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Administrative data

Description of key information

Veilex 2 using information from CP Acetate and apply read across results in non skin sensitisation.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Study initiated: end fo March 1981 and reporting 30th April
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Currently no LLNA study is available for assessment. The Guinea Pig Maximization Test (GPMT) has been carried out as an animal test to predict human sensitization for over a decade and is recommended by international test guidelines such as OECD.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
Animals were housed in suspended cages with wire mesh floors, with free access to tap water and Vitamin C-enriched Guiney-pig Diet Standard F.D.I. No 803189W. Hay was given once a week.
Animal room temperature was 21oC and the air exchange was maintained at 15 air changes/hour
Lighting was controlled using a 12 hour light/dark cycle.
Route:
intradermal and epicutaneous
Vehicle:
paraffin oil
Concentration / amount:
Intradermal injection were in 1% v/v liquid paraffin
Route:
epicutaneous, occlusive
Vehicle:
paraffin oil
Concentration / amount:
Intradermal injection were in 1% v/v liquid paraffin
No. of animals per dose:
15 test animals and 15 control animals
Details on study design:
A 4x6 cm area of dorsal skin on the scapular region of the guiney-pig was clipped free of hair with electric clippers. Three pairs of intradermal injections were made simulataneously into this area. Injections were as follows: 1) Freund's complete adjuvant was diluted with an equal volume of water for injection; 2) Cyclocitronellene acetate 10% v/v in liquid paraffin and; 3) Cyclocitronellene 10% in a 50:50 mixture of Freund's adjuvant and liquid paraffin.
Topical application One week after the injections, the same 4x6 cm interscapular area was clipped and shaved free of hair. A 2x4 cm patch of Whatmen No 3 mm paper was saturated with cyclocitronellene acetate as supplied (100%). The patch was placed on the skin and covered by a length of impermeable plastic adhesive tape (5 cm width 'Blenderm'). This in turn was firmly secured by elastic adhesive bandage ('Elastoplast' of 5 cm width) wound around the torso of the animal and fixed with 'Sleek" impervious plastic adhesive tape. The dressing was left in place for 4h hours.
The control animals were treated similarly but with the exception that the test compound was omitted from the intradermal injection and the topical application.
Challenge controls:
Challenge applications were applied 2 weeks after last exposure using 20 and 10% in liquid paraffin. The challenge sites were evaluated 24, 48 and 72 hours after removal of the patches
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.2 mL and 20%
No. with + reactions:
3
Total no. in group:
14
Clinical observations:
Localised dermal reaction (restricted to a small area)
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0.2 mL and 20%. No with. + reactions: 3.0. Total no. in groups: 14.0. Clinical observations: Localised dermal reaction (restricted to a small area).
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.2 mL and 20%
No. with + reactions:
4
Total no. in group:
14
Clinical observations:
Localised dermal reaction (restricted to a small area)
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.2 mL and 20%. No with. + reactions: 4.0. Total no. in groups: 14.0. Clinical observations: Localised dermal reaction (restricted to a small area).
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
0. 2 ml and 20%
No. with + reactions:
2
Total no. in group:
14
Clinical observations:
dryness and sloughing of the epidermis
Remarks on result:
other: Reading: other: 3rd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 0. 2 ml and 20%. No with. + reactions: 2.0. Total no. in groups: 14.0. Clinical observations: dryness and sloughing of the epidermis.
Key result
Reading:
other: Overall result of the test
Hours after challenge:
24
Group:
test chemical
Dose level:
20%
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0.2 ml and 20%
No. with + reactions:
4
Total no. in group:
14
Clinical observations:
Localised dermal reaction (restricted to a small area)
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0.2 ml and 20%. No with. + reactions: 4.0. Total no. in groups: 14.0. Clinical observations: Localised dermal reaction (restricted to a small area).
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.2 ml and 20%
No. with + reactions:
3
Total no. in group:
14
Clinical observations:
Localised dermal reaction (restricted to a small area)
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.2 ml and 20%. No with. + reactions: 3.0. Total no. in groups: 14.0. Clinical observations: Localised dermal reaction (restricted to a small area).
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
negative control
Dose level:
0.2 ml and 20%
No. with + reactions:
3
Total no. in group:
14
Clinical observations:
Localised dermal reaction (restricted to a small area) and one animal showed dryness and sloughing of the epidermis
Remarks on result:
other: see Remark
Remarks:
Reading: other: 3rd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 0.2 ml and 20%. No with. + reactions: 3.0. Total no. in groups: 14.0. Clinical observations: Localised dermal reaction (restricted to a small area) and one animal showed dryness and sloughing of the epidermis.

Animals

Skin reaction

Scores

 

 

 

 

 

Result

Scoring after (hours

Challenge concentrations

 

24

10%

24h

20%

48

10

48

20

72

10

72

20

 

Controls

 

7/14

4/14

6/14

3/14

5/14

3/14

-

Test animals

Reaction*

4/14

3/14

5/14

3/14

5/14

0/14

-

*Skin reaction mainly consisted of localised dermal reactions (restriction to small area of the challenge site) and are therefore not considered skin sensitisation reactions.

Interpretation of results:
other: not sensitising
Remarks:
according to CLP and its amendments (EC 1272/2008)
Conclusions:
Under the results of this study the test substance is not sensitising
Executive summary:

In a Maximisation test (OECD TG 406), with intradermal concentrations of 10% and challenge concentrations of 10 and 20% the skin sensitisation of the substance was investigated. In the test animals and controls localised dermal reactions were seen, which were thought to be related to skin irritation rather than sensitisation because the number and frequency of the findings were similar in the treated groups and the test animals. Therefore the substance is not considered skin sensitising.

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

For Veilex 2 no animal information is available to assess the skin sensitisation potential of the substance. There is some human data which will be used for support. To cover the endpoint GPMT information from CP Acetate will be used for which also human data are available.

In the summary below first the HRIPT information from Veilex 2 is presented followed with information from CP acetate. Thereafter other supporting information will be presented and finally the read across justification.

Veilex 2 HRIPT

In a repeated insult patch test the neat test substance was applied to 52 subjects in a series of 15 alternate day applications, each of 24 hours duration. Two weeks after the 15th application, the subjects were patched with a challenge application of the test material. Under these conditions, the material did not produce any visible skin changes characteristic of primary irritation or sensitization. Skin changes signifying reaction to injury were observed in one subject patched with the test substance during applications 2 through 15. Based on these results, the test substance is not considered a primary irritant or sensitizing agent, but would be considered a very mild fatiguing agent.

CP acetate Key Source GPMT

In a Maximisation test (OECD TG 406), with intradermal concentrations of 10% and challenge concentrations of 10 and 20% the skin sensitisation of the substance was investigated. In the test animals and controls localised dermal reactions were seen, which were thought to be related to skin irritation rather than sensitisation because the number and frequency of the findings were similar in the treated groups and the test animals. Therefore the substance is not considered skin sensitising.

CP Acetate Supporting source HRIPT

In a repeated insult patch test 25%, 0.4 mL test substance was applied directly to a Webril swatch patch by means of a calibrated dropper. The test patches were applied to the upper arms of 44 panelists. The patch was removed after twenty-four hours. After nine applications, the participants were challenged. For the final challenge application duplicate patches were applied, one to the original site and one to a skin site which had not previously received any patches. The test material did not produce any visible skin changes consistent with those deemed characteristic of a primary irritant or sensitizer.

Veilex 1 Supporting source HRIPT

In a repeated insult patch test the neat test substance was applied directly to an occluded patch, which was applied to a predesignated site, covered, and sealed with overlapping strips of Blenderm tape. This cover was kept intact for twenty-four hours, the seal was broken and the patch removed. The skin sites were examined and gross changes, if present, were graded on a scale of 1 to 4. Absence of any visible skin changes was assigned a 0 value. After the patch was removed, the skin sites were rested for twenty-four hours. This cycle was repeated in this manner on Mondays, Wednesdays, and Fridays. On weekends, a forty-eight-hour rest period was permitted between removal and re-application of the test material. After the fifteenth application, the participants were rested for two weeks before being challenged. The test material was applied to the same sites under occlusion for twenty-four hours. At the end of twenty-four hours, the skin sites were examined immediately and following at intervals of twenty-four and forty-eight hours. The test material did not produce any visible skin changes consistent with those deemed characteristic of a primary irritant or sensitizer. It did produce visible skin changes consistent with those of a fatiguing agent in 10 out of 50 individuals.

The skin sensitization of Veilex#2 (CAS#13487-27-9) using read across from substance CP Acetate (CAS#25225-10-9) and Veilex#1 (CAS#63449-88-7)

Introduction and hypothesis for the analogue approach

Veilex#2 has acyclohexylethyl backbonewith anacetate estergroup attached. For this substance there are not sufficient data available regarding skin sensitization. In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests, i. e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the sensitizing potential of Veilex#2 the analogue approach is selected because for one closely related analogue, CP Acetate sensitization information is available which can be used for read across. Furthermore, there is supporting information available of a second analogue, Veilex#1.

Hypothesis: Veilex#2 has similar sensitization potential compared to CP Acetate as thetwo methyl groups attached to the meta-position of the cyclohexylethyl backbone in CP Acetate are not expected to influence the sensitization potential.

Available information: The target chemical Veilex#2 is tested undiluted in a Human Repeated Insult Patch Test (HRIPT) and the test receives a reliability of 4, due to limitation in documentation. The source chemical CP Acetate has been tested in a well conducted Guinea Pig Maximisation Test (similar to OECD TG 406) and receives a reliability of 2. Furthermore CP Acetate is tested at 25% in a HRIPT and this test receives a reliability of 2 as well. In addition, another HRIPT for a second source chemical, Veilex#1 is available in which the undiluted substance has been tested. The result receives a reliability of 2.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemicals are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for sensitization, of all substances.

Purity / Impurities

Veilex#2 is a mono-constituent with a purity close to 100%. There are no impurities affecting skin sensitization which are not covered by CP Acetate.

Analogue approach justification

According to Annex XI 1.5 read across can be used to replace testing when the similarity can be based on a common backbone and a common functional group.

CP Acetate is selected from a number of cyclic acetates which is the most similar in structure (ECHA guidance, 2015, RAAF). Based on the current experimental information cyclohexyl-acetates are considered non-sensitisers (e.g. Belsito et al. 2008). 

Structural similarities and differences:Veilex#2 as well as the structural analogues have a common cyclohexylethyl backbone. CP Acetate, has two methyl groups attached to the meta-position of the cyclohexylethyl backbone, while Veilex#2 and Veilex#1 do not have additional substituents. An acetate ester is attached to the cyclohexylethyl backbone of Veilex#2 and CP Acetate, while Veilex#1 has a butyrate ester attached.These differences between the target and source chemicals are not expected influence significantly the sensitising potential of thesechemicals.

Toxico-kinetic similarities and differences:

Absorption:Veilex#2, CP Acetate and Veilex#1 have similar molecular weight and physico-chemical properties indicating similar absorption characteristics. All are liquids, the molecular weight (170.3 - 198.3 g/mol)and log Kow (Ca. 3.2 – 3.8) indicate that Veilex#2 and its source chemicals will be dermally absorbed to some extent.

Metabolism:Although metabolism is of lesser importance for local effects compared to systemic effects some local metabolism in the skin by carboxyl -esterases can occur. It can be anticipated that Veilex#2 will metabolise to acetic acid (CAS#64-19-7) and 1-cyclohexylethanol (CAS#1193-81-3) while CP Acetate will metabolise to 1-(3,3-dimethylcyclohexyl)ethanol (CAS#25225-09-6) and acetic acid. Finally, it is anticipated that Veilex#1 will metabolise to butanoic acid (CAS#107-92-6) and 1-cyclohexylethanol

 

Fig. 1. The metabolisation pathway of Veilex#1 and Veilex#2 and CP Acetate.

 

Similarities in results for toxicological endpoints between the target and the source chemical(s)

The most relevant is the similarities between the local skin effects of the target and source chemicals since skin sensitization is a local effect. Veilex#2, Veilex#1 and CP Acetate are not classified and labelled for skin irritation.

Uncertainty of the prediction:There is no remaining uncertainty, in view of similarities in structure, toxico-kinetic profile (absorption and metabolism) and reactivity profile between the substances. For skin sensitization two main causes for induction are known. Skin sensitization is caused by covalent binding between the negatively charged skin proteins and the positively charged carbon-atom in the molecular structure due to adjacent electrophilic substructures such as oxygen atoms. This covalent binding between these two is the onset of an immunological reaction as presented in ECHA’s R.7.3.4.1. This onset can also be caused by radicals. Radical formation may be caused by hydroperoxides and peroxides: R-O-OH bonds or R1-O-O-R2 bonds, respectively. For Veilex#2 and its source chemicals the carbon-ester would be the potential site for attack for proteins in the skin. Due to the limitedly positively charged carbon of this ester, the proteins will not bind (sufficiently) to cause an immunological reaction. This is because of the absence of additional electrophilic activating groups on the alpha or beta position of the ester e.g. no halogens and no double or triple bonds.

There are no structural alerts regarding sensitization for the target chemical, source chemicals and their metabolites (Toxtree V2.6.13 and OECD toolbox V3.3.0.132). Therefore the sensitization data of both CP Acetate and Veilex#1 can be used for read across to Veilex#2.Therefore, read across can be applied. In accordance with ECHA guidance (2015, RAAF) a quality score of 5 can be assigned.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data Matrix at the end of this document.

Conclusions for hazard assessment and classification and labelling:

When using read across the result should be applicable for hazard assessment and classification and labelling and presented with reliable and adequate documentation.

For Veilex #2 no experimental skin sensitization data are available. The analogue CP Acetate is not skin sensitizing in a GPMT (OECD TG 406) test. In view of the close similarity between Veilex#2 and CP Acetate and the documentation above it is shown that Veilex #2 is not a skin sensitizer either.

Final conclusion on hazard and C&L:Veilex#2 is not skin sensitizing substance. Classification and labelling is not needed for this endpoint according to CLP Regulation (EC) No. 1272/2008 and its updates.

Data matrix for the read across to Veilex#2, Veilex#1, and CP Acetate

Common names

Veilex#2

CP Acetate

Veilex#1 (CP Butyrate)

Chemical structures

 

Target

Key source

Support source

CAS no

13487-27-9

25225-10-9

63449-88-7

Registration information

REACH 2018 registration

Not registered

Not registered

Empirical formula

C10H18O2

C12H22O2

C12H22O2

Physico-chemical data

 

 

 

Molecular weight

170.25

198.304

198.304

Physical state

liquid

liquid

liquid

Melting point,oC

< -20

13.46

< -20

Boiling point,oC

215.7

>204

246.5

Vapour pressure, Pa

38.5 at 24 °C

6.7

6.5 at 24 °C

Water solubility, mg/L

43 at 24 °C

7.462

23.8 at 24 °C

Log Kow

3.2 at 25 °C

4.42

5.2 at 20 °C

Human health endpoints

 

 

 

Skin irritation

No irritation (IFF, 1977

No irritation (IFF, 1983)

No irritation OECD TG 404 (IFF, 1977)

Skin sensitisation

Read across from CP Acetate and Veilex#1

 

 

No sensitization HRIPT (52 subjects) (concentration 100%)(IFF, 1977)

Not a sensitizer in a Maximisation test (IFF/BBA, 1981)

 

No sensitization HRIPT (concentration 25% and 44 number of subjects)

Read across from CP Acetate and Veilex#2

 

 

No sensitization HRIPT (concentration 100% and 50 number of subjects) (IFF, 1976)

 

References

Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.M., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H., RIFM Expert Panel, 2008, A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients, Food and Chem. Toxicol., 46, S1-27.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

In view of the negative result obtained with read across substance CP acetate in the maximisation study and supported by the negative results obtained with HRIPT studies with the test substance and read across substance Veilex 1, the substance does not need to be classified for skin sensitisationaccording to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.