Registration Dossier

Administrative data

Description of key information

Skin corrosion: Not corrosive based on absence of acid and based groups indicating corrosion. In a HRIPT test up to 75% no corrosion and no irritation was seen. Absence of skin corrosion is further supported in the in vitro skin irritation test where the substance is borderline irritant/non-irritant:

- Skin (OECD TG 439): irritating  (borderline irritant/non irritant)

- Eye (QSAR): not irritating

- Respiratory irritation: Based on absence of human data and absence of other data indicating such an effect.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

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

Respiratory irritation

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

Additional information

Skin corrosion:

Not corrosive based on absence of acid and based groups indicating corrosion. The functional ketone group is not very reactive in absence of adjacent (beta position) electrophilic groups such as halogens, oxygens and/or double bonds. Absence of skin corrosion is further supported in the in vitro skin irritation test where the substance is borderline irritant/non-irritant. Also in a HRIPT study no corrosion was found up to 75%.

Skin irritation

In vitro skin irritation according to OECD TG 439: The key study was an in vitro skin irritation study that was performed in accordance with OECD TG 431 (EPISKIN). The key study indicated that OTNE is irritating to the skin, based on a mean tissue viability of <50% (48%). The key study was performed as a repeat of a supporting in vitro skin irritation study, in which a mean tissue viability of 55% was measured, which would lead to non-classification. As the tissue viability was a borderline result in the range 45 -55% a conservative approach is applied and the substance is considered a skin irritant.

Skin irritation: Human patch test

Another supporting study is a human skin irritation patch test. In this occlusive patch test, 0.3 ml OTNE in 3:1 diethyl phthalate:ethanol or 3:1 ethanol:diethyl phthalate at concentrations of 20, 40, 60, and 75% was applied to the backs of male and female subjects for two 24-hour periods over a 96-hour study period. Sites were assessed approximately 48 hours after each treatment period. Under these conditions, OTNE elicited negligible dermal irritation potential in humans.

In vivo skin irritation in a 90 -day repeated dose dermal toxicity studies: Skin irritation observed in subchronic (90 -day) dermal toxicity studies performed in rats and mice are included in the present section. Solutions of OTNE in ethanol were applied to the skin of rat and mice for 5 days per week for 3 months, without occlusion. 10 rodents were tested in each dose group. Doses were 6.25%, 12.5%, 25% and 50% OTNE in ethanol and 100% OTNE, on approx. 10% of body surface area.

In rats these doses correspond approximately to 31.25 to 500 mg/kg bw in rats. In all male and female rats (except in 62.5 mg/kg bw/day OTNE males) the incidences of minimal to mild hyperplasia and hyperkeratosis at the site of application were significantly greater than those in their respective control groups. Therefore the NOEC in rats is 6.25%.

In mice these dosed correspond to 125 to 2.000 mg/kg bw. All exposure groups developed skin hyperkeratosis, hyperplasia, chronic active inflammation, fibrosis, epidermal suppurative inflammation, and hair follicle hyperplasia. No corrosion was observed but a clear NOAEC in mice is not found. The LOEC is 6.25%.

Both rats and mice were dermally exposed to OTNE in ethanol without occlusion of the treated site. Therefore, the local effects observed as a result of dermal exposure may have been confounded, as grooming by the animals can have influenced the skin effects, actual dermal dose and/or dermal exposure time. The effects seen may be an under or over-estimation of repeated dose skin irritation. As a result of these methodological limitations, the derivation of a dose descriptor (NOAEC or LOAEC) for local effects via the dermal exposure route is deemed inappropriate. Nevertheless, the skin irritant effects reported in this study are considered to support the conclusion for the skin irritation endpoint.

Eye irritation

The key information available for the eye irritating potential of OTNE was adequate QSAR. The model of AP Worth and MTD Cronin as published in Journal of Molecular Structure (TheoChem) 622 (2003) 97-111 ("The use of discriminant analysis, logistic regression and classification tree analysis in the development of classification models for human health effects") was used to predict the irritating potential of OTNE based on its molecular weight and structural analogues.

The substance has a MW of 234 g/mol, which is higher than the model's threshold value (137 g/mol) for prediction of eye irritation. Additionally, two structural analogues (2,6-dimethyl-4-heptanone, 6,10,14-trimethyl-2-pentadecanone) of OTNE are classified as not irritating to the eyes.

Based on the predicted values in the model, the substance does not need to be classified as irritant (molecular weight higher than threshold value and non-irritating property of structural analogues).

Tabulated summary on the QSAR prediction, the (Q)SAR methodology and the relevance for REACH:

 

Reliability of prediction

Scientific validity of

 method

Relevance for REACH C&L

Defined Endpoint

QSAR based on OECD TG 405 information and DSD criteria

QSAR based on OECD TG 405 information and DSD criteria

REACH requires information similar to OECD TG 405

The algorithm

Prediction according to algorithm: OTNE has MW of 234, which is much > 137 and therefore not an eye irritant

Liquid organic substances with MW >137 are not eye irritants

(Q)SARs are allowed methodology when used according to Annex XI

Applicability domain

OTNE is within the domain, considering i) being a liquid; ii) MW range used in the model and; iii) other cyclic ketons are present in the training set

See substances in training set, cyclic ketons are included

Eye irritation hazards for OTNE has to be assessed under REACH

Uncertainty

Limited, because OTNE does not have additional groups which may lead to higher eye irritation e.g. higher electrophilicity

Limited uncertainty, see paper of Worth and Cronin, 2000

The uncertainty of the result is limited, because the QSAR is based on OECD TG 405. In addition OTNE is within the domain

Mode of action explanation

OTNE has insufficient reactive properties to cause eye irritation or corrosion

Not explained, but liquids with MW > 137 are expected to limitedly penetrate the eye barriers

The QSAR result of OTNE covers the mode of actions in OECD TG 405 because the training set is based on this type of tests

Klimisch code

1

Sufficiently valid

Sufficiently relevant

Translation into

Not an eye irritant according to DSD and therefore also not CLP

Uses DSD criteria: CLP criteria are very similar to DSD

Result is based on DSD criteria which are very similar to CLP

Actual use into DSD and CLP

Not an eye irritant

Adequacy

Sufficiently adequate, no further information needed

Respiratory irritation

For respiratory irritation mostly human data are used for the assessment because no suitable in vitro or in vivo tests are available that can identify respiratory irritation (REACH guidance R.7.2.12). There are no human data such as indicated in R7.2.12 the ECHA guidance that indicate respiratory reactions of the substance e.g. from consumer experience or occupational exposure. Also in view of the borderline skin irritation potential, the substance is not corrosive or severely irritating which further minimizes the respiratory irritation hazard (ECHA guidance: R.7.2.12.1, 2017).

Justification for classification or non-classification

Based on the available information OTNE needs to be classified as a skin irritant (Skin Irrit. Cat 2) according to EU CLP (EC 1272/2008 and its updates): H315 and the phrase -Causes skin irritation-, needs to be assigned.

Based on the available information the substance does not need classified for eye and respiratory irritation, according to EU CLP (EC 1272/2008 and its updates).