Registration Dossier

Administrative data

Description of key information

Skin sensitisation (read across from Etaphen, which is tested in an OECD TG 429): not sensitising

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 September 2003 - 19 January 2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
mouse local lymphnode assay (LLNA)
Test material information:
Composition 1
Species:
mouse
Strain:
CBA/Ca
Remarks:
CBA/Ca/Ola/Hsd
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Harlan Interfauna UK Limited, Blackthorne, Bicester, Oxon, UK. - Age at study initiation: Young adults- Weight at study initiation: No data- Housing: 4 animals/ cage- Diet (e.g. ad libitum): Ad libitum- Water (e.g. ad libitum): Ad libitum- Acclimation period: 5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 22 - Humidity (%): 30-70- Air changes (per hr): minimum of 15- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
other: ethanol/diethylphthalate 1:3
Concentration:
2.5%, 5%, 10%, 25% or 50% (w/v)
No. of animals per dose:
4
Details on study design:
PRE-SCREEN TESTS:Not performed.MAIN STUDY- Clinical observations: All animals were observed at least once daily for signs of systemic toxicity.- Body weights: The body weight of each mouse was recorded on Day 1 (prior to dosing) and Day 6 (prior to termination).ANIMAL ASSIGNMENT AND TREATMENT- Criteria used to consider a positive response: 3-fold or greater increase in dpm as compared to the control group (Stimulation Index > 3)TREATMENT PREPARATION AND ADMINISTRATION:- In accordance with OECD TG 429.
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Statistics:
The EC3 value was derived by interpolating between two points on the Stimulation Index (SI) axis, one immediately above and the other immediately below the SI value of 3. These datapoints have the co-ordinates "a" (concentration at SI immediately above 3), "b" (SI of "a"), c (concentration at SI immediately below 3) and d (the SI of "c"), which are used to calculate the EC3 value by use of the standardfollowing equation: EC3=[(3-d)/(b-d)]x(a-c)+c.
Positive control results:
The application of the positive control item, Hexylcinnamaldehyde, resulted in a more than 3-fold increase in isotope incorporation for all three tested concentrations (SI > 6).
Key result
Parameter:
EC3
Test group / Remarks:
All test groups
Remarks on result:
not determinable
Remarks:
All SI < 3
Parameter:
SI
Value:
1.06
Test group / Remarks:
2.5% (w/v)
Parameter:
SI
Value:
1.01
Test group / Remarks:
5% (w/v)
Parameter:
SI
Value:
0.87
Test group / Remarks:
10% (w/v)
Parameter:
SI
Value:
0.95
Test group / Remarks:
25% (w/v)
Parameter:
SI
Value:
0.84
Test group / Remarks:
50% (w/v)
Cellular proliferation data / Observations:
CELLULAR PROLIFERATION DATAMean DPM at 0 (vehicle), 2.5, 5, 10, 25 and 50% (w/v) were 5432, 5776, 5504, 4709, 5167 and 4536, respectively.DETAILS ON STIMULATION INDEX CALCULATIONThe following SI values were derived at 2.5, 5, 10, 25 and 50% (w/v): 1.06, 1.01, 0.87, 0.95, 0.84. EC3 CALCULATIONThe EC3 value could not be calculated because there were no concentrations tested that resulted in an SI ≥ 3. The EC3 value is therefore expected to be above 50% (w/v).CLINICAL OBSERVATIONS:No clinical signs reported.BODY WEIGHTS:Only raw data reported.
Interpretation of results:
other: Not skin sensitizer
Remarks:
According to EU CLP 1272/2008 and its amendments.
Conclusions:
Under the conditions of this test, Etaphen did not induce a Stimulation Index (SI) above 3 and an EC3 value could not be calculated (>50%). Based on these results, the substance is considered not to be a sensitiser and does not need to be classified for skin sensitisation in accordance with the criteria outlined in Annex I of 1272/2008/EC (CLP) and its amendments.
Executive summary:

The skin sensitisation potential of Etaphen has been tested according to OECD TG 429: Local Lymph Node Assay in mice. At doses of 2.5, 5, 10, 25 and 50% (w/v), the substance induced SI values of 1.06, 1.01, 0.87, 0.95 and 0.84, respectively. The EC3 could not be calculated as there were no concentrations tested that resulted in an SI ≥ 3. Based on these results, the substance is considered not to be a sensitiser and does not need to be classified for skin sensitisation in accordance with the criteria outlined in Annex I of 1272/2008/EC (CLP)

and its amendments

.
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The information is derived from read across
Justification for type of information:
Executive summary. The skin sensitization of Peomosa is assessed by using read across from Etaphen (60-12-8) resulting in absence of skin sensitization for Peomosa.Full details are provided in the study record.Structural similarities and differences: Peomosa and Etaphen both have an aromatic ring to which an ethanol group is attached. The primary alcohol is the functional group. The structural difference between Etaphen and Peomosa is an additional methyl group on the ortho position of the phenyl ring of the latter. This difference will not influence the reactivity of the alcohol functional group because it is too distant. Peomosa and Etaphen have similar water solubility and log Kow values, indicating that these substances will be absorbed by the skin to a similar extent. Toxico-kinetics: The skin absorption is expected to be similar for both substances in view of their similar molecular weights and being liquids. Also their similar physico-chemical properties support a similar absorption. Toxico-dynamics: For skin sensitization the parent substance is generally the key factor. However, in some cases the primary degradation or metabolisation products may cause sensitization. The metabolism processes for both substances are similar. Etaphen will be metabolized/oxidized into its carboxylic acid (phenylacetic acid) and Peomosa will be metabolised analogously (yielding the corresponding ortho-methyl acid), and no significant differences in skin sensitization potential are expected. Remaining uncertainties: There are no remaining uncertainties because Etaphen is a structurally very close analogue to Peomosa, differing only by a methyl group, which does not influence the reactivity.
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Positive control results:
The application of the positive control item, Hexylcinnamaldehyde, resulted in a more than 3-fold increase in isotope incorporation for all three tested concentrations (SI > 6).
Key result
Parameter:
EC3
Test group / Remarks:
All test groups
Remarks on result:
not determinable
Remarks:
All SI < 3
Parameter:
SI
Value:
1.06
Test group / Remarks:
2.5% (w/v)
Parameter:
SI
Value:
1.01
Test group / Remarks:
5% (w/v)
Parameter:
SI
Value:
0.87
Test group / Remarks:
10% (w/v)
Parameter:
SI
Value:
0.95
Test group / Remarks:
25% (w/v)
Parameter:
SI
Value:
0.84
Test group / Remarks:
50% (w/v)
Cellular proliferation data / Observations:
CELLULAR PROLIFERATION DATA
Mean DPM at 0 (vehicle), 2.5, 5, 10, 25 and 50% (w/v) were 5432, 5776, 5504, 4709, 5167 and 4536, respectively.

DETAILS ON STIMULATION INDEX CALCULATION
The following SI values were derived at 2.5, 5, 10, 25 and 50% (w/v): 1.06, 1.01, 0.87, 0.95, 0.84.

EC3 CALCULATION
The EC3 value could not be calculated because there were no concentrations tested that resulted in an SI ≥ 3. The EC3 value is therefore expected to be above 50% (w/v).

CLINICAL OBSERVATIONS
No clinical signs reported.

BODY WEIGHTS
Only raw data reported.
Interpretation of results:
other: Not skin sensitizer
Remarks:
According to EU CLP 1272/2008 and its amendments.
Conclusions:
Under the conditions of this test, Etaphen did not induce a Stimulation Index (SI) above 3 and an EC3 value could not be calculated (>50%). Based on these results, the substance is considered not to be a sensitiser and does not need to be classified for skin sensitisation in accordance with the criteria outlined in Annex I of 1272/2008/EC (CLP) and its amendments. The results for Etaphen are read-across to Peomosa.
Executive summary:

The skin sensitisation potential of the test substance has been tested according to OECD TG 429: Local Lymph Node Assay in mice. This study is used for read-across to Peomosa. At doses of 2.5, 5, 10, 25 and 50% (w/v), the substance induced SI values of 1.06, 1.01, 0.87, 0.95 and 0.84, respectively. The substance was not tested up to 100% because systemic toxicity can be expected: 25 ul on each ear (= 50 mg) on a 20 gram mouse results in 2500 mg/kg bw (50 mg*1000/20), while the LC50 in rats is 1600 mg/kg bw. At all concentrations the SI =<3 and therefore the EC3 value was not met. Based on these results, the substance is considered not to be a sensitiser and does not need to be classified for skin sensitisation in accordance with the criteria outlined in Annex I of 1272/2008/EC (CLP) and its amendments.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
9 May 1990 - 14 June 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reference:
Composition 1
Qualifier:
no guideline followed
Principles of method if other than guideline:
The skin sensitizing potential of the test item was investigated in a human Repeated Insult Patch Test (hRIPT). This method consists of two phases. Phase I is the induction phase where the product is applied to the back of the subject under occlusion. This is done 9 times during the course of 3 weeks. This is followed by 10 to 21 days rest after which the skin is exposed to the product again in Phase II. The skin response seen on the challenge site is then scored at 24 and 48 hours after application.
GLP compliance:
no
Type of study:
patch test
Justification for non-LLNA method:
This hRIPT study is considered a valid method for the assessment of the skin sensitisation potential of the test item.
Test material information:
Composition 1
Species:
other: Human
Strain:
other: Not relevant
Sex:
male/female
Details on test animals and environmental conditions:
TEST SUBJECTS- Age at study initiation: ranging from 20 to 68 years
Route:
epicutaneous, occlusive
Vehicle:
other: Alcohol SD 39C
Concentration / amount:
6.25% test article / 0.2 mL/patch
Day(s)/duration:
9 applications in 3 weeks / 24 hours exposure
Adequacy of induction:
not specified
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: Alcohol SD 39C
Concentration / amount:
6.25% test article / 0.2 mL/patch
Day(s)/duration:
10-21 days after induction / duration not specified
Adequacy of challenge:
not specified
No. of animals per dose:
54 human subjects (5 males and 49 females)
Details on study design:
MAIN STUDY A. INDUCTION EXPOSURE - No. of exposures: 9 - Exposure period: 24 hours - Control group: Not applicable - Site: Back of each subject, between the scapulae and waist, adjacent to the spinal mid-line. - Frequency of applications: 9 application in 3 weeks - Duration: 3 weeks - Concentrations: 6.25% B. CHALLENGE EXPOSURE - No. of exposures: 1 - Day(s) of challenge: 10-21 days after induction (rest period) - Exposure period: No data - Control group: Not applicable - Site: Previously unpatched (virgin) test site - Concentrations: 6.25% - Evaluation (hr after challenge): 24 and 48 hours
Challenge controls:
Not included
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
6.25%
No. with + reactions:
1
Total no. in group:
53
Clinical observations:
1 subject displayed a barely perceptible effect
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
6.25%
No. with + reactions:
0
Total no. in group:
53
Clinical observations:
No clinical signs noted
Remarks on result:
no indication of skin sensitisation

During the induction phase of the study, 3 test subjects experienced barely perceptible and 3 test subjects experiend mild responses. None of these responses were considered to be irritant or allergic in nature. The remaining subjects displayed no effects in the induction phase. One subject discontinued the study in the induction phase due to personal reasons. During the challenge phase only 1 subject displayed a barely perceptible effect (at 24 hours reading). This response was considered to be irritant or allergic in nature.

Interpretation of results:
study cannot be used for classification
Conclusions:
Under the conditions of this test, the test item did not induce skin sensitisation in human subjects.
Executive summary:

The skin sensitising potential of the test substance has been tested in a human Repeated Insult Patch Test. 54 subjects were selected for the study, which was completed by 53 subjects. The induction phase consisted of 9 occlusive patch applications of the 6.25% test substance over 3 weeks. Following a rest period of 10-21 days, the challenge was performed with the same concentration of test substance (virgin site). Non-specific test responses were noted in 7 out of 53 subjects in the induction and challenge phase. None none of these non-specific responses were considered to be irritant or allergic in nature. Based on the results of this study, the substance was not considered to be a skin sensitizer. 

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The skin sensitization is based on read across to Etaphen. First the study with the analogue is described and thereafter the read across justification is presented.

Skin sensitization study with Etaphen:

In the key study, the skin sensitisation potential of Etaphen has been tested according to OECD TG 429: Local Lymph Node Assay in mice. This study is used for read-across to Peomosa. At doses of 2.5, 5, 10, 25 and 50% (w/v), the substance induced SI values of 1.06, 1.01, 0.87, 0.95 and 0.84, respectively. The substance was not tested up to 100% because systemic toxicity can be expected: 25 ul on each ear (= 50 mg) on a 20 gram mouse results in 2500 mg/kg bw (50 mg*1000/20), while the LC50 in rats is 1600 mg/kg bw. At all concentrations the SI =<3 and therefore the EC3 value was not met. Based on these results, the substance is considered not to be a sensitiser and does not need to be classified for skin sensitisation in accordance with the criteria outlined in Annex I of 1272/2008/EC (CLP) and its amendments.

Read-across justification: Peomosa and its non-sensitising properties using read across from Etaphen

Introduction and hypothesis for the read across

For Peomosa no skin sensitisation data are available. Therefore additional information is used in accordance with Article 13 of REACH where it is said thatlacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, SARs, grouping and read-across.

Hypothesis:Peomosa is not expected to have sensitising properties based on analogue information.

Available experimental information:For the structurally related Etaphen a well conducted LLNA test (OECD TG 429) is available, showing the absence of skin sensitisation.

Target and Source chemical(s):The information on Peomosa and the analogue information from Etaphen are presented in the data matrix.

Purity / Impurities

The purity and impurities of the target chemical do not indicate skin sensitisation potential other than indicated by the parent substance. The impurities are all below < 10%.

 Analogue justification

According to REACH Annex XI an analogue approach and structural alert information can be used to replace testing when information from different sources provides sufficient evidence to conclude that this substance has or does not have a particular dangerous property. The result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation.

Analogue selection:According to ECHA guidance (RAAF, 2015) a clear documentation is needed on the selection of potential source substances. Etaphen was selected because it differs only in one methyl group from Peomosa and for Etaphen reliable skin sensitisation information is available.

Structural similarities and differences:Peomosa and Etaphen both have an aromatic ring to which an ethanol group is attached. The primary alcohol is the functional group. The structural difference between Etaphen and Peomosa is an additional methyl group on the ortho position of the phenyl ring of the latter. This difference will not influence the reactivity of the alcohol functional group because itis too distant. Peomosa and Etaphen have similar water solubility and log Kow values, indicating that these substances will be absorbed by the skin to a similar extent.

Toxico-kinetics: The skin absorption is expected to be similar for both substances in view of their similar molecular weights and being liquids. Also their similar physico-chemical properties support a similar absorption.

Toxico-dynamics: For skin sensitization the parent substance is generally the key factor. However, in some cases the primary degradation or metabolisation products may cause sensitization. The metabolism processes for both substances are similar. Etaphen will be metabolized/oxidized into its carboxylic acid (phenylacetic acid) and Peomosa will be metabolised analogously (yielding the corresponding ortho-methyl acid), and no significant differences in skin sensitization potential are expected.

Remaining uncertainties:There are no remaining uncertainties because Etaphen is a structurally very close analogue to Peomosa, differing only by a methyl group, which does not influence the reactivity.

In the ECHA guidance (RAAF, 2015) terminology it receives a score of 5 (acceptable with high confidence), because the rationale for the selection of the analogues is clearly documented and there is supporting evidence provided.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data Matrix below.

 

Conclusions per endpoint for C&L

When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation.Etaphen is selected as an analogue because of its similarity in structure, bioavailability and reactivity. Etaphen is not considered sensitizing and therefore Peomosa is not a skin sensitizer.

Final conclusion on C&L:Peomosa is not sensitising, and it does not need to be classified and labelled for sensitisation according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 and its amendments.

 

Data matrix with information on Peomosa and analogues important for assessment of skin sensitising properties.

Common names

Peomosa

Etaphen

CAS number

19819-98-8

60-12-8

Molecular structure

Empirical formula

C9H12O

C8H10O

Molecular weight

136.94

122.17

Physico-chemical properties

 

 

Appearance

Liquid

Liquid

Vapour pressure at 25oC (Pa)

1.9 (measured)

3.24 (EpiSuite)

Water solubility at 20oC (mg/L)

12339(measured) 

21990 (EpiSuite)

Log Kow

2.1 (measured)

1.6 (EpiSuite)

Human health

 

 

Skin sensitisation animal test

Read across to Etaphen

Not sensitising (LLNA)

 

Justification for classification or non-classification

Based on the results presented above, Peomosa is considered not to be a sensitiser and does not need to be classified for skin sensitisation in accordance with the criteria outlined in Annex I of the CLP Regulation (1272/2008/EC) and its amendments.