Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
17-01-2018 to 23-02-2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Type of sensitisation studied:
skin
Study type:
study with volunteers
Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other:
Version / remarks:
US FDA Regulation: CFR Title 21, Part 50, Protection of Human Subjects
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
other:
Version / remarks:
US FDA Regulation: CFR Title 21 Part 56, Institutional review Boards
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
other:
Version / remarks:
US FDA Regulation: CFR Title 21, Part 312, Investigational New Drug Application
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
other:
Version / remarks:
The RFIM human repeated insult patch test protocol ; V.T. Politano & A.M. Api, Regulatory Toxicology and Pharmacology 52 (2008) 35–38
Deviations:
yes
Remarks:
Utilised an occlusive patch rather than semi-occlusive (typically used to enhance the sensitivity of the test method)
GLP compliance:
no
Remarks:
Testing was conducted under laboratory/clinical Quality Assurance procedures (raw data retailed at the named laboratory/clinic)

Test material

Constituent 1
Reference substance name:
Reaction mass of (4E,8Z)-cyclododeca-4,8-dien-1-one and (4Z,8E)-cyclododeca-4,8-dien-1-one and (4E,8E)-cyclododeca-4,8-dien-1-one
EC Number:
941-893-5
Cas Number:
15229-79-5
Molecular formula:
C12H18O
IUPAC Name:
Reaction mass of (4E,8Z)-cyclododeca-4,8-dien-1-one and (4Z,8E)-cyclododeca-4,8-dien-1-one and (4E,8E)-cyclododeca-4,8-dien-1-one
Test material form:
liquid
Details on test material:
- Physical state: Liquid
- Storage condition of test material: Not reported. Presumed to be ambient conditions in original container.
- Other: pale yellow

Method

Type of population:
general
Ethical approval:
confirmed and informed consent free of coercion received
Subjects:
- Number of subjects exposed: 117 (a sufficient number to provide 100 completed subjects ; 1 discontinued due to protocol deviation and 8 discontinued for personal reasons; no subjects discontinued due to test material / test item reaction)
- Sex: 41 Male / 67 Female (n = 108 total) completed the study ; 3 males and 6 females (n = 8) discontinued the study
- Age: 20 – 69 years old
- Race: Not reported.
- Demographic information: Not reported.
- Other: The subjects chosen were dependable and able to read and understand instructions. The subjects did not exhibit any physical or dermatological or medical condition that would precluded application test article or determination potential effects of the test item.
Clinical history:
- History of allergy or casuistics for study subject or populations: None reported. Per: The RFIM human repeated insult patch test protocol ; V.T. Politano & A.M. Api, Regulatory Toxicology and Pharmacology 52 (2008) 35–38 wherein it indicates: “The subjects should not exhibit any physical or dermatological condition which would preclude application of the test articles. The subjects must fit all of the inclusion and exclusion criteria listed”. The laboratory/clinic reported SOPs and protocols match the above (documented in the full study report).
- Symptoms, onset and progress of the disease: Not applicable.
- Exposure history: None.
- Aggravating factors both in home and workplace: Not applicable.
- Family history: Not reported ; however will be screened for and excluded per the aforementioned standard methodology.
- Medical history (for respiratory hypersensitivity): Not applicable.
- Any other allergic or airway disorders: however will be screened for and excluded per the aforementioned standard methodology.
- Smoking history: Not applicable.
- Other: See table 1: Inclusion and exclusion criteria within V.T. Politano & A.M. Api, Regulatory Toxicology and Pharmacology 52 (2008) 35–38 for further information on the utilised protocols of the HRIPT.
Controls:
None
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: webril/adhesive patch occlusive patch
- Vehicle / solvent: non-per se ; the test item was reported as 2.4% [test item name] ; it can be presumed that the vehicle utilised (85%) will be a standard vehicle such as Ethanol or DEP or similar commonly utilised within the HRIPT test ; The preferred vehicle of the RIFM is 75% diethyl phthalate (DEP)/25% EtOH as referenced within: Politano & Api, Regulatory Toxicology and Pharmacology 52 (2008) 35–38
- Concentrations: Single ; 2.4%
- Volume applied: 0.3 mL
- Testing/scoring schedule: (1) Induction phase: 0.3 mL was placed onto the patch and applied to the left side of the back with the test site indelibly marked and the test site recorded on the subjects individual data form. Each subject was instructed that the patch was to remain in place and kept dry for approximately 24 hours, at which time the patch was to be removed by the subject. An approximately 24-hour period, during which no test material was applied, followed the weekday patch removals; an approximately 48-hour period followed the weekend patch removals. A series of nine (9) Induction patchings were completed over a period of approximately three weeks. (2) Challenge phase: After a rest phase of ca. 2 weeks (no applications) the challenge patch was applied to a previously unpatched (virgin) site typically the opposite side of the back. The site was scored at 24 , 48, 72 and 96 hours after application. All subjects were instructed to report any delayed skin reactivity that occurred after the final challenge patch reading.
- Removal of test substance: None, see above
- Other: Not applicable.

EXAMINATIONS
- Grading/Scoring system: Dermal responses for both the Induction and Challenge phases of the study were scored according to the following scale, with additional footnotes as applicable :
0 = No visible reaction
± = Faint, minimal erythema
1 = Erythema
2 = Intense erythema, induration
3 = Intense erythema, induration, vesicles
4 = Severe reaction with erythema, induration, vesicles, pustules (may be weeping)
E = Edema
- = No reading
N9R = No 9th reading
All other observed dermal reactions/events (e.g. edema, dryness, hypo- or hyperpigmentation) would be when applicable, be appropriately recorded on the datasheet and described.
- Statistical analysis: None.
- Other: Not applicable.

Results and discussion

Results of examinations:
SYMPTOMS
- Frequency, level, duration of symptoms observed: 107/108 indicated score = 0 ; 1/108 indicated score ± (Faint, minimal erythema) during the 9th induction only, this was not considered an adverse effect/event ; 9 individuals did not complete the study due to protocol deviation or due personal reasons unrelated to the study conduct

NO. OF PERSONS WITH/OUT REACTIONS COMPARED TO STUDY POPULATION
- Number of subjects with positive reactions: 0/108
- Number of subjects with negative reactions: 108/108
- Number of subjects with equivocal reactions: Not applicable
- Number of subjects with irritating reactions: Not applicable

RESULT OF CASE REPORT: Negative ; the test item was “dermatologist-tested” and did not induce reaction considered to be skin irritation or show evidence of induced contact dermatitis in human subjects. No adverse reactions or adverse events were reported in any of the subjects

OTHER RESULTS: Nine (9/117) subjects discontinued due to protocol deviation or due personal reasons unrelated to the study conduct. Discontinued panellist data are shown up to the point of discontinuation, but are not used in the conclusions section of the final report.

Any other information on results incl. tables

Table 1. summary of dermatologic response data for the main study is the provided in the following table:

Response

Induction evaluation number

Challenge Phase

 

1

2

3

4

5

6

7

8

9

24h

48h

72h

96h

0

115

114

114

112

112

111

111

110

108

108

108

108

108

±

 

 

 

 

 

 

 

 

1

 

 

 

 

1

 

 

 

 

 

 

 

 

 

 

 

 

 

1E

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

2E

 

 

 

 

 

 

 

 

 

 

 

 

 

3E

 

 

 

 

 

 

 

 

 

 

 

 

 

4E

 

 

 

 

 

 

 

 

 

 

 

 

 

-

 

 

 

 

 

 

 

 

 

 

 

 

 

N9R

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

9 out of 117 subjects discontinued for reasons unrelated to the study (all score = 0 prior to discontinuing)

108 out of 108 subjects that concluded the study indicated a maximum score = 0 during challenge with only one (1) other observations noted Faint, minimal erythema during induction reading 9 in one subject.

Note: subject 44 Male with the induction reading 9: ± (Faint, minimal erythema) continued into challenge phase and presented 0 scores at all challenge time points

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, there was no evidence of sensitisation and/of significant irritation to the test item (which consisted of the test substance at 2.4% concentration in vehicle).
Executive summary:

The study was conducted as a human repeat insult patch test under occlusive dressing according or equivalent or similar to to: US FDA Regulation: CFR Title 21, Parts 50, 56 and 312. Applicant assessment indicates that the test protocol could be considered: equivalent or similar to the RFIM human repeated insult patch test protocol cited in: V.T. Politano & A.M. Api, Regulatory Toxicology and Pharmacology 52 (2008) 35–38. The test article (consisting of the test substance at 2.4% concentration) was tested was to determine the irritation and/or sensitisation potential of the test article after repeated application under occlusive patch test conditions to the skin of human subjects (exclusive panel). A total of 117 volunteer subjects, 44 males and 73 females ranging in age from 20 to 69 years, were empanelled for the test which were a sufficient number to provide 100 completed subjects ; 1 discontinued due to a protocol deviation and 8 discontinued for personal reasons; no subjects discontinued due to test material / test item reaction. The induction phase consisted of placing 0.3 mL test item onto the occlusive patch and applied to the left side of the back with the test site indelibly marked and the test site recorded on the subjects individual data form. Each subject was instructed that the patch was to remain in place and kept dry for approximately 24 hours, at which time the patch was to be removed by the subject. An approximately 24-hour period, during which no test material was applied, followed the weekday patch removals; an approximately 48-hour period followed the weekend patch removals. A series of nine (9) Induction patchings were completed over a period of approximately three weeks. The challenge phase was conducted after a rest phase of ca. 2 weeks (no applications) whereby, the challenge patch was applied to a previously unpatched (virgin) site typically the opposite side of the back. The site was scored at 24 , 48, 72 and 96 hours after application. 108 out of 108 subjects that concluded the study indicated a maximum score zero (0) during challenge with only one other observation noted: faint, minimal erythema during induction reading 9 in one subject. No adverse reactions or adverse events were reported in any of the subjects. Under the conditions of this study, there was no evidence of sensitisation and of irritation to the test item (which consisted of the test substance at 2.4% concentration in vehicle).