehicle and not by the test substance itself.
Therefore, no treatment-related changes were observed.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects on: clinical signs; mortality; body weight; haematology; clinical chemistry; gross pathology; histopathology.

Critical effects observed:

not specified

Conclusions:

In a 28 day oral gavage study a NOAEL of 1000 mg/kg bw/day was found for male and female Wistar rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) 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. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for grouping of substances and read-across

There are only limited data available on repeated dose toxicity of isobutyl laurate (CAS 37811-72-6). In order to fulfil the standard information requirements set out in Annex VIII, 8.6, 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 repeated dose toxicity

CAS	Chemical name	Molecular weight [g/mol]	Repeated dose toxicity Oral	Repeated dose toxicity Inhalation	Repeated dose toxicity Dermal
37811-72-6 (a)	Isobutyl laurate	256.42	RA: CAS 110-27-0	--	--
110-27-0 (b)	Isopropyl myristate	270.45	Experimental result: NOAEL =1000 mg/kg bw/day (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 substance is 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 repeated dose toxicity is available with isobutyl laurate (CAS 37811-72-6). Therefore, read across from the structurally analogue substance isopropyl myristate (CAS 110-27 -0) was applied.

 

Repeated dose toxicity (oral)

A reliable key repeated dose toxicity study (28-day) with isopropyl myristate (CAS 110-27-0) is available and was performed equivalent or similar to OECD TG 407 (Gloxhuber, 1983). Only limited details on test substance purity are available. Groups of 10 Wistar rats of each sex were administered the test material at doses of 100, 500 and 1000 mg/kg bw/day or vehicle alone (olive oil) via oral gavage for 28 days on 5 consecutive days per week. Five additional animals per sex per dose were included as recovery group for analysis of possible post-exposure reversibility of intoxication symptoms. Urinalysis, neurobehavioural examinations and ophthalmoscopy were not performed. Clinical observations, body weight changes, haematology, clinical chemistry, organ weight measurements as well as gross and histopathological examinations revealed no treatment-related abnormalities or adverse effects. Histopathology revealed hyperplastic changes in the non-glandular stomach of treated and control animals. Manifest mucosal hyperplasia was found in animals of the highest dose group. In few cases the mucosal hyperplasia was found combined with a submucosal inflammatory edema. In the recovery group these findings were not present in the non-glandular stomach, indicating the reversibility of the changes. The changes were judged to be induced by the olive oil used as vehicle and not by the test substance itself.

Therefore, no treatment-related changes were observed. Based on the results of the study and due to the absence of any toxicological relevant adverse effect a subacute NOAEL of 1000 mg/kg bw/day was derived for isopropyl myristate.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from structural analogues. 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 assessment of quality, duration and dose.

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 repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.