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Toxicological information

Sensitisation data (human)

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Endpoint:
sensitisation data (humans)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
24 August 2005 to 06 October 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
This human study is not conducted in accordance with any recognised test guideline, but suffi cient details of the methodology are provided.
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
sensitisation data (humans)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
24 August 2005 to 06 October 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
This human study is not conducted in accordance with any recognised test guideline, but suffi cient details of the methodology are provided.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included under 'Attached justification' and 'Cross-reference'.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
4-methyl-4-phenylpentan-2-ol (source chemical) is the hydrolysis product of 1,3-dimethyl-3-phenylbutyl acetate (target chemical). Hydrolysis of 3-dimethyl-3-phenylbutyl acetate is expected to occur in the human body, with enzyme activity playing an important role. As the hydrolysis is expected to occur, read across from the hydrolysis product product 4-methyl-4-phenylpentan-2-ol is considered to be appropriate.

2. SOURCE AND TARGET CHEMICAL(S)
4-methyl-4-phenylpentan-2-ol would be one of the hydrolysis products of 1,3-dimethyl-3-phenylbutyl acetate, along with acetic acid (acetate ion), if the substance underwent hydrolysis. The target substance is the acetate of the test substance 4-methyl-4-phenylpentan-2-ol. In 1,3-dimethyl-3-phenylbutyl acetate, the hydroxyl group in the 2 position of the pentane backbone is replaced by an acetate group (O-C(CH3)=O).
These two substances have similar melting point, boiling point, density, surface tension and vapour pressure properties. Although there is a difference in water solubility, both substances are soluble to some extent. Partition coefficient values are similar, at 2.82 and 3.55 for the source and target substance respectively. Neither of the substances would be considered to be bioaccumulative. As both substances have flash points >60 ºC they are not considered to be flammable.
3. ANALOGUE APPROACH JUSTIFICATION
The read across justification is based on the fact that 4-methyl-4-phenylpentan-2-ol would be one of the hydrolysis products of 1,3-dimethyl-3-phenylbutyl acetate, along with acetic acid (acetate ion), if the substance underwent hydrolysis. Hydrolysis would only be expected to occur at high and low pH values. Initial studies have shown low hydrolysis at pH 4 (< 3 % after 120 hours) and moderate hydrolysis at pH 9 (ca 27 % after 120 hours). The test item showed a moderate hydrolysis rate (t1/2 ≤ 30 d) at pH 9 and 50 °C. At pH 9 at 20 and 30 °C only a slow hydrolysis (t1/2 > 30 d) was observed and at 20 °C the half live was > 1 year indicating no significant hydrolysis of the test item in a study according to OECD Guideline 111 and EC Method C.7 (Lange 2015).
While no data is available for the hydrolysis of 1,3-dimethyl-3-phenylbutyl acetate at gastric pH values (pH 1.2), hydrolysis data is available for two related esters, namely butyl acetate (CAS No. 123-86-4, EC no. 204-658-1) and phenylethyl acetate (CAS no. 103-45-7, EC 203-113-5) in artificial gastric fluid at 37 ºC (Longland et al, 1977). The acid hydrolysis half-life for these two esters was 318 and 300 minutes for butyl acetate and phenylethyl acetate, respectively. In the same study, hydrolysis in artificial pancreatic juice adjusted to pH 7.5 was measured to be 66 and 29.7 minutes respectively, for butyl acetate and phenylethyl acetate. In rat liver and small intestinal mucosa preparations the hydrolysis half-life for butyl acetate was 8.13 minutes and 1.8 minutes respectively. The study showed that enzyme activity was a major contributing factor in the hydrolysis of the two esters and that studies employing liver and small intestine preparations reflect more accurately the hydrolytic fate of esters in in vitro toxicological evaluations.
1,3-dimethyl-3-phenylbutyl acetate would react similarly to butyl acetate and phenylethyl acetate and therefore would be expected to hydrolyse rapidly to 4-methyl-4-phenylpentan-2-ol and acetate ion. A review of the human health data from the sodium acetate registration dossier indicates that there are no reported hazards associated with exposure to a variety of acetate ions for any of the toxicological endpoints. Consequently, it can be concluded that the acetate ion would not be expected to contribute to any of the potential toxicological endpoints required under REACH.

4. DATA MATRIX
See 'Attached justification'.
Reason / purpose for cross-reference:
read-across source
GLP compliance:
no
Ethical approval:
not specified
Results of examinations:
NO. OF PERSONS WITH/OUT REACTIONS COMPARED TO STUDY POPULATION
- Number of subjects with positive reactions: 0
- Number of subjects with negative reactions: 56
- Number of subjects with equivocal reactions: 0
- Number of subjects with irritating reactions: 0

Conclusions:
The substance did not indicate a potential for dermal irritition or allergic contact sensitisation.
Executive summary:

The study was conducted to determine by repetitive epidermal contact the potential of a test material to induce primary or cumulative irritation and/or allergic contact sensitisation.

Patches were applied three times a week (at least 48 hour intervals) for total of 9 applications. The application site (upper back between the scapulae) was marked to ensure continuity of application.

Test material, approximately 0.2 mL, was applied to a 0.75 x 0.75 inch adhesive dressing which was then applied to each of 56 test subjects as an occlusive patch. Following application, removal and

scoring of the first patch, participants were instructed to remove patches at home 24 hours after application. Approximately 2 weeks after the final induction phase of 9 applications, a challenge patch was applied to a virgin site adjacent to the original induction patch. Patches were removed after 24 hours and scored 24 hours and 72 hours after application. The following evaluation scheme was used : 0 = No visible skin reaction ; + = Barely perceptible or spotty erythema ; 1 = Mild erythema covering most of the test site ; 2 = Moderate erythema, possible presence of mild edema ; 3 = Marked erythema, possible edema; 4 = Severe erythema, possible edema, vesiculation, bullae and/or ulceration

All participants, those completing and those who did not complete the study, recorded scores of zero (0) either during the induction phase (10 observations) or challenge phase (2 observations). The substance

did not indicate a potential for dermal irritiation or allergic contact sensitisation.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Type of sensitisation studied:
skin
Study type:
study with volunteers
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:

Fifty six (56) participants male and female - aged 21 to 79 - were selected and 52 completed the study.
Approximately 0.2 mL of the substance, 4-methyl-4-phenylpentan-2-ol, or an amount to cover the contact surface was applied to cover a 0.75 inch x 0.75 inch absorbent pad portion of an adhesive dressing. This was then applied to the appropriate treatment site of the occlusive a patch.
Induction - Patches were applied 3 times a week, for a total of 9 applications. Patches were removed 24 hours after application and there was a 24 hour rest period between the first two of the weekly patch removals and a 48 hour period after the 3rd weekly patch removal.
Challenge - Approximately two weeks after final application a challenge patch was applied to a virgin test site adjacent to the application site. Patches were removed after 24 hours and scored 24 hours and 72 hours after application.
Evaluation Key:
0 = No visible skin reaction
+ = Barely perceptible or spotty erythema
1 = Mild erythema covering most of the test site
2 = Moderate erythema, possible presence of mild edema
3 = Marked erythema, possible edema
4 = Severe erythema, possible edema, vesiculation, bullae and/or ulceration
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4-methyl-4-phenylpentan-2-ol
EC Number:
218-002-7
EC Name:
4-methyl-4-phenylpentan-2-ol
Cas Number:
2035-93-0
Molecular formula:
C12H18O
IUPAC Name:
4-methyl-4-phenylpentan-2-ol

Method

Type of population:
general
Ethical approval:
not specified
Subjects:
- Number of subjects exposed: 56
- Sex: male and female
- Age: 21 to 79 years old
- Race:
- Demographic information:
- Other:
Controls:
no
Route of administration:
dermal
Details on study design:
TYPE OF TEST(S) USED: patch test (epicutaneous test)

ADMINISTRATION
- Type of application: occlusive
- Description of patch: 0.75 x 0.75 inch adhesive dressing
- Vehicle / solvent: none
- Concentrations: 98.6% pure
- Volume applied: approximately 0.2mL
- Testing schedule:
Induction phase: Patches were applied three times a week (at least 48 hour intervals) for total of 9 applications. Following application, removal and scoring of the first patch, participants were instructed to remove patches at home 24 hours after application.
Challenge phase: Approximately 2 weeks after the final induction phase of 9 applications, a challenge patch was applied to a virgin site adjacent to the original induction patch. Patches were removed after 24 hours and scored 24 hours and 72 hours after application.
- Removal of test substance: Patches were removed after 24 hours

EXAMINATIONS
- Grading/Scoring system:
0 = No visible skin reaction ;
+ = Barely perceptible or spotty erythema ;
1 = Mild erythema covering most of the test site ;
2 = Moderate erythema, possible presence of mild edema ;
3 = Marked erythema, possible edema;
4 = Severe erythema, possible edema, vesiculation, bullae and/or ulceration

Results and discussion

Results of examinations:
NO. OF PERSONS WITH/OUT REACTIONS COMPARED TO STUDY POPULATION
- Number of subjects with positive reactions: 0
- Number of subjects with negative reactions: 56
- Number of subjects with equivocal reactions: 0
- Number of subjects with irritating reactions: 0

Applicant's summary and conclusion

Conclusions:
The substance did not indicate a potential for dermal irritation or allergic contact sensitisation.
Executive summary:

The study was conducted to determnie by repetitive epidermal contact the potential of a test material to induce primary or cumulative irritation and/or allergic contact sensitisation.

Patches were applied three times a week (at least 48 hour intervals) for total of 9 applications. The application site (upper back between the scapulae) was marked to ensure continuity of application.

Test material, approximately 0.2 mL, was applied to a 0.75 x 0.75 inch adhesive dressing which was then applied to each of 56 test subjects as an occlusive patch. Following application, removal and

scoring of the first patch, participants were instructed to remove patches at home 24 hours after application. Approximately 2 weeks after the final induction phase of 9 applications, a challenge patch was applied to a virgin site adjacent to the original induction patch. Patches were removed after 24 hours and scored 24 hours and 72 hours after application. The following evaluation scheme was used : 0 = No visible skin reaction ; + = Barely perceptible or spotty erythema ; 1 = Mild erythema covering most of the test site ; 2 = Moderate erythema, possible presence of mild edema ; 3 = Marked erythema, possible edema; 4 = Severe erythema, possible edema, vesiculation, bullae and/or ulceration

All participants, those completing and those who did not complete the study, recorded scores of zero (0) either during the induction phase (10 observations) or challenge phase (2 observations). The substance

did not indicate a potential for dermal irritiation or allergic contact sensitisation.

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