2-propylheptan-1-ol

Endpoint summary

Description of key information

QSAR (Times): negative sensitization potential (substance was in domain of the system)

Modified Draize test in guinea pigs (equivalent to OECD 406) with the structural analogue Isodecanole (CAS 25339 -17 -7) : no indication of a sensitizing potential

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to the attached justification in chapter 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Group:

test chemical

No. with + reactions:

0

Remarks on result:

no indication of skin sensitisation

Group:

negative control

No. with + reactions:

0

Remarks on result:

no indication of skin sensitisation

Reference 2

Endpoint:

skin sensitisation: in chemico

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
OASIS TIMES v2.27.19.13

2. MODEL (incl. version number)
Skin sensitization with autoxidation; v. 21.26

3. SMILES IDENTIFIERS USED AS INPUT FOR THE MODEL
CCCCCC(CCC)CO

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: In vivo: skin sensitization
- Unambiguous algorithm: refer to QMRF
- Defined domain of applicability:
1. General parametric requirements - includes ranges of variation of log KOW and MW. It specifies in the domain only those chemicals that fall in the range of variation of the MW and log Kow defined on the bases of the correctly predicted training set chemicals. This layer of the domain is applied only on parent chemicals.
2. Structural domain - it is represented by list of atom - centered fragments extracted from the chemicals in the training set. The training chemicals were split into two subsets: chemicals correctly predicted by the model and incorrectly predicted
chemicals. These two subsets of chemicals were used to extract characteristics determining the "good" and "bad" space of the domain. Extracted characteristics were split into three categories: unique characteristics of correct and incorrect chemicals (presented only in one of the subsets) and fuzzy characteristics presented in both subsets of chemicals. Structural domain is applied on parent chemicals, only.
3. Mechanistic domain - in SS model it includes: Interpolation space: this stage of the applicability domain of the model holds only for chemicals for which an additional COREPA model is required. It estimates the position of the target chemicals in the population density plot built in the parametric space defined by the explanatory variables of the model by making use the training set chemicals. Currently, the accepted threshold of population density is 10%.
The mechanistic domain is applied on the parent structures and on their metabolites.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
External Validation: For substances in the applicability domain, a predictivity of 100% was found for 100 industrial chemicals for the distinction of non-sensitizers versus sensitizers of GHS Category 1. The evaluation has been published in W. Teubner, A. Mehling, P.X. Schuster, K.Guth, B. A. Worth, J. Burton, B. van Rawenzwaay, R. Landsiedel: Computer models versus reality: How well do in silico models currently predict the sensitization potential of a substance, Regulatory Toxicology and Pharmacology 67 (2013) 468-485

Statistics for goodness-of-fit: For 875 chemicals, the TIMES-SS model was able to predict correctly 90% of the strong sensitizers, 55% of the weak sensitizers and 77% of the non-sensitizers, i.e., an overall performance of 78 %. Sensitivity: 78 %, Specificity: 77 %

- Mechanistic interpretation:
The TIMES-SS (Tissue Metabolism Simulator for skin sensitization) model integrates a simulator of skin metabolism together with a number of “local” QSAR models for assessing the reactivity of specific alerts. A skin metabolism simulator was developed based on empirical and theoretical knowledge (not enough reported observed skin metabolism data). The transformation probabilities (defining the priority of their execution) were parameterized to reproduce skin sensitization data. The simulator comprises of about 420 transformations, which can be divided into four main types: abiotic transformations, covalent interaction with proteins, Phase I and Phase II reactions. Autoxidation (AU) of chemical is also accounted for. Interactions with skin proteins are grouped into three types: leading to strong or weak skin
sensitization effect and interactions requiring QSAR models to quantify the potency of sensitization of the alerting groups. The QSAR models were developed by the COmmon PAttern Recognition (COREPA) approach [3]. The skin sensitization model predicts skin sensitization effect in three classes: strong, weak and non-sensitizers.
Reliability of alerts in the TIMES-SS model has been also evaluated to provide transparent mechanistic reasoning for predicting sensitization potential. Alert performance was defined as the ratio between the number of correct (positive and negative) predictions and the total number of chemicals within the local training set that triggered the alert. The alert performance was assessed based on the predictions on parents, autoxidation products simulated by the external AU simulator and metabolites as simulated by the skin metabolism simulator embedded in TIMES-SS model. Four different categories of reliability were defined:
High reliability – alert performance higher than 60% and more than 5 chemical in local (transformation/alert) training set
Low reliability – performance less than 60% and more than 5 chemicals in training set
Undetermined reliability – less than 5 chemicals in training set
Undetermined (theoretical) – there are no chemicals supporting the alert in the local training set

5. APPLICABILITY DOMAIN
- Descriptor domain:
Log(Kow): range = [ -13.2 .. 15.4 ]
calculated: 3.71 (In domain)
MOL._WEIGHT: range = [ 30 .. 738 ]Da
calculated: 158Da (In domain)
--> Conclusion: The chemical fulfils the general properties requirements.

- Structural fragment domain: The following ACF are identified: Fragments in correctly predicted training chemicals – 100.00%, Fragments in non-correctly predicted training chemicals – 0.00%, Fragments not present in the training chemicals – 0.00%
--> Conclusion: The chemical is in the interpolation structural space

- Mechanistic domain: Interpolation space
- Similarity with analogues in the training set: not reported

6. ADEQUACY OF THE RESULT
The substance falls in the applicability domain of the model. The model was found to give reliable predictions for industrial chemicals. It is therefore considered to be acceptable for REACH.

The substance is considered to be non skin seniziting.

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May/July 2008

Principles of method if other than guideline:

TIMES-SS v.2.27.19.13 - Skin sensitization with autoxidation v.21.26 (structure-toxicity and structure-metabolism relationships)

GLP compliance:

no

Key result

Remarks on result:

no indication of skin sensitisation

Interpretation of results:

GHS criteria not met

Conclusions:

The registrant considers this predication as valid because TIMES-SS was validated with 100 substances from the registrant's portfolio (Teubner et al., Regulatory Toxicology and Pharmacology 67 (2013) 468–485). All predictions that fullfilled all domain requirements were correct (Specificity 100%).

The QSAR program calculated a negative sensitization potential of the test substance. The substance is in domain of the system.

Reference 3

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

yes

Remarks:

no adjuvant used; 4 instead of 5 control animals; 4 pairs of intradermal injection used for induction; no induction in control animals performed; only intradermal induction; non-occlusive coverage during topical challenge

GLP compliance:

no

Type of study:

other: modified draize test

Justification for non-LLNA method:

The LLNA method was not established yet by the time the study was conducted.

Species:

guinea pig

Strain:

Hartley

Sex:

male/female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: from own colony (Unilever Research Laboratory, Great Britain)
- Weight at study initiation: about 350 g
- Housing: in pairs of the same sex
- Diet: pelleted guinea pig diet, cabbage, and hay; ad libitum
- Water: ad libitum

Route:

intradermal

Vehicle:

not specified

Concentration / amount:

0.25%; 0.1 ml (at 4 sites)

Day(s)/duration:

once

Adequacy of induction:

highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically

No.:

#1

Route:

intradermal and epicutaneous

Vehicle:

not specified

Concentration / amount:

intradermal challenge concentration: 0.1%; 0.1 ml (one flank)
topical challenge concentration: 10%; 0.1 ml (other flank; non-occlusive coverage)

Day(s)/duration:

14 days after induction; readout 24 h after challenge

Adequacy of challenge:

other: for the intradermal challenge a concentration giving slight but perceptible irritation with no oedema was used; for topical challenge a concentration causing no irritation was selected

No.:

#2

Route:

intradermal and epicutaneous

Vehicle:

not specified

Concentration / amount:

intradermal challenge concentration: 0.1%; 0.1 ml (one flank)
topical challenge concentration: 10%; 0.1 ml (other flank; non-occlusive coverage)

Day(s)/duration:

7 days after 1st challenge in case of a negative result after the first challenge

Adequacy of challenge:

other: for the intradermal challenge a concentration giving slight but perceptible irritation with no oedema was used; for topical challenge a concentration causing no irritation was selected

No. of animals per dose:

10 (4 males, 6 females (or visa versa))

Details on study design:

RANGE FINDING TESTS:
Preliminary irritation test:
- Intradermal injection: Four animals of the same sex and weighing about 450 g were each injected intradermally on the shaved flanks with 0.1 ml aliquots of a range of concentrations of tests material in a suitable solvent. The reactions were examined for size (two largest diameters), erythema and edema 24 h later and the concentration giving slight but perceptible irritation with no edema was selected as the injection challenge concentration (ICC).
- Topical application: Aliquots (0.1 ml) of a range of concentrations of test substance in a suitable solvent were applied in small circular areas to the shaved flanks of 4 guinea pigs of the same sex and weighing about 450 g. The reactions were examined for erythema 24 h later and the highest concentration which caused no irritation was selected as the application challenge concentration (ACC).

MAIN STUDY:

10 guinea pigs were injected intradermally aliquots of 2.5 times the ICC at 4 sites which overlie the 2 auxillary and 2 inguinal lymph nodes. 14 days later each animal was challenged intradermally in one flank and topical in the other with 0.1 ml test substance preparation. The topical application was done by spreading 0.1 ml onto the shaven flank in a small circular area, which was not covered. 24 hours later the reactions were scored and apparent sensitization reactions were confirmed 7 days later by a second challenge with controls included. In the absence of sensitization reactions at first challenge the induction and challenge procedures were repeated, but this time a comfirmatory challenge with controls was included irrespective of any apparent sensitization reactions at the previous challenge.
Reactions were examined under a Philips color-matched unit with 3 Philips 40 W actinic blue 05 fluorescent tubes and 3 Philips 40 W white 35 fluorescent tubes. Each injection reaction was given a total score based on size (2 largest diameters), erythema and edema. Individual reactions were considered positive when their total score was significantly greater than the average total score for control reactions. Application reactions were scored on a 0 to +++ scale and individual reactions were considered positive if (a) they were + or greater and (b) there were no erythema reactions in controls.

Challenge controls:

At the challenge controls were inlcuded. 4 previously untreated animals of the same sex and weight were treated intradermally and topically on opposite flanks with 0.1 ml of the test substance at concentrations of 0.1% for the intradermal challenge and 10% for the topical challenge.

Positive control substance(s):

no

Group:

test chemical

No. with + reactions:

0

Remarks on result:

no indication of skin sensitisation

Group:

negative control

No. with + reactions:

0

Remarks on result:

no indication of skin sensitisation

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

There were no experimental data concerning the sensitisation potential of 2-Propylheptan-1-ol available.

Therefore, a QSAR was conducted using the model "Skin sensitization with autoxidation" of the software OASIS TIMES. The QSAR program calculated a negative sensitization potential of the test substance. This QSAR prediction is considered to be valid, because the substance was in domain of the system.

Furthermore, the prediction is confirmed by a skin sensitisation study in guinea pigs with the structural analogue Isodecanol (CAS 25339-17-7).

In a modified Draize procedure (similar to OECD 406) 10 Hartley strain albino guinea pigs were treated with Isodecanol by intradermal injection to induce a potential sensitisation and challenged 2 weeks later by both intradermal and topical application. No sensitizing potential of the test substance could be determined (Sharp, D.W., 1978).

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available QSAR data and experimental test results with a structural analogue are reliable and suitable for classification purposes under Regulation 1272/2008. The substance is predicted to be not sensitizing. In addition a structural analogue did not show a skin sensitising potential in an experimental study with guinea pigs. As a result the substance is not considered to be classified for skin sensitisation under Regulation (EC) No. 1272/2008, as amended for the thenth time in Regulation (EU) No 2017/776.