Butyl ricinoleate

Endpoint summary

Description of key information

The substance and its analogues are not irritating to skin and eye

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Remarks:

Acute dermal toxicity protocol

Adequacy of study:

key study

Study period:

2007

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: OECD 402, Acute Dermal Toxicity

Principles of method if other than guideline:

Relevant data are obtained on the endpoint in studies of acute dermal toxicity and skin sensitisation

GLP compliance:

not specified

Remarks:

not specified in publication

Species:

rabbit

Strain:

not specified

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

5000 mg/kg bw. Considering a density of 0.9326 and average weight of a test rabbit of 2 kg, a dose of approximately equivalent to 2.7 ml was applied to the torso of the animals

Duration of treatment / exposure:

Not specified

Observation period:

Not specified

Number of animals:

6

Details on study design:

not specified

Irritation parameter:

other: qualitative assessment

Remarks:

visual examination

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

no indication of irritation

Remarks:

no skin irritation effects noted among the other pathologies described in report

Irritant / corrosive response data:

In an acute dermal toxicity study with 6 rabbits with occlusive exposure for 24 h, 1 animal died and necropsy results were described. No mention was made of skin irritation.

Interpretation of results:

GHS criteria not met

Conclusions:

An acute dermal toxicity study in rabbits was informative for the endpoint of skin irritation. Animals exposed to the analogue test substance under an aggressive protocol failed to show notable skin irritation. This data suggests that, like other structural analogues, the target (registered) test substance is not a skin irritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage)

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Vertellus, Lot# 0000143574
- Expiration date of the lot/batch: 2018 March 21

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature, closed container, in a dry, well ventilated location
- Stability under test conditions: assumed to be stable

Species:

cattle

Strain:

not specified

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Local slaughterhouse, e.g. A. Moksel AG, Buchloe, Germany.

ENVIRONMENTAL CONDITIONS : room temperature, closed container, in a dry, well ventilated location

The tissue surrounding the eyeball was carefully pulled away and the cornea was excised leaving a 2 to 3 mm rim of sclera. The isolated corneas were stored in a petri dish containing HBSS. Before mounting the corneas in corneal holders (BASF, Duratec) with the endothelial side against the O-ring of the posterior chamber, they were visually examined for defects and any defective cornea were discarded. The anterior chamber was then positioned on top of the cornea and tightened with screws. The chambers of the corneal holder were then filled with RPMI (without phenol red) containing 1% FBS and 2 mM L-glutamine (complete RPMI). The posterior chamber was always be filled first. The corneas were incubated for one hour at 32 ± 1 °C.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent positive control

yes, concurrent negative control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 750 µL

Duration of treatment / exposure:

10 min

Duration of post- treatment incubation (in vitro):

2 hr

Number of animals or in vitro replicates:

3

Details on study design:

SELECTION AND PREPARATION OF CORNEAS : The assay used isolated corneas obtained as a by-product from animals freshly slaughtered at an abattoir, e.g. A. Moksel AG, Buchloe, Germany.

QUALITY CHECK OF THE ISOLATED CORNEAS : The eyes were carefully examined for defects and any defective eyes will be discarded.

NUMBER OF REPLICATES : 3

NEGATIVE CONTROL USED : Physiological saline 0.9% NaCl

SOLVENT CONTROL USED (if applicable) : N/A

POSITIVE CONTROL USED : 100% Ethanol

APPLICATION DOSE AND EXPOSURE TIME : 750 µL, 10 min

TREATMENT METHOD: Closed chamber

POST-INCUBATION PERIOD: Yes, 2 hr

REMOVAL OF TEST SUBSTANCE
- Number of washing steps after exposure period: 3
- POST-EXPOSURE INCUBATION: Yes, 2 hr

METHODS FOR MEASURED ENDPOINTS:
- Corneal opacity: BASF-OP3.0, Duratec
- Corneal permeability: passage of sodium fluorescein dye measured with the aid of UV/VIS spectrophotometry (OD490) , Jenway 6405
- Others (e.g, pertinent visual observations, histopathology): Each cornea was observed visually and pertinent observations were recorded.

SCORING SYSTEM: In Vitro Irritancy Score (IVIS)

DECISION CRITERIA: Opacity is determined using a manufacturer-specific formula, using illuminance through a holder without cornea and illuminance through a holder with cornea as independent variables. Change in opacity between treated and untreated samples is determined, and the irritation potential of the test substance is evaluated based upon the following conditions:
≤ 3: No Category
> 3; ≤ 55: No prediction can be made
> 55: Category 1

Irritation parameter:

in vitro irritation score

Run / experiment:

mean

Value:

1.1

Negative controls validity:

valid

Positive controls validity:

valid

Irritation parameter:

cornea opacity score

Run / experiment:

mean

Value:

0.91

Negative controls validity:

valid

Positive controls validity:

valid

Irritation parameter:

other: permeability score

Run / experiment:

mean

Value:

0.013

Negative controls validity:

valid

Positive controls validity:

valid

Other effects / acceptance of results:

OTHER EFFECTS:
- Visible damage on test system: None

DEMONSTRATION OF TECHNICAL PROFICIENCY:

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: Yes
- Acceptance criteria met for positive control: Yes
- Range of historical values if different from the ones specified in the test guideline: N/A

Interpretation of results:

GHS criteria not met

Conclusions:

The test substance was evaluated for potential to cause eye irritation using an ex vivo BCOP assay according to OECD guideline 437. An in vitro irritation score of 1.10 was calculated based on corneal opacity and permeability following treatment of the ex vivo eye model with the test substance. The test substance did not meet GHS criteria for classification of eye irritation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Experimental data are lacking on a guideline skin irritation test of butyl ricinolate. As an ester of ricinoleic acid, the primary fatty acid of castor oil, the substance is not considered a skin irritant in experimental or clinical settings. Dermaleffects (sensitisation and irritation) were not observed for an analogue, methyl ricinoleate (Manciaux, 1999) or ethyl ricinoleate (clinical studies, Johnson, 2007). No local irritation was demonstrated for the methyl ester of 12-hydroxystearic acid in skin and eye irritation testing (Gross, 2018). The Cosmetic Ingredient Review Expert Panel (CIR) concluded that castor oil derived esters are not irritating (Johnson, 2007). 

Using the structure of the IATA for skin irritation (ECHA, 2016), the follow analysis is obtained:

1. There are no physico-chemical properties of butyl ricinoleate which are associated with skin irritation.

2. There are existing human clinical data on a structural analogue, ethyl ricinoleate, which shows no skin irritation under 48-hour occlusive patches (Johnson, 2007). The overall assessment on a category of structurally related ricinoleate compounds is that the category members overall are not skin irritants for exposures from intentionally applied consumer products (Johnson, 2007). There are clinical case reports of the acid itself resulting in skin irritation; these are evaluated by the Expert Panel of toxicologists and clinicians of the CIR; these data have not changed the panel’s conclusion that the category members are non-irritants. Sato et al., 1996, showed that the esters of C8-C18 carboxylic acids are essentially nonirritating in comparison with the activity of a series of carboxylic acids, alcohols and aldehydes. The findings of patch testing as well as nitrocellulose-replica analysis of the local skin anatomy revealed that C8-C12 carboxylic acids were the most irritating of the series, whereas C16-C18 showed no irritation. The acids were relatively more irritating than alcohols and aldehydes, but esters of all chain lengths were nonirritating.

3. In experimental studies in rabbits, ethyl ricinoleate showed no skin irritation in an acute dermal toxicity study (Johnson, 2007). Methyl ricinoleate showed no skin irritation in an epicutaneous sensitisation study (Manciaux, 1999).  Another structural analogue, the methyl ester of 12-hydroxystearic acid, showed no dermal irritation in an OECD 492in vitroreconstructed skin model (Gross, 2018). These data are supportive of the position of the CIR that ricinoleate esters are not skin irritants. In experimental research experience, Patzelt et al., 2011, documented the failure of oils (fatty acid glyceryl esters) to penetrate into the stratum corneum.  Mack-Correa and colleagues, 2013, using trans-epidermal water loss (TEWL) and various microscopic techniques, documented the lack of percutaneous absorption of glyceryl trioleate whereas the corresponding acid, oleic acid, was measured quantitatively in the dermis, and was associated with interruption of the normal lipid structure of the skin.

4. Structure-activity relationship modeling was not undertaken, as there are few models which have been validated for prediction of this outcome.

5. As there is no indication of skin irritation as a result of dermal exposure, the possibility of skin corrosion from exposure is not entertained.

The result of this integrated evaluation of the existing data on butyl ricinoleate analogues and category members is that the esters of ricinoleate have adequate data indicating that butyl ricinoleate is not a skin irritant.

References:

ECHA, 2016. Information Requirement and the Chemical Safety Report, Endpoint specific Guidance, Chapter R.7a, v.5.0, December.

Gross, C. 2018. Test Report, Eurofins Biopharma, Munich, Germany, 22 March. 2018.

Johnson, W., Jr. 2007. Int. J. Toxicol. 26 (Suppl 3):31-77.

Mack-Correa, M.C., Mao, G., Saad, P., et al., 2014. Exper. Dermatol. 23: 39-44

Patzelt, A., Lademann, J., Richter, H., et al., 2012. Skin Research Technol. 18: 364-369.

Sato A., Obata, K., Ikeda, Y. 1996. Contact Dermatitis, 34:12-16.

Justification for classification or non-classification

The substance does not meet the criteria for classification as a skin or eye irritant, according to Regulation EC No. 1272/2008.