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Toxicological information

Sensitisation data (human)

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Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
10 April to 23 May 23 1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Good Clinical Practices; protocol developed

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997
Reference Type:
other: protocol
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Type of sensitisation studied:
skin
Study type:
study with volunteers
Test guideline
Qualifier:
according to
Guideline:
other: Kaidbey, K. (1991) Dermatology, 4th edition. Marzulli, F. and Maibach, HI (eds) Hemisphere Publishing Corporation, NY, NY, 595-605; adaptation of Kaidbey, KH and Kligman, AM (1980) Contact Dermatitis 6:161-169.
Principles of method if other than guideline:
Evaluation of AHTN for induction of photoallergy by repetitive application to skin of human volunteers. Induction was via 6 24-hour closed applications each irradiated at patch removal with UVA/UVB at 2xMED. After a 2 week rest, challenge was via closed 24 hr application followed by 16 joules UVA and 0.75 MED UVB. Additional challenge site was irradiated 10 minutes after application and covered for 24 hr.
GLP compliance:
no
Remarks:
Good Clinical Practice (GCP) Guidelines and the Standard Operating Procedures of the Hill Top Companies.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
AHTN supplied by the Research institute of Fragrance Materials: 10% AHTN in vehicle Ethanol/Diethyl Phthalate (75:25)
SAMPLE B: 10% AHTN in 75% ethanol/25% diethyl phthalate (clear colourless liquid)
SAMPLE G: 3% AHTN in 75% ethanol/25% diethyl phthalate and irradiated sample with 10 Joules UVA (clear colourless liquid)

Method

Type of population:
general
Ethical approval:
other: signed informed consent
Subjects:
-Number of subjects exposed: 32
-Sex: 13 males, 19 females
-Age: 18 years or older
-Race: not given
-Demographic information: not given
Clinical history:
Not reported but inclusion criteria included sunburn and tanning history and exclusion criteria included severe reactions form exposure to sunlight, taking certain drugs (e.g., sulfa drugs, tetracyclines, phenothiazine, tranquilizers, antiemetics, etc.), insulin-dependent diabetes, bi-lateral mastectomy for cancer involving removal of lymph nodes, clinically significant skin diseases, asthma, immunological disorders, cancer treatment within past 6 months, use of any prescribed anti-inflammatory drug, immunosuppressive drugs, or antihistamines, topical drugs used at patch site, pregnancy/lactation, other medical conditions deemed by investigators to cause ineligibility, participation in other patch tests for irritation/sensitization within past 4 weeks, damaged skin around test site, and/or participation in allergy/photoallergy study.
Controls:
SAMPLE A: vehicle control (75% ethanol/25% diethyl phthalate)
SAMPLE E: Photodegradation product 4001(0.1% 4,4,5,7,7,11-hexamethyl-12,12-dioxa-tricyclo[8,4,0.0(3.8)] tetra-deca-1,3(8),9-triene-11-ol in 75% ethanol/25% diethyl phthalate
SAMPLE F: Photodegradation product 400(1% 6-acetyl-7-formyl-1,1,2,4,4-pentamethyltetralin in 75% ethanol/25% diethyl phthalate
SAMPLE Z: untreated (blank) control
Route of administration:
dermal
Details on study design:
Unprotected naïve skin of each subject was exposed to a series of 5 UVB/UVA exposures that were graduated by 25% the previous dose to determine the minimum erythema dose (MED) for each subject. 24 hours later, the sites were assessed visually and the smallest dose of energy that produced erythema at the site borders was considered the MED. For the induction phase, 0.2 ml test substance was applied by pipette to a site of the paraspinal region. Untreated or blank site was also prepared. 10 minutes later, the site was exposed to 2xMED (UVA/UVB). Each site was covered by patches (2x2 cm non-woven cotton pad) covered and secured with a 4x4 cm occlusive hypoallergenic tape (Blenderm). Test substance (Samples A and B) and patches were applied to sites 2 times per week for 3 successive weeks and kept in place for 24 hours at each application. Sites were evaluated and scored. If there was a strong erythema reaction, an alternate site was used or the UVA/UVB dose was reduced. Treatment was discontinued until challenge or the subject was excused if a 3rd strong reaction was noted. There was a 2-week rest period. For the challenge period, subjects were treated in a similar manner on naïve sites with duplicate sites of 0.2 ml of test substance or untreated control under occlusion for 24 hours. In addition, additional sites were prepared with 0.2 ml of test substance and irradiated within 10 min with 16 Joules of UVA and then 0.75 MED UVB. One of the duplicate site sets had the patches removed and irradiated in the same manner. Three samples (E, F, and G) were included in the non-irradiated control set of patches during the challenge phase. As per a protocol deviation, Sample G was irradiated with 10 Joules UVA and then applied to non-irradiated challenge site. All sites were evaluated and scored for inflammatory response at ~ 1, 24, 48, and 72 hours after irradiation and non-irradiated patch removal. Reactivity during the induction period and observations of non-irradiated sites provide a baseline for photoallergy interpretation. If required a rechallenge was conducted in the same manner as the challenge. Adverse events were recorded. No statistical analyses were conducted.

Results and discussion

Results of examinations:
23 subjects completed the study. 9 subjects withdrew primarily for not adhering to study schedule or deciding not to participate.
Blue discoloration on skin for 13 of the 23 subjects treated with the blank control.
Minimal irritation to skin during induction and challenge phases except for one subject showing strong erythema at the irradiated test sites at 48-hour challenge. It decreased by 72 hours and was considered to be related to UV exposure past subject’s MED.
Slight to mild signs of dermal irritation were obtained during the induction period. However, these reactions were observed in both AHTN-treated and vehicle-treated sites at about the same rate. There was no clear increase in the severity of the dermal irritation during the progress of the induction phase. After the challenge, slight irritation was observed in irradiated sites more often than in non-irradiated sites. However, upon comparison, differences between AHTN-treated and vehicle-control sites were not observed, neither with respect to severity nor with respect to incidence. No cross-reactions to the photodegradation products of AHTN were seen.

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, AHTN showed no evidence of photoallergy.
Executive summary:

Human subjects were tested for photoallergy in a repeated insult patch test with 3 or 10% AHTN in 75% ethanol/25% diethyl phthalate with or without irradiation.

The study design was an adaptation of the procedure described by Kaidbey & Kligman consisted of the following phases:

The induction phase was a 6 Repetitive 24-hour occluded patch application of (A) vehicle control - 75% ethanol 25% diethyl phthalate (DEP), (B) 10% AHTN in 75% ethanol 25% DEP & (Z) a blank patch were carried out on skin sites for 3 weeks (2 application/week). Within 10 minutes of removal of the material, the patch sites were exposed to UVB/UVA radiation.

During the rest period after the induction period, the subjects did not receive any application of materials or UV radiation for approximately 2 weeks.

In the challenge phase, a 24 hour occluded patch application of triplicate patches of the vehicle and 10% AHTN in ethanool/DEP was made to new sites. 2 Sets of the triplicate patches were exposed to UVB & UVA radiation for evaluation of photosensitisation potential while the other induced contact sensitisation. Other fragrance materials were also used to evaluate contact sensitisation. One set of the irradiated patches was irradiated following removal of 24 hour occluded patches. The other set of irradiated patches was irradiated within 10 min following application of test product.

In the rechallenge, the challenge schedule is repeated on selected subjects if required to evaluate possible false positive or negative reactions. The same procedure will be followed as for the challenge.

No evidence of photoallergy was noted following the challenge phase.