[No public or meaningful name is available]

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

experimental study

Remarks:

Repeated insult patch test in humans (HRIPT)

Adequacy of study:

supporting study

Study period:

6 Dec 2021 - 17 Jan 2022

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

The study followed SGS Standard Protocol #100 (approved by Clarus Institutional Review Board, CIRB, on 25 Jan 2021) and SGS Standard Operating Procedures, and the study is reported in detail.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2022

Report date:

2022

Materials and methods

Type of sensitisation studied:

skin

Study type:

study with volunteers

Principles of method if other than guideline:

Principle of test
To evaluate the potential of the test material, as a result of repeated applications, to induce dermal sensitisation in human subjects.

Short description of test conditions
This test was conducted according to SGS Standard Protocol #100 and SGS Standard Operating Procedures.

Induction Phase
A webril/adhesive patch (25 mm Hill Top Chamber System®) was used occlusively. Using a precise, repeating syringe, 0.3 ml of each Test Material was applied to each designated patch. As per SGS Standard Operating Procedures (SOP) (SGS Form:SOP/RIPT), the left side of the back was usually the test area for the Induction Phase. The subject’s skin was marked with a surgical marker at the left side of the test site. The test site was recorded on the anatomical diagram of each subject’s individual Data Form. In addition, at that time, the prospective placement of the Challenge test site was also recorded on the anatomical diagram.

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.

Each subject returned to SGS on the appropriate day. The test site was observed by the SGS technician, and the reaction scored and recorded. The identical test site was then repatched until nine (9) Induction patchings were completed.

In accordance with SGS SOP, if a subject was unable to make up a missed patching during the same week, the subject was either patched four days the following week or was patched at the end of the Induction Phase. Any absences and make-up days are noted by the dates on the individual Data Form.

A series of nine (9) Induction patchings was completed over a period of approximately three weeks.

Rest Period
A Rest Period of approximately two weeks followed the last Induction patching; no test material was applied during the Rest Period. Subjects were instructed to notify SGS if they experienced any reaction during the Rest Period.

Challenge Phase
At the Challenge Phase, the original Induction test site was observed and each subject queried as to whether any reaction was experienced during the Rest Period. Any reactions were recorded on the Data Form. A webril/adhesive patch (25 mm Hill Top Chamber System®) was used occlusively. Using a precise, repeating syringe, 0.3 ml of each Test Material was applied to each designated patch. As per SGS RIPT SOP, the opposite side of the back was usually the virgin test site for the Challenge Phase.

As per SGS RIPT SOP, the Challenge patch was applied to the virgin site only. Each subject was again instructed to keep the patch on and dry.

Each subject returned to SGS approximately 48 hours later (Challenge Reading 1), at which time the patch was removed and the Challenge site scored and recorded by the SGS technician. The original test site was also observed.

Each subject returned to SGS at approximately 72 hours (Challenge Reading 2), approximately 96 hours (Challenge Reading 3) and approximately 168 hours (Challenge Reading 4) post-patching for additional observations; reactions were scored and recorded.

Subjects
Each potential subject completed an SGS Subject History Form (SHF), including relevant medical history (an updated SHF is secured approximately every 18 months). At each subject’s first visit to SGS, the subject completed a Permission To Release Personal Health Information Form in conformity with the Health Insurance Portability and Accountability Act (HIPAA) and provided proof of age. Each accepted subject was assigned a permanent SGS Identification Number. No subject was used if he or she exhibited any dermatological or other medical or physical condition that would preclude topical application of the Test Material. Upon enrollment, no subject reported using any medication that would interfere with the sensitization results. No known pregnant nor nursing women or minor subjects were used on this RIPT. A total of 121 subjects were enrolled; 108 subjects completed the test. Two subjects were discontinued due to a protocol violation. Two subjects were discontinued due to screen failure. Three subjects were discontinued due to reporting a positive COVID test result. Six subjects discontinued due to personal reasons / Investigator termination. No subject discontinued due to test material reaction.

Parameters analysed / observed
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 / DR = Dryness / P = Peeling / S = Staining / ^ = Hyperpigmentation / Hypopigmentation / TR = Tape Reaction / C = Change of test site / N9R = No 9th reading / - = No patch application and/or reading / X = Discontinued. The test sites were scored using the modified scoring scale of the International Contact Dermatitis Research Group System: Fisher, Alexander A., Contact Dermatitis, Lea & Febiger, Philadelphia, 2008: p 27.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of (±)-(4RS,4aRS,8RS,8aRS)-4-ETHYL-8,8a-DIMETHYLOCTAHYDRO-1(2H)-NAPHTHALENONE and (±)-(4RS,4aSR,8SR,8aSR)-4-ETHYL-8,8a-DIMETHYLOCTAHYDRO-1(2H)-NAPHTHALENONE and (±)-(4RS,4aSR,8RS,8aSR)-4-ETHYL-8,8a-DIMETHYLOCTAHYDRO-1(2H)-NAPHTHALENONE

Molecular formula:

C14H24O

IUPAC Name:

Reaction mass of (±)-(4RS,4aRS,8RS,8aRS)-4-ETHYL-8,8a-DIMETHYLOCTAHYDRO-1(2H)-NAPHTHALENONE and (±)-(4RS,4aSR,8SR,8aSR)-4-ETHYL-8,8a-DIMETHYLOCTAHYDRO-1(2H)-NAPHTHALENONE and (±)-(4RS,4aSR,8RS,8aSR)-4-ETHYL-8,8a-DIMETHYLOCTAHYDRO-1(2H)-NAPHTHALENONE

Test material form:

liquid

Details on test material:

Physical state: liquid
Storage condition of test material: Dry area, protected from light and at room temperature
Other: Colourless liquid

Method

Type of population:

general

Ethical approval:

confirmed and informed consent free of coercion received

Remarks:

Legally valid written IRB-Approved Informed Consent, in conformity with: 21 CFR 50.25, Subtitle A, Protection of Human Subjects, was secured from each subject.

Subjects:

- Number of subjects exposed: 108
- Sex: 82 female and 26 male
- Age: 18 - 69 years
- Race: Not reported

Clinical history:

Each potential subject completed an SGS Subject History Form (SHF), including relevant medical history (an updated SHF is secured approximately every 18 months). At each subject’s first visit to SGS, the subject completed a Permission To Release Personal Health Information Form in conformity with the Health Insurance Portability and Accountability Act (HIPAA) and provided proof of age. Each accepted subject was assigned a permanent SGS Identification Number. No subject was used if he or she exhibited any dermatological or other medical or physical condition that would preclude topical application of the Test Material. Upon enrollment, no subject reported using any medication that would interfere with the sensitization results. No known pregnant nor nursing women or minor subjects were used on this RIPT. An appropriate clearance period had elapsed since a subject was patched on a Repeated Insult Patch Test (RIPT) or a Photoallergy Test (PA) before being used in this RIPT.

Controls:

All subjects were patched with negative control: sterile 0.9% isotonic saline (NaCI CAS 7647-14-5) without preservative (result: did not induce dermal sensitisation) and vehicle control: 1:3 ethanol (CAS 64-17-5) : diethyl phthalate (CAS 84-66-2) (result: did not induce dermal sensitisation).

Route of administration:

dermal

Details on study design:

TYPE OF TEST USED: HRIPT - human repeated insult patch test (epicutaneous)

ADMINISTRATION
- Type of application: occlusive
- Description of patch: Webril/adhesive patch (25 mm Hill Top Chamber System®)
- Vehicle: 1:3 ethanol (CAS 64-17-5) : diethyl phthalate (CAS 84-66-2)
- Concentration: 12.7% of test material in vehicle
- Volume applied: 0.3 ml
- Testing/scoring schedule: INDUCTION PHASE: Nine 24h induction patchings per subject (during around three weeks) on the left side of the back. After each induction patching, the patch was removed after 24h by subjects themselves and scored 24-48h after removing the patch. REST PERIOD: After induction phase, subjects were not exposed to the test material for two weeks. CHALLENGE PHASE: One 48h challenge patching on the right side of the back followed by the first challenge reading after 48h. Other challenge readings were conducted 72h (challenge reading 2), approximately 96h (challenge reading 3) and approximately 168h (challenge reading 4) after removing the challenge patch.

EXAMINATIONS
- Grading/Scoring system: 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 / DR = Dryness / P = Peeling / S = Staining / ^ = Hyperpigmentation / Hypopigmentation / TR = Tape Reaction / C = Change of test site / N9R = No 9th reading / - = No patch application and/or reading / X = Discontinued. The test sites were scored using the modified scoring scale of the International Contact Dermatitis Research Group System: Fisher, Alexander A., Contact Dermatitis, Lea & Febiger, Philadelphia, 2008: p 27.

Results and discussion

Results of examinations:

No adverse reactions or adverse events related to the Test Material were exhibited / reported by any subject during this test.

Erythema, edema, dryness, staining, peeling and hyperpigmentation / hypopigmentation are possible, expected endpoints and not considered adverse reactions.

This test was conducted under the supervision of a Board-Certified Dermatologist, a Co-Investigator. At Challenge Reading 3, the Dermatologist participated in the scoring of the subjects.

Any other information on results incl. tables

For more details, the full test report available as an attachement.

Applicant's summary and conclusion

Conclusions:

In this repeated insult patch test, the test material at 12.7% in 1:3 EtOH/DEP, did not induce dermal sensitisation in human subjects.

Executive summary:

To test dermal sensitisation potential of the test material, the human repeated insult patch test (HRIPT) was conducted. Test material concentration was 12.7% in vehicle (1:3 EtOH:DEP). The concentration was not expected to induce dermal sensitisation according to the internal assessment based on in vitro skin sensitisation data, data from close analogues and expert judgement. All patchings were conducted occlusively using a webril/adhesive patch (25 mm Hill Top Chamber System®).

The effects were recorded during 13 reading sessions and results were scored and recorded. The scoring was done by using the modified scoring scale of the International Contact Dermatitis Research Group System: Fisher, Alexander A., Contact Dermatitis, Lea & Febiger, Philadelphia, 2008: p 27. In the HRIPT test, erythema, edema, dryness, staining, peeling and hyperpigmentation / hypopigmentation are possible, expected endpoints and were not considered adverse reactions.

Volunteered test subjects (108, 26 males and 82 females, age 18-69) without dermal or other medical conditions, and who are not minors, pregnant or nursing, were selected to the test. The test consisted of three phases: induction, rest and challenge. In the induction phase, subjects were exposed to the test material for 24 hours repeating exposure phase for nine times. Observations and scoring were made 24-48 hours after removal of the patch. During the rest period subjects were not exposed to the test material. In the challenge phase, subjects were exposed to the test material for 48 hours following the first challenge reading. After removal of the challenge patch, three more challenge readings were conducted after 72, 96 and 168 hours. 

No adverse reactions or adverse events related to the test material were observed in any volunteered subject in this repeated insult patch test. As a conclusion, test material at 12.7% in 1:3 EtOH/DEP, did not induce dermal sensitisation in human subjects.