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Description of key information

GPMT, Not sensitising (Read Across, OECD406, WoE, Rel2)


QSAR, Not sensitising (TIMES prediction)


Not sensitising in humans up to 10% (HRIPT)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation, other
Remarks:
QSAR
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
27 November 2015
Reliability:
2 (reliable with restrictions)
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
Remarks:
Regulatory accepted model for assessment of chemical substances. The substance falls inside the applicability domain of the model.
Justification for type of information:
QSAR prediction
Qualifier:
according to guideline
Guideline:
other: REACH guidance on QSARs and grouping of chemical, R6, May 2008
Deviations:
not applicable
Principles of method if other than guideline:
TIMES (TIssue MEtabolism Simulator) model for Skin sensitization (TIMES-SS model) - Skin sensitization with autoxidation v.21.25
GLP compliance:
no
Remarks:
(not applicable)
Parameter:
other: OASIS TIMES v. 2.27.16 prediction
Vehicle controls validity:
not applicable
Negative controls validity:
not applicable
Positive controls validity:
not applicable
Remarks on result:
positive indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation alert

Predicted value (model result): Non sensitiser 

Concomitant predictions:

Vapour pressure, Pa = 19

AmountAduct/mol/ = 0.0000

Applicability domain (OECD Principle 3):

a. Domain:

i. Parameter domain: Log(Kow): range = [ -13.2 .. 15.4 ]

calculated: 3.02 (In domain)

MOL._WEIGHT:

range = [30 .. 738]Da

calculated: 154 Da (In domain)

Conclusion: The chemical fulfils the general properties requirements

ii. 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

iii. Mechanistic domain:

Interpolation space

Domain result: N/A

b. Structural analogues: Analogue chemicals found in the training set

c. Considerations on structural analogues: No additional comments on structural analogues are provided by the author of prediction

 

The uncertainty of the prediction (OECD principle 4):

Comments on the uncertainty are not provided by the author of prediction

 

The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5):

Comments on the mechanistic interpretation of the model prediction are not provided by the author of prediction
Interpretation of results:
GHS criteria not met
Conclusions:
OASIS TIMES evaluation showed no skin sensitisation alert. The substance falls inside the applicability domain of the model.
Executive summary:

OASIS TIMES v. 2.27.17 software was used to predict the skin sensitisation of the substance. No structural alert was identified for skin sensitisation. The substance falls inside the applicability domain of the model.

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:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Further information is included as attachment to Iuclid section 13]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across approach is based on the hypothesis that the source and target substances have similar physico-chemical, toxicological, ecotoxicological and environmental fate properties because of their structural similarity.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target and the source substances (Table 1) are 1,2-branched pentyl cyclopentane. The source substance is an alcool, while the target substance is a ketone. The source substance is the secondary alcohol formed by metabolism of the Target substance and its trans isomer. The substance-specific data did not indicate any differences in reactivity between cis- and trans- isomers of 1,2-branched pentyl cyclopentane.

3. ANALOGUE APPROACH JUSTIFICATION
Based on structural similarity and comparable physicochemical and toxicological properties (especially similar acute dermal toxicity profile), the source and the target substances are expected to have similar skin sensitisation profile.
This hypothesis is supported by the QSAR predictions for Skin sensitisation using OASIS TIMES (See Table 3), that predicted the substance as a "non-sensitiser" (Rel. 2), the prediction falls within the applicability domain of the model.. To strengthen the conclusion on this endpoint, a read-across to the source substance was used.
The study performed on the source substance (OECD 406, GLP) is adequate and reliable for the purpose of the prediction based on read-across. The test material used represents the source substance as described in the hypothesis in terms of purity and impurities. The results of the studies are adequate for the purpose of classification and labelling.
Therefore, based on the considerations above, it can be concluded that the results of the skin sensitisation study conducted with the source substance are likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirement of Annex VII, 8.7.2.

4. DATA MATRIX
See Iuclid section 13
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Positive control results:
8 out 10 in the test group gave positive response to 50 % Hexyl cinnamic aldehyde resulting in a response incidence of 80 %. None of the animals in the test group exhibited positive response to acetone alone. None of the animals in the control group responded positively to 50% hexyl cinnamic aldehyde or acetone alone. These results confirm that hexyl cinnamic aldehyde is a sensitizer under the conditions of this study and the test system is therefore considered to be validated.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
50%
No. with + reactions:
8
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100 %
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
1 animal was killed in extremis on the day of patch removal following topical induction and was found to have a prolapsed uterus following a post-mortem examination
Remarks on result:
other:
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100 %. No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: 1 animal was killed in extremis on the day of patch removal following topical induction and was found to have a prolapsed uterus following a post-mortem examination.
Reading:
2nd reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100 %
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100 %. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100 %
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100 %. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0 %
No. with + reactions:
0
Total no. in group:
9
Clinical observations:
one control animal was found dead in its cage prior to the challenge application. No abnormalities were detected following a post-mortem examination
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0 %. No with. + reactions: 0.0. Total no. in groups: 9.0. Clinical observations: one control animal was found dead in its cage prior to the challenge application. No abnormalities were detected following a post-mortem examination.

none

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the source substance, the target substance is not classified as a skin sensitizer according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and of the Directive 67/548/EEC
Executive summary:

In a dermal sensitization study performed according to the OECD test guideline no. 406 and in compliance with GLP, the source substance was tested in female Hartley guinea-pigs using the Guinea-Pig Maximisation Test method (20 treated animals + 10 controls).


The preliminary study determined the concentration to be used for the induction and challenge phases of the main study.


 


The test material, diluted in light liquid paraffin at 5% (v/v), was administered by injection for intradermal induction. As the substance was not a skin irritant, 24 hours prior to the topical application, the site was pre-treated with 10% w/w sodium lauryl sulphate in light liquid paraffin. Topical induction was performed with the test material as supplied, 7 days after intradermal injections. For the challenge, 21 days after study initiation, the test material was tested undiluted.


 


One test animal was killed in extremis on the day of patch removal following topical induction and was found to have a prolapsed uterus following a post-mortem examination.


Following challenge, none of the remaining 19 test animals responded positively at the 24 or 48 hour observations, resulting in a response incidence of 0 %. Similarly, none of the 19 animals responded positively to challenge with the vehicle.


 


One control animal was found dead in its cage prior to the challenge application. No abnormalities were detected following a post-mortem examination.


None of the remaining 9 control animals responded positively to challenge with either undiluted test article or the vehicle (diethylphtalate), at any of the observations, resulting in a response incidence of 0 %.


 


The historical positive control, hexyl cinnamic aldehyde, produced evidence of skin sensitization in 8 of 10 animals at 50 %, resulting in a response incidence of 80 %. These results confirmed that hexyl cinnamic aldehyde is a sensitizer under the conditions of this study and the test system was therefore considered to be validated.


 


Under the test conditions, the source substance is not classified as a skin sensitizer.


Based on the source substance, the target substance is not classified as a skin sensitizer according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and of the Directive 67/548/EEC


This study is considered as acceptable and satisfies the requirement for sensitisation endpoint.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
From August 23 to September 29, 1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP study conducted according to OECD test Guideline No. 406 without any deviation. The study was fully reliable (Klimisch score = 1), however the reliability score was lowered to 2 which is the maximum score for read-across. The supporting substance is considered adequate for read-across purpose (see IUCLID section 13 for additional justification).
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Test was conducted before establishment of LLNA method
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: D. Hall, Darley Oaks, Burton-on-Trent, Staffordshire, England.
- Age at study initiation: young
- Weight at study initiation: 250-300 g
- Housing: in groups of up to 5 in stainless steel grid bottomed cages.
- Diet (e.g. ad libitum): pelleted diet ad libitum (SQC FD1 guinea pig diet with added vitamin C produced by Special Diets Services, Witham, Essex).
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days for the animals used for the preliminary study and 18 days for those selected for the main tests.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 40-69 %
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: no data
Route:
intradermal and epicutaneous
Vehicle:
other: light liquid paraffin for intradermal induction
Concentration / amount:
- Intradermal induction: 5%
-Topical induction: 100 %
- Challenge: 100 %
Route:
epicutaneous, occlusive
Vehicle:
other: light liquid paraffin for intradermal induction
Concentration / amount:
- Intradermal induction: 5%
-Topical induction: 100 %
- Challenge: 100 %
No. of animals per dose:
5 preliminary test animals, 20 test animals, 10 control animals
Details on study design:
RANGE FINDING TESTS:
- Intradermal injections: 0.1 mL aliquot of 50%, 25%, 10%, 5%, 1% and 0.5% v/v concentrations in light liquid paraffin. 1 guinea-pig pretreated 7 d before with 4 intradermal injections of 1:1 FCA/water. The highest concentration which produced an acceptable localised response at each injection site was 5%.
- Topical induction and challenge: 100%, 50%, 25% and 12.5% v/v in diethylphtalate. 4 guinea-pigs pretreated with FCA/water as described above. Undiluted test article was found to be non-irritant when applied topically and was therefore selected for the topical induction phase and the challenge phase of the main study.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2, intradermal injections and topical application
- Exposure period: 48h for topical application
- Test groups:
INTRADERMAL: 3 pairs of intradermal injection (0.1 mL) on Day 0 as follows:
- 1/ 50% v/v FCA/distilled water
- 2/ test substance 5% in light liquid paraffin
- 3/ test substance 5% in 50:50 distilled water/FCA
Six days after the intradermal induction, as the undiluted test material was non-irritant, the test area of all animal was treated topically with 10 % sodium lauryl sulphate in light liquid paraffin in order to produce irritation.
TOPICAL: 7 days after intradermal injections, the test substance (100%) was applied (patches of Whatman No. 3 filter paper, 4cm x 2cm) and covered with a strip of "Blenderm" surgical tape secured in place and wrapped with "Elastoplast" elastic adhesive bandage (occlusive tape).
- Control group: similarly treated with the exception that the diethylphtalate was topically applied instead of the test substance
- Site: clipped dorsal area between the shoulders

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 14 d after the topical induction application, i.e. 21 d after study initiation
- Exposure period: 24 hours
- Test and control groups: 100% on the anterior aspect of the left flank. Similarly treated than topical induction (patches 2cm x 2 cm). Right flanks were treated with vehicle alone (diethylphtalate):
- Site: flanks
- Concentrations: 100%
- Evaluation (hr after challenge): approximately 24 and 48 hours after patch removal.
Challenge controls:
Hexyl cinnamic aldehyde was used as a positive control as this is known to be a sensitizer. The material was administered as a 25 % concentration in light liquid paraffin for the intradermal injections and a 50 % concentration in ethanol for the topical induction (after 10% SLS application). Challenge was conducted at concentrations of 50% in acetone. This positive control study took place during the period from 1995-02-22 to 1995-03-18
Positive control substance(s):
yes
Remarks:
Hexyl cinnamic aldehyde
Positive control results:
8 out 10 in the test group gave positive response to 50 % Hexyl cinnamic aldehyde resulting in a response incidence of 80 %. None of the animals in the test group exhibited positive response to acetone alone. None of the animals in the control group responded positively to 50% hexyl cinnamic aldehyde or acetone alone. These results confirm that hexyl cinnamic aldehyde is a sensitizer under the conditions of this study and the test system is therefore considered to be validated.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
50%
No. with + reactions:
8
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100 %
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
1 animal was killed in extremis on the day of patch removal following topical induction and was found to have a prolapsed uterus following a post-mortem examination
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100 %. No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: 1 animal was killed in extremis on the day of patch removal following topical induction and was found to have a prolapsed uterus following a post-mortem examination.
Reading:
2nd reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100 %
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100 %. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100 %
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100 %. No with. + reactions: 0.0. Total no. in groups: 19.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0 %
No. with + reactions:
0
Total no. in group:
9
Clinical observations:
one control animal was found dead in its cage prior to the challenge application. No abnormalities were detected following a post-mortem examination
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0 %. No with. + reactions: 0.0. Total no. in groups: 9.0. Clinical observations: one control animal was found dead in its cage prior to the challenge application. No abnormalities were detected following a post-mortem examination.

none

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the test material is not classified as a skin sensitizer according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and of the Directive 67/548/EEC
Executive summary:

In a dermal sensitization study performed according to the OECD test guideline no. 406 and in compliance with GLP, the test material was tested in female Hartley guinea-pigs using the Guinea-Pig Maximisation Test method (20 treated animals + 10 controls).

The preliminary study determined the concentration to be used for the induction and challenge phases of the main study.

 

The test material, diluted in light liquid paraffin at 5% (v/v), was administered by injection for intradermal induction. As the substance was not a skin irritant, 24 hours prior to the topical application, the site was pre-treated with 10% w/w sodium lauryl sulphate in light liquid paraffin. Topical induction was performed with the test material as supplied, 7 days after intradermal injections. For the challenge, 21 days after study initiation, the test material was tested undiluted.

 

One test animal was killed in extremis on the day of patch removal following topical induction and was found to have a prolapsed uterus following a post-mortem examination.

Following challenge, none of the remaining 19 test animals responded positively at the 24 or 48 hour observations, resulting in a response incidence of 0 %. Similarly, none of the 19 animals responded positively to challenge with the vehicle.

 

One control animal was found dead in its cage prior to the challenge application. No abnormalities were detected following a post-mortem examination.

None of the remaining 9 control animals responded positively to challenge with either undiluted test article or the vehicle (diethylphtalate), at any of the observations, resulting in a response incidence of 0 %.

 

The historical positive control, hexyl cinnamic aldehyde, produced evidence of skin sensitization in 8 of 10 animals at 50 %, resulting in a response incidence of 80 %. These results confirmed that hexyl cinnamic aldehyde is a sensitizer under the conditions of this study and the test system was therefore considered to be validated.

 

Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and of the Directive 67/548/EEC.

This study is considered as acceptable and satisfies the requirement for sensitisation endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Existing human data (HRIPT, Biotoxicology, 1978) concluded that the registered substance has no skin sensitization potential at 10% in White petrolatum. However, the reliability of those data was not considered adequate to meet the REACH requirements and to make a conclusion on classification and labelling.

Therefore, a weight-of evidence approach using the HRIPT result, the GPMT result on the supporting substance (2-pentylcyclopentan-1-ol, see IUCLID section 13 for read-across justification), and a QSAR, which together are considered sufficiently robust to conclude on the skin sensitisation potential of the substance.

The GPMT study on 2-pentylcyclopentan-1-ol (Toxicol, 1995, rel.2) was performed according to the OECD test guideline no. 406 and in compliance with GLP using the Guinea-Pig Maximisation Test method (20 treated animals + 10 controls).

The test material diluted in light liquid paraffin at 5% (v/v) was administered by injection for intradermal induction. As the substance was not a skin irritant, 24 hours prior to the topical application, the site was pre-treated with 10% w/w sodium lauryl sulphate in light liquid paraffin. Topical induction was performed with the test material as supplied, 7 days after intradermal injections. For the challenge, 21 days after study initiation, the test material was tested undiluted.

One test animal was killed in extremis on the day of patch removal following topical induction and was found to have a prolapsed uterus following a post-mortem examination.

Following challenge, none of the remaining 19 test animals responded positively at the 24 or 48 hour observations, resulting in a response incidence of 0 %. Similarly, none of the 19 animals responded positively to challenge with the vehicle.

The historical positive control, hexyl cinnamic aldehyde, produced evidence of skin sensitization in 8 of 10 animals at 50 %, resulting in a response incidence of 80 %. These results confirmed that hexyl cinnamic aldehyde is a sensitizer under the conditions of this study and the test system was therefore considered to be validated.

Under the test conditions, the supporting substance is not a skin sensitizer.

OASIS TIMES prediction is "non-sensitizer" (Rel. 2). The substance falls inside the applicability domain of the model.

Based on the whole data, it can be concluded that the substance is not a skin sensitizer.


Migrated from Short description of key information:
Skin sensitisation: Not sensitising, WoE (GPMT data on a supporting substance, HRIPT, QSAR)

Justification for selection of skin sensitisation endpoint:
No key study was selected since all studies were used within a weight-of-evidence approach.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No 1272/2008.

Self-classification:

Based on the available information, no additional self-classification is proposed according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP.

No information is available regarding respiratory sensitisation.