Registration Dossier
Registration Dossier
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EC number: 947-393-3 | CAS number: -
Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Remarks:
- Human Repeat Insult Patch Test
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 9 January to 17 February 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- sensitisation data (humans)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 9 January to 17 February 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Type of sensitisation studied:
- skin
- Study type:
- study with volunteers
- Principles of method if other than guideline:
- MARZULLI-MAIBACH METHOD: The Marzulli-Maibach test is a reference test to study the sensitizing potential of a product. The investigational product was applied under maximized conditions (occlusion) during 3 weeks (Induction phase). After a two-week resting period, the investigational product was re-applied on the same site (Challenge phase). If the investigational product was allergenic, it induced a cutaneous reaction during the challenge phase.
- GLP compliance:
- no
- Remarks:
- Good clinical practice
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Robertet / 1928083
- Appearance: Liquid
- Date of receipt: 07 December 2011
STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Between 15 °C and 25 °C - Type of population:
- general
- Ethical approval:
- confirmed and informed consent free of coercion received
- Subjects:
- - Number of subjects recruited: 115
- Number of subjects exposed: 102
- Sex: 26 men and 76 women
- Age: Average age: 34.8 ± 12.9 years old (extreme values: 19 - 63 years old).
Others:
- Non-Included: 7 (did not fulfill the inclusion criteria at Day 1)
- Study premature withdrawals: 6 (Subjects no.19 and 53: Subjects' decision to withdrawal from the study at Day 3 because of strong smell of the products; Subjects no. 11 and 93: Subjects' decision to withdrawal from the study at Day 5 because of strong smell of the products; Subject no. 28: Lost to follow-up at Day 36; Subject no. 60: Lost to follow-up at Day 15) - Clinical history:
- The subjects were included according to the following criteria:
Inclusion criteria:
The voluntary subjects satisfied the following criteria:
Female or male,
Aged from 18 to 70 years old,
Not showing tattoo, scars, pigmented areas, important pilosity and dermatological lesions on the back and not receiving any anti-inflammatory or anti-allergic medication,
Subjects with Social Security (health insurance) coverage (according to the requirements of the MACEDONIAN REPUBLIC),
Able and willing to give a written informed consent.
Non-inclusion criteria:
The voluntary subjects did not satisfy the following criteria:
Who had applied a care product on the sites of application during the 24 hours before the beginning of the study,
Who had not washed the sites of the application with water 2 hours before the beginning of the study,
Pregnant woman or in the process of breast feeding,
Who had taken part to a patch test in the 15 days before the beginning of the study,
Who had tattoos on the back,
Who had scars on the back,
Who showed pigmented areas on the back,
Who had a very important pilosity on the back,
Who showed dermatological lesions on the back,
Presenting a medical history of medical or psychiatric illness, or of allergy to cosmetic products, or of major surgery, likely to be a health hazard for them according to the investigator,
Who suffered from any acute or chronic illnesses,
Who were under drugs or under a period of pharmacological efficacy,
Who presented confusions due to the excessive alcohol absorption or toxic substances,
Who presented dermatological inflammations,
Who were under a medical treatment, including an anti-allergic or anti-inflammatory treatment,
Unwilling to give their written informed consent,
PERITESCO's or I.C.T.C' s employees,
Who could not be contacted in case of emergency by phone,
Who did not fulfill the above inclusion criteria. - Controls:
- A semi occlusive patch receiving no product was applied in the same conditions and was considered as a non-treated control.
- Route of administration:
- dermal
- Details on study design:
- LOCATION: The study was carried out at the clinical unit of Skopje in MACEDONIA.
DESIGN: The study was blinded and randomized.
TYPE OF TEST(S) USED: Patch test (epicutaneous test)
ADMINISTRATION
- Type of application: Semiocclusive
- Description of patch: Trumed® Inc (size: 1.9 cm x 1.9 cm i.e. 3.61 cm2)
- Frequency: Induction phase: 3 times a week during 48 hours or 72 hours; Challenge phase: once during 48 hours
- Duration: Induction phase: 3 weeks; Duration Resting phase: 14 days; Challenge phase: 1 week
- Concentrations: Undiluted (8% (3646 µg/cm2) EtOH/DEP(25/75))
- Volume applied: 160 µL
- Removal of test substance: After removal of the patches, the sites were wiped with a cotton pad soaked with warm distilled water.
CONDITIONS OF USE:
INDUCTION PHASE:
- During the Induction Phase, the investigational product was applied on a predetermined site under semi occlusive patch (the semi occlusive patches were applied, on a right split back, in a zone limited by the spine of the scapula in top, the last coast in bottom, the dorsal rachis in inside and a vertical fIctitious line passing by the lower end of the scapula outwards). A semi-occlusive patch receiving no product was applied in the same conditions and was considered as a non-treated control. 160 µL of the investigational product was applied undiluted. Each time, the patches (treated and non-treated) remained applied during 48 or 72 hours before removal and replaced on the same site.
- The investigator performed:
A clinical examination before each application of the investigational products; the application of the patches (treated and non-treated) on Days 1, 3, 5/6*, 8, 10, 12/13*, 15, 17, 19/20* and 22**.
At each visit, the patches were replaced by one with the same investigational product and applied on the same site (except in case of occurrence of a reaction making the application of new patches impossible).
* Subjects no. 104, 105, 106, 107 and 108 began the study 2 days later, so they did not have any visit at Day 5, Day 12 and Day 19, but at Day 6, Day 13 and Day 20.
** Additional application day for subjects no. 3, 13, 67, 69, 89, 95, 97 and 103, as they did not have any application nor reading performed one day during the induction phase.
RESTING PHASE:
- During the 14-day Resting Phase, no product was applied on the sites used during the Induction phase or on the contralateral split-back which was used during the Challenge phase.
CHALLENGE PHASE:
- For the challenge phase, a symmetrical zone of controlateral split back (left) is used as the zone tested for the induction phase.
- During the challenge phase (Day 34/36*), the investigational product was applied under semi occlusive patch on the induction sites and on the contralateral sites. A semi occlusive patch receiving no product was applied in the same conditions and was considered as a non-treated control. The patches (treated and non-treated) remained applied during 48 hours and removed afterwards.
- A series of reading were practiced immediately (Day 36/38*), 24 hours (Day 37/39*), and 48 hours (Day 38/40*) after the patches removal.
* Subjects no. 104, 105, 106, 107 and 108 began the study 2 days later, therefore their challenge phase was performed on Day 34, Day 36, Day 37 and Day 38 instead of Day 36, Day 38, Day 39 and Day 40.
EXAMINATIONS
- Grading/Scoring system:
The clinical examination was carried out on the back on the treated zones according to the following scale:
Erythema (E)
0: no reaction
1: very slight reaction: pale pink erythema, homogeneous, not well delimited
2: slight reaction: clear pink erythema, homogeneous, well delimited, without oedema
3: moderate reaction: clear red erythema, homogeneous, well delimited, with or without slight oedema
4: severe reaction: dark red erythema, homogeneous, well delimited with or without an obvious oedema
Vesicles (V)
0: no reaction
1: obvious vesicles
Pruritus (P)
0: no reaction
1: obvious itching
Desquamation (visual and tactile evaluation) (D)
0: no reaction
1: fine desquamation
2: moderate desquamation
3: severe with large squamas
OTHERS:
Constraints of the study:
- During the Induction Phase, the patches application areas had not to be wet.
- During the repeated readings of the challenge phase, no wash, except for the daily personal hygiene habits, or any application of any kind of product was allowed.
- During the whole test, sun or UV voluntary exposure was not allowed. - Results of examinations:
- SYMPTOMS
- During the induction phase, no sign was observed on the control site and the investigational product site.
- During the challenge phase, no sign was observed on the control site and on the investigational product site, neither on the homolateral side nor on the controlateral site.
- In this study, no adverse event or serious adverse event was observed by the investigating dermatologists.
NO. OF PERSONS WITH/OUT REACTIONS COMPARED TO STUDY POPULATION
- Number of subjects with positive reactions: 0
- Number of subjects with negative reactions: 102
- Number of subjects with irritating reactions: 0
DETERMINATION OF THE SENSITIZING POTENTIAL:
No significant clinical manifestation of intolerance or allergy was observed by the investigator.
DETERMINATION OF THE IRRITATION INDEX Z:
The investigational product presents an irritation index of: Z = 0.000; the investigational product is therefore considered as practically non-irritant.
Note: Z is calculated on the parameters erythema (including oedema) and desquamation; Z is calculated on the data of the induction phase. - Conclusions:
- Under the conditions of the study, the investigational product PATCHOULI FRACTION (ALPHA GUAIENE) 290737 8% (3646 µg/cm2) EtOH/DEP(25/75) tested undiluted, under semi occlusive patch, can be considered as non-sensitizing.
- Executive summary:
A cutaneous tolerance and sensitizing potential study of the investigational product, PATCHOULI FRACTION (ALPHA GUAIENE) 290737 8% (3646 µg/cm2) EtOH/DEP(25/75) tested undiluted was conducted by patches application, according to the Marzulli-Maibach sensitization method. The data of 102 female and male subjects aged from 19 to 63 years old were analyzed during the study. The subjects were willing and able to give a written informed consent. The study was carried out at the clinical unit of Skopje in MACEDONIA. The study was blinded and randomized.
Duration: Induction phase: 3 weeks (3 times a week during 48 hours or 72 hours); Duration Resting phase: 14 days; Challenge phase: 1 week (once during 48 hours)
INDUCTION PHASE: During the Induction Phase, the investigational product was applied (160 µL) on a predetermined site under semi occlusive patch (back). A semi-occlusive patch receiving no product was applied in the same conditions and was considered as a non-treated control. Each time, the patches (treated and non-treated) remained applied during 48 or 72 hours before removal and replaced on the same site.
RESTING PHASE: During the 14-day Resting Phase, no product was applied on the sites used during the Induction phase or on the contralateral split-back which was used during the Challenge phase.
CHALLENGE PHASE: During the challenge phase (Day 34/36*), the investigational product was applied under semi occlusive patch on the induction sites and on the contralateral sites. A semi occlusive patch receiving no product was applied in the same conditions and was considered as a non-treated control. The patches (treated and non-treated) remained applied during 48 hours and removed afterwards.
A clinical examination was performed by the investigating dermatologist during the Induction Phase on Days 1, 3, 5/6, 8, 10, 12/13, 15, 17, 19/20 and 22/24, and during the Challenge Phase on Days 34/36, 36/38, 37/39 and 38/40.
During the induction phase, no sign was observed on the control site and the investigational product site. During the challenge phase, no sign was observed on the control site and on the investigational product site, neither on the homolateral side nor on the controlateral site. In this study, no adverse event or serious adverse event was observed by the investigating dermatologists. No significant clinical manifestation of intolerance or allergy was observed by the investigator. The investigational product presents an irritation index of: Z = 0.000; the investigational product is therefore considered as practically non-irritant.
Under the conditions of the study, the investigational product PATCHOULI FRACTION (ALPHA GUAIENE) 290737 8% (3646 µg/cm2) EtOH/DEP(25/75) tested undiluted, under semi occlusive patch, can be considered as non-sensitizing.
Table 7.10.4/1: Induction phase – results
Days |
Investigational product |
% of subjects - reaction |
Semi-Occlusive control |
% of subjects - reaction |
Day 1 |
Normal examination |
0 |
Normal examination |
0 |
Day 3 |
No reaction |
0 |
No reaction |
0 |
Day 5/6* |
No reaction |
0 |
No reaction |
0 |
Day 8 |
No reaction |
0 |
No reaction |
0 |
Day 10 |
No reaction |
0 |
No reaction |
0 |
Day 12/13* |
No reaction |
0 |
No reaction |
0 |
Day 15 |
No reaction |
0 |
No reaction |
0 |
Day 17 |
No reaction |
0 |
No reaction |
0 |
Day 19/20* |
No reaction |
0 |
No reaction |
0 |
Day 22 |
No reaction |
0 |
No reaction |
0 |
Day 24** |
No reaction |
0 |
No reaction |
0 |
* Subjects no. 104, 105, 106, 107 and 108 began the study 2 days later, so they did not have any visit at Day 5, Day 12 and Day 19, but at Day 6, Day 13 and Day 20.
** Additional application day for subjects no. 3, 13, 67, 69, 89, 95, 97 and 103 as they did not have any application nor reading performed one day during the induction phase.
Table 7.10.4/2: Challenge phase – results
Days |
Sites |
Investigational product |
% of subjects - reaction |
Semi-Occlusive control |
% of subjects - reaction |
Day 34/36* |
H |
Normal examination |
0 |
Normal examination |
0 |
C |
Normal examination |
0 |
Normal examination |
0 |
|
Day 36/38* |
H |
No reaction |
0 |
No reaction |
0 |
C |
No reaction |
0 |
No reaction |
0 |
|
Day 37/39* |
H |
No reaction |
0 |
No reaction |
0 |
C |
No reaction |
0 |
No reaction |
0 |
|
Day 38/40* |
H |
No reaction |
0 |
No reaction |
0 |
C |
No reaction |
0 |
No reaction |
0 |
H: homolateral site; C: contralateral site
* Subjects no.104, 105, 106, 107 and 108 began the study 2 days later, therefore their challenge phase was performed on Day 34, Day 36, Day 37 and Day 38 instead of Day 36, Day 38, Day 39 and Day 40.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- MARZULLI-MAIBACH METHOD: The Marzulli-Maibach test is a reference test to study the sensitizing potential of a product. The investigational product was applied under maximized conditions (occlusion) during 3 weeks (Induction phase). After a two-week resting period, the investigational product was re-applied on the same site (Challenge phase). If the investigational product was allergenic, it induced a cutaneous reaction during the challenge phase.
- GLP compliance:
- no
- Remarks:
- Good clinical practice
- Type of study:
- other: Study with volunteers
- Justification for non-LLNA method:
- Available study on volunteers
Test material
- Reference substance name:
- Rectified Essential Oil of Pogostemon cablin (Lamiaceae) with high content in alpha and delta guaiene obtained from leaves by distillation.
- EC Number:
- 947-393-3
- Molecular formula:
- Not applicable (UVCB)
- IUPAC Name:
- Rectified Essential Oil of Pogostemon cablin (Lamiaceae) with high content in alpha and delta guaiene obtained from leaves by distillation.
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Robertet / 1928083
- Appearance: Liquid
- Date of receipt: 07 December 2011
STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Between 15 °C and 25 °C
In vivo test system
Test animals
- Species:
- other: Human
- Strain:
- other: non relevant
- Sex:
- male/female
- Details on test animals and environmental conditions:
- - Number of subjects recruited: 115
- Number of subjects exposed: 102
- Sex: 26 men and 76 women
- Age: Average age: 34.8 ± 12.9 years old (extreme values: 19 - 63 years old).
Others:
- Non-Included: 7 (did not fulfill the inclusion criteria at Day 1)
- Study premature withdrawals: 6 (Subjects no.19 and 53: Subjects' decision to withdrawal from the study at Day 3 because of strong smell of the products; Subjects no. 11 and 93: Subjects' decision to withdrawal from the study at Day 5 because of strong smell of the products; Subject no. 28: Lost to follow-up at Day 36; Subject no. 60: Lost to follow-up at Day 15)
Ethical approval: confirmed and informed consent free of coercion received
The subjects were included according to the following criteria:
Inclusion criteria:
The voluntary subjects satisfied the following criteria:
Female or male,
Aged from 18 to 70 years old,
Not showing tattoo, scars, pigmented areas, important pilosity and dermatological lesions on the back and not receiving any anti-inflammatory or anti-allergic medication,
Subjects with Social Security (health insurance) coverage (according to the requirements of the MACEDONIAN REPUBLIC),
Able and willing to give a written informed consent.
Non-inclusion criteria:
The voluntary subjects did not satisfy the following criteria:
Who had applied a care product on the sites of application during the 24 hours before the beginning of the study,
Who had not washed the sites of the application with water 2 hours before the beginning of the study,
Pregnant woman or in the process of breast feeding,
Who had taken part to a patch test in the 15 days before the beginning of the study,
Who had tattoos on the back,
Who had scars on the back,
Who showed pigmented areas on the back,
Who had a very important pilosity on the back,
Who showed dermatological lesions on the back,
Presenting a medical history of medical or psychiatric illness, or of allergy to cosmetic products, or of major surgery, likely to be a health hazard for them according to the investigator,
Who suffered from any acute or chronic illnesses,
Who were under drugs or under a period of pharmacological efficacy,
Who presented confusions due to the excessive alcohol absorption or toxic substances,
Who presented dermatological inflammations,
Who were under a medical treatment, including an anti-allergic or anti-inflammatory treatment,
Unwilling to give their written informed consent,
PERITESCO's or I.C.T.C' s employees,
Who could not be contacted in case of emergency by phone,
Who did not fulfill the above inclusion criteria.
Results and discussion
- Positive control results:
- No positive control
In vivo (non-LLNA)
Resultsopen allclose all
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- Patchouli Fraction Alpha Guaiene 8% undiluted
- No. with + reactions:
- 0
- Total no. in group:
- 102
- Clinical observations:
- No significant clinical manifestation of intolerance or allergy was observed by the investigator.
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- other: Non performed
- Group:
- negative control
- Remarks on result:
- not measured/tested
- Reading:
- other: Non perfomed
- Group:
- positive control
- Remarks on result:
- not measured/tested
Any other information on results incl. tables
Table 7.10.4/1: Induction phase – results
Days |
Investigational product |
% of subjects - reaction |
Semi-Occlusive control |
% of subjects - reaction |
Day 1 |
Normal examination |
0 |
Normal examination |
0 |
Day 3 |
No reaction |
0 |
No reaction |
0 |
Day 5/6* |
No reaction |
0 |
No reaction |
0 |
Day 8 |
No reaction |
0 |
No reaction |
0 |
Day 10 |
No reaction |
0 |
No reaction |
0 |
Day 12/13* |
No reaction |
0 |
No reaction |
0 |
Day 15 |
No reaction |
0 |
No reaction |
0 |
Day 17 |
No reaction |
0 |
No reaction |
0 |
Day 19/20* |
No reaction |
0 |
No reaction |
0 |
Day 22 |
No reaction |
0 |
No reaction |
0 |
Day 24** |
No reaction |
0 |
No reaction |
0 |
* Subjects no. 104, 105, 106, 107 and 108 began the study 2 days later, so they did not have any visit at Day 5, Day 12 and Day 19, but at Day 6, Day 13 and Day 20.
** Additional application day for subjects no. 3, 13, 67, 69, 89, 95, 97 and 103 as they did not have any application nor reading performed one day during the induction phase.
Table 7.10.4/2: Challenge phase – results
Days |
Sites |
Investigational product |
% of subjects - reaction |
Semi-Occlusive control |
% of subjects - reaction |
Day 34/36* |
H |
Normal examination |
0 |
Normal examination |
0 |
C |
Normal examination |
0 |
Normal examination |
0 |
|
Day 36/38* |
H |
No reaction |
0 |
No reaction |
0 |
C |
No reaction |
0 |
No reaction |
0 |
|
Day 37/39* |
H |
No reaction |
0 |
No reaction |
0 |
C |
No reaction |
0 |
No reaction |
0 |
|
Day 38/40* |
H |
No reaction |
0 |
No reaction |
0 |
C |
No reaction |
0 |
No reaction |
0 |
H: homolateral site;C: contralateral site
* Subjects no.104, 105, 106, 107 and 108 began the study2days later, therefore their challenge phase was performed on Day34,Day 36,Day37and Day38 instead of Day36, Day38,Day39 and Day 40.
Applicant's summary and conclusion
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- Under the conditions of the study, the investigational product PATCHOULI FRACTION (ALPHA GUAIENE) 290737 8% (3646 µg/cm2) EtOH/DEP(25/75) lot 1928083 tested undiluted, under semi occlusive patch, can be considered as non-sensitizing.
- Executive summary:
A cutaneous tolerance and sensitizing potential study of the investigational product, PATCHOULI FRACTION (ALPHA GUAIENE) 290737 8% (3646µg/cm2) EtOH/DEP(25/75) lot 1928083 tested undiluted was conducted by patches application, according to the Marzulli-Maibach sensitization method. The data of 102 female and male subjects aged from 19 to 63 years old were analyzed during the study. The subjects were willing and able to give a written informed consent. The study was carried out at the clinical unit of Skopje in MACEDONIA. The study was blinded and randomized.
Duration:Induction phase: 3 weeks (3 times a week during 48 hours or 72 hours); Duration Resting phase: 14 days; Challenge phase: 1 week (once during 48 hours)
INDUCTION PHASE: During the Induction Phase, the investigational product was applied (160 µL) on a predetermined site under semi occlusive patch (back). A semi-occlusive patch receiving no product was applied in the same conditions and was considered as a non-treated control. Each time, the patches (treated and non-treated) remained applied during 48 or 72 hours before removal and replaced on the same site.
RESTING PHASE: During the 14-day Resting Phase, no product was applied on the sites used during the Induction phase or on the contralateral split-back which was used during the Challenge phase.
CHALLENGE PHASE: During the challenge phase (Day 34/36*), the investigational product was applied under semi occlusive patch on the induction sites and on the contralateral sites. A semi occlusive patch receiving no product was applied in the same conditions and was considered as a non-treated control. The patches (treated and non-treated) remained applied during 48 hours and removed afterwards.
A clinical examination was performed by the investigating dermatologist during the Induction Phase on Days 1, 3,5/6,8, 10,12/13,15, 17,19/20and22/24,and during the Challenge Phase on Days34/36, 36/38, 37/39and38/40.
During the induction phase, no sign was observed on the control site and the investigational product site. During the challenge phase, no sign was observed on the control site and on the investigational product site, neither on the homolateral side nor on the controlateral site. In this study, no adverse event or serious adverse event was observed by the investigating dermatologists. No significant clinical manifestation of intolerance or allergy was observed by the investigator. The investigational product presents an irritation index of: Z = 0.000; the investigational product is therefore considered as practically non-irritant.
Under the conditions of the study, the investigational product PATCHOULI FRACTION (ALPHA GUAIENE) 290737 8% (3646 µg/cm2) EtOH/DEP(25/75) lot 1928083 tested undiluted, under semi occlusive patch, can be considered as non-sensitizing.
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