Cyclopropanecarboxylic acid, 2-[1-(3,3-dimethylcyclohexyl)ethoxy]-2-methylpropyl ester

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

15-02-2006 to 12-04-2006

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:

2006

Report date:

2006

Materials and methods

Type of sensitisation studied:

skin

Study type:

study with volunteers

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other:

Version / remarks:

US FDA Regulation: CFR Title 21, Part 312, Investigational New Drug Application

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other:

Version / remarks:

US FDA Regulation: CFR Title 21, Part 50, Protection of Human Subjects

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other:

Version / remarks:

US FDA Regulation: CFR Title 21 Part 56, Institutional review Boards

Deviations:

no

Test guideline 4

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:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

460-490-0

EC Name:

-

Cas Number:

477218-42-1

Molecular formula:

C18H32O3

IUPAC Name:

2-[(1S)-1-[(1R)-3,3-dimethylcyclohexyl]ethoxy]-2-methylpropyl cyclopropanecarboxylate; 2-[(1S)-1-[(1S)-3,3-dimethylcyclohexyl]ethoxy]-2-methylpropyl cyclopropanecarboxylate

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: clear liquid

Method

Type of population:

general

Ethical approval:

confirmed and informed consent free of coercion received

Subjects:

- Number of subjects exposed: 110 (a sufficient number to provide 100 completed subjects)
- Sex: 20 Male / 90 Female
- Age: 18 – 74 years old
- Race: Not reported.
- Demographic information: Not reported.
- Other: The subjects chosen were dependable and able read and understand instructions. The subjects did not exhibit any physical or dermatological 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”.
- 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: modified Parke-Davis Readi-Bandage occlusive patch
- Vehicle / solvent: non-per se ; the test item was reported as 15% [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 ; 15%
- Volume applied: 0.2 mL
- Testing/scoring schedule: (1) Induction phase: 0.2 mL was placed onto the patch and applied to the upper arm. The subjects were instructed to remove the patch 24 hours after application. Twenty-four hour rest periods followed the Tuesday and Thursday removals and 48-hour rest periods followed each Saturday removal. Subjects returned to the Testing Facility and the site was scored by a trained examiner just prior to the next patch application. If a subject developed a positive reaction of a level 2 erythema or greater during the Induction phase or if, at the discretion of the Study Director, the skin response warranted a change in site, the patch was applied to a previously unpatched, adjacent site for the next application. If a level 2 reaction or greater occurred at the new site, no further applications were made. However, any reactive subjects were subsequently Challenge patch tested. (2) Challenge phase: After a rest phase of ca. 2 weeks (no applications) the challenge patch was applied to a previously unpatched (virgin) site. The site was scored at 24 and 72 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 6-point scale:
0 = No evidence of any effect
+ = Barely perceptible (Minimal, faint, uniform or spotty erythema)
1 = Mild (Pink, uniform erythema covering most of the contact site)
2 = Moderate (Pink-red erythema uniform in the entire contact site)
3 = Marked (Bright red erythema with/without petechiae or papules)
4 = Severe (Deep red erythema with/without vesiculation or weeping)
All other observed dermal sequelae (e.g. edema, dryness, hypo- or hyperpigmentation) were appropriately recorded on the datasheet and described as mild, moderate or severe.
- Statistical analysis: None.
- Other: Not applicable.

Results and discussion

Results of examinations:

SYMPTOMS
- Frequency, level, duration of symptoms observed: 97/110 indicated score = 0 ; 13 individuals did not complete the study due to personal reasons unrelated to the study conduct

NO. OF PERSONS WITH/OUT REACTIONS COMPARED TO STUDY POPULATION
- Number of subjects with positive reactions: 0/97
- Number of subjects with negative reactions: 97/97
- 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 skin irritation or show evidence of induced contact dermatitis in human subjects.

OTHER RESULTS: Thirteen (13/110) subjects discontinued for personal reasons unrelated to the conduct of the study. 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									Total	Challenge Phase
	1	2	3	4	5	6	7	8	9		24h	72h
Negative	97	97	97	97	97	97	97	97	97	97	97	97
Equivocal	0	0	0	0	0	0	0	0	0	0	0	0
Positive	0	0	0	0	0	0	0	0	0	0	0	0

 

13 out of 110 panelist discontinued for reasons unrelated to the study (all score = 0 prior to discontinuing)

97 out of 97 panelists that concluded the study indicated a maximum score = 0 with no other observations noted

Applicant's summary and conclusion

Conclusions:

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 15% concentration in vehicle).

Executive summary:

The study was conducted as a human repeat insult patch test under occlusive dressing according to: US FDA Regulation: CFR Title 21, Parts 50, 56 and 312 under GLP conditions. The test article (consisting of the test substance at 15% 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 110 volunteer subjects, 20 males and 90 females ranging in age from 18 to 74 years, were empanelled for the test. 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. 0.2 mL of the test article was applied every Monday, Wednesday and Friday until 9 applications had been made with the use of occlusive dressing to increase test sensitivity applied to the upper arm in the induction phase. The subjects were instructed to remove the patch 24 hours after application. Twenty-four hour rest periods followed the Tuesday and Thursday removals and 48-hour rest periods followed each Saturday removal. Subjects returned to the Testing Facility and the site was scored by a trained examiner just prior to the next patch application.If a subject developed a positive reaction of a level 2 erythema or greater during the Induction phase or if, at the discretion of the Study Director, the skin response warranted a change in site, the patch was applied to a previously unpatched, adjacent site for the next application. If a level 2 reaction or greater occurred at the new site, no further applications were made. However, any reactive subjects were subsequently Challenge patch tested. In the challenge phase: after a rest phase of ca. 2 weeks (no applications) the challenge patch was applied to a previously unpatched (virgin) site. The site was scored at 24 and 72 hours after application. All subjects were instructed to report any delayed skin reactivity that occurred after the final challenge patch reading. 13 out of 110 panellist discontinued for reasons unrelated to the study (all score = 0 prior to discontinuing). 97 out of 97 panellists that concluded the study indicated a maximum score = 0 with no other observations noted. There was no skin reactivity observed at any time during the course of the study.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 15% concentration in vehicle).