Registration Dossier

Administrative data

Description of key information

Skin Irritation:
1,3 propanediol dicaprylate is assessed to be non-irritant by weight-of-evidence assessment based both on read-across and the EPISKIN in-vitro model.
Eye Irritation:
Propanediol dicaprylate is assessed to be non-irritant by weight-of-evidence based HETCAM and SIRC in-vitro models and read-across. No animal testing needs to be performed to confirm that assessment.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin Irritation Assessment:

The structure of 1,3 propanediol dicaprylate was assessed by the skin irritation rules published by the German Federal Institute for Risk Assessment (BfR) (Saliner, 2007) and that are part of Toxmatch (Version 1.05) (Gallegos-Saliner, 2008) and the OECD toolbox (Version 1.1, 2008). To support the weight-of-evidence approach, the registrant provided a study report on skin irritation for the structurally related substance 1,2-propanediol, diester with C8-C10 fatty acids as well as an EPSKIN in-vitro study.

At its 26th meeting, held on 26-27 April 2007, the ECVAM Scientific Advisory Committee (ESAC) made the following statement on the validity of in vitro tests for skin irritation: "The EPISKIN method is considered to be a reliable and relevant stand-alone test for predicting rabbit skin irritation, when the endpoint is evaluated by MTT reduction, and for being used as a replacement for the Draize skin irritation test (OECD 404, method B.4 of Annex V to Directive 67/548/EEC) for the purposes of distinguishing between R38 skin irritating and non-skin irritating substances."

Accordingly, the EPISKIN model is recommended in the guidance on information requirements and chemical safety assessment (Chapter R.7a) issued by the European Chemicals Agency (ECHA) in May 2008. Specifically, it is considered valid for the prediction of irritant and non-irritant chemicals for Annex VII (1 - 10 tpa). At the moment, it has not yet been finally endorsed as a stand-alone replacement for the animal study (OECD 404), but it may serve as part of a weight-of-evidence statement as indicated in Annex XI of the REACH legislation.

 

a) Prediction of the irritating properties of 1,3 propanediol dicaprylate applying Toxmatch was not successful, because the outcome of the prediction was "Unknown".

 

b) Prediction based on read-across

Study on skin irritation in rabbits with Diester C8-C10 of propylene glycol (EViC-CEBA, 1985)

The study was performed using six white rabbits. In the report, very limited details are given regarding the procedure; OECD guideline 404 is given as a reference, but the 24h-application time, the observation time points, occlusive wrapping and the testing of both intact and damaged skin is inconsistent with the OECD guideline. The skin was investigated after the application and on day 3. No oedema were observed. Grade 1 erythema was observed in two of six animals after removal of the patch. On day 3, the skin condition did not improve in one and got worse the other one of the two animals. A third animal showed a grade 1 erythema.

 

This test design is a lot more stringent than the OECD 404 guideline, which requires semi-occlusive application for 4 hours only. It shows that the propylene glycol diester is not a severe irritant. Healing of the skin was only assessed until the third day after the beginning of the treatment whereas for hazard classification reversibility within 14 or 21 days is relevant. Therefore this study can only be used as part of the weight-of-evidence approach.

 

c) Prediction based on in-vitro study

In-vitro study with reconstituted human epidermis (EpiSkinTM model) with propanediol dicaprylate (BIO-HC, 2008)

The in-vitro study was performed with the substance as identified on the first page and under GLP. The viability of the human reconstituted epidermis samples was not affected by treatment with propanediol dicaprylate as assessed by the MTT assay. Specifically, the viability of the treated culture was 102% compared to the solvent control cultures. Treatment with the positive control reduced the viability to 12%.

 

It is concluded that there is sufficient data for a weight-of-evidence assessment for skin irritation of 1,3 propanediol dicaprylate and that no animal testing (OECD 404) is necessary. 1,3 propanediol dicaprylate is not irritant to skin and no hazard classification regarding skin irritation is required.

Eye Irritation Assessment:

Read-across:

Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS# 68583-51-7 referred as source substance) is proposed as structural analogues for the target substance 1,3-propanediol dioctanoate (CAS# 56519-71-2). Both substances are diesters with propanediol (1,3-propanediol or 1,2-propanediol) of similar molecular size, containing the same functional groups. Due to the lack of human health data on eye irritation by 1,3-propanediol dioctanoate, an eye irritation study with source substance is suggested to be used for closing the respective data gap in the target substance dossier. Similarities in structure and physico-chemical properties are supposed to form a basis for the analogue approach. 

Eye irritation by propanediol dicaprylate is assessed by using the results of a GLP study performed according to OECD guideline 405 with the structural analogue Propylene glycol dicaprylate/dicaprate (Kästner, 1988). Each of the four male rabbits received a single instillation of 0.1 mL Propylene glycol dicaprylate/dicaprate into one eye without washing, while the untreated eye served as control. The eyes were graded 1, 6, 24, 48 and 72 h after instillation. No effects on cornea and iris as well as no chemosis was observed during the observation period. Only mild conjunctival redness was noted in 2 animals, but these effects disappeared within 24 h. Based on the observations, the mean scores for cornea, iris, conjunctivae and chemosis were all found to be 0, respectively. Thus, propylene glycol dicaprylate/dicaprate can be regarded as not irritating.

The only structural differences between the target and source chemicals are that the propanediol moiety in the source substance is 1,2-propanediol, whereas in the target sucbtance it is 1,3-propanediol. One hydrocarbon chain of the source substance is two CH2 – groups longer compared to the length in target substance (C10 instead of C8). Although these features account for differences in PC-parameters , e.g. melting point, both substances are liquids at ambient conditions. They are non-volatile substances of similar density, boiling at temperatures exceeding 300 °C. The logarithmic partition coefficients are >7 and water solubilities are below 0.1 mg/L. With the help of OECD QSAR Toolbox v2.2 it can be determined, whether inclusion and exclusion rules are fulfilled for the target substance as well as for the source substance (experimentally non-irritating). Inclusion rules are based on structural alerts and exclusion rules are based on physico-chemical parameters. Both sets of rules are referred to as BfR Inclusion/Exclusion Rules, because they were developed at or in cooperation with German Federal Institute for Risk Assessment (BfR - Bundesinstitut für Risikobewertung). The two substances have the same profiles with respect to BfR Inclusion and Exclusion Rules. It is the water solubility rule from the latter set that accounts for a non-irritant character of both substances. Thus, read across is justified for this endpoint because of similarity in structure, PC parameters and rule-based profiles of target substance and source substance and no eye irritation by propanediol dicaprylate is expected.

 

Additionally, the following information is taken from the material safety datasheet of Cognis GmbH (SDS no. 63629, revised September 4, 2002): A fatty acid ester of propylene glycol termed Myritol PC PH was examined via the rabbit study for eye irritation (OECD 405) and found to be slightly irritating to eyes and not to require a hazard classification. The validity of information given on the material safety datasheets cannot be assessed.

 

To support the weight-of-evidence approach, the registrant provided a report on two in vitro eye irritation studies performed with propanediol dicaprylate.

 

At its 26th meeting, held on 26-27 April 2007, the ECVAM Scientific Advisory Committee (ESAC) recommended that further work on the HETCAM test should be performed before this test can be validated. Nevertheless, it was recommended that a substance identified as an irritant in the HETCAM test should be classified as a severe eye irritant (R41).

 

Accordingly, the in-vitro models are recommended solely as part of a weight-of-evidence argument in the guidance on information requirements and chemical safety assessment (Chapter R.7a) issued by the European Chemicals Agency (ECHA) in May 2008.

 

Public databases were searched for information regarding structurally related products.

 

In-vitro studies:

a)            HET-CAM test (BIO-HC, 2008)

The study was performed under GLP. Sodium lauryl sulphate was used as positive control and confirmed the validity of the study. No haemorrhages and no coagulation was observed. Hyperaemia of with a score of 1 was recorded for one of the four chorio-allantoic membranes. Therefore the overall score is 0.25 which shows that the test item is practically non-irritant. The overall score for the positive control was 12.0

b)           CFIO - test (BIO-HC, 2008)

The study was performed under GLP: The assay determines the cytotoxicity of a test item to a permanent cell line of rabbit cornea fibroblast cells (SIRC). Cells were grown on a porous membrane and then put in another vessel coated with the test item for 0.5, 1 and 4 hours. Damage to the cornea fibroblasts was assessed via the MTT assay. Compared to the control incubation, the viability was 96%, 92% and 100% after 0.5, 1 and 4 hours, respectively. Exposure to sodium lauryl sulphate resulted in a viability of 12% after 0.5 hours. The overall cytotoxicity index (IMC-c) was calculated to be 2.6 which means that the test item is in the most harmless of the four categories of this test and is considered to be non irritant to eyes.

This test was not investigated by ECVAM. It only addresses toxicity to cornea cells whereas the in vivo study also requires assessment of effects to iris and conjunctivae.

 

Other properties:

Propanediol dicaprylate was shown to be non irritant in the EPISKIN assay (BIO-HC, 2008) and is predicted to be of low acute oral and dermal toxicity based on experimental data of the metabolites caprylic acid and 1,3-propanediol. There are no physical or chemical properties that indicate that it is irritating to eyes. In contrast, Propanediol dicaprylate is structurally related to triacylglycerols which are dietary fats. For dietary fats, no animal studies for eye irritation were found, but practical experience has proven them to be non irritant.

 

It is concluded that there is sufficient data for a weight-of-evidence assessment for eye irritation of propanediol dicaprylate. Propanediol dicaprylate is not irritant to eyes and no hazard classification regarding eye irritation is required.

 

Justification for classification or non-classification

Skin Irritation:

It is concluded that there is sufficient data for a weight-of-evidence assessment for skin irritation of 1,3 propanediol dicaprylate and that 1,3 propanediol dicaprylate is not irritant to skin and no hazard classification regarding skin irritation is required.

 

Eye Irritation:

It is concluded that there is sufficient data for a weight-of-evidence assessment for eye irritation of propanediol dicaprylate and that propanediol dicaprylate is not irritant to eyes and no hazard classification regarding eye irritation is required.