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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
from September 13, 2010 to October 22, 2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
skin irritation / corrosion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Repeated insult patch test was conducted. This test was conducted under the supervision of a Board-Certified Dermatologist, a Co-Investigator.
GLP compliance:
no
Remarks:
Not relevant (clinical study)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): HRIPT 146-1 [piperonal 2.5% (2953 µg/cm2) in 1:3 ethanol:diethyl phthalate]

Method

Type of population:
not specified
Subjects:
- Number of subjects exposed: 120 subjects (47 male and 73 female) enrolled; 112 subjects (42 male and 70 female) completed the test.
- Sex: male and female
- Age: The subjects range in age from 18-69.
- Race: Not reported.
- Other: Each potential subject completed an Harrison Research Laboratories (HRL) Subject History Form (HRL Form: SHF), including relevant medical history (An updated Subject History Form is secured approximately every two years). Each accepted subject was assigned a permanent HRL Identification Number. No known pregnant nor nursing women were used on this Repeated Insult Patch Test (RIPT). No minor subjects were used on this RIPT.
An appropriate clearance period had elapsed since a subject was patched on a RIPT or a Photoallergy Test (PA) before being used in this RIPT.
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.
Ethical approval:
confirmed and informed consent free of coercion received
Route of exposure:
dermal
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
TYPE OF TEST(S) USED: repeated insult patch test (epicutaneous test)

ADMINISTRATION
- Type of application: occlusive
- Description of patch: Webril/adhesive patch (25 mm Hill Top Chamber System) was used occlusively.
- Vehicle / solvent: 1:3 ethanol:diethyl phthalate
- Concentrations: 2.5%
- Volume applied: 0.3 mL
- Testing/scoring schedule:
Induction Phase:
A series of nine (9) induction patchings were completed over a period of approximately 3 weeks. Each subject was instructed that the patches were to remain in place and kept dry for approximately 24 hours, at which time the subject returned to HRL and HRL technician removed the patches. The subjects removed the patches themselves on Saturdays. A 24-hour period, during which no test materials were applied, followed the removal of the Monday and Wednesday patch applications; a 48-hour period followed the Friday patch applications.
If a subject missed a patching during an Induction week, the subject was given a make-up patching/patch removal appointment at the end of the Induction Phase. If a subject missed a patch removal, the subject was instructed to remove the patches him/herself. A make-up day was not necessary if a patch removal was missed.
Rest Period: A rest period of approximately 2 weeks followed the last induction patching; no test materials were applied during the rest period.
Challenge Phase: The original induction test sites were observed and each subject queried as to whether any reaction was experienced during the rest period. At 24, 48, 72, and 96 hours after exposure, the patches were removed and the challenge sites were scored.
- Removal of test substance: After 24 hours of exposure, the subject returned to HRL and an HRL technician removed the patches. The subjects removed the patches themselves on Saturdays.
- Other: Using a precise, repeating syringe, each test material was applied to each designated patch. The left side of the back was usually the test area for the Induction Phase. The subject’s skin was marked with gentian violet surgical marker at the left side of each test site. The test sites were recorded on the anatomical diagram of each subject’s individual data form. In addition, at this time, the prospective placement of the challenge test sites was also recorded on the anatomical diagram. The right side of the back was usually the virgin test site for the challenge phase.
Examinations:
EXAMINATIONS
- Grading/Scoring system: 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, 1986: p 26.
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
S:staining
P:peeling
^:hyperpigmentation
C:change of test site
-:no patch application and/or reading
N9R:no 9th reading
X:discontinued
Medical treatment:
Not applicable.

Results and discussion

Clinical signs:
RESULT OF CASE REPORT: No serious adverse events related to the test material occurred during this test.
Results of examinations:
NO. OF PERSONS WITH/OUT REACTIONS COMPARED TO STUDY POPULATION
HRIPT 146-1:
During the Induction phase, one subject #112 (HRL #36601), exhibited a 1-level plus edema reaction; the test site was changed. The new test site exhibited a low-level(±) reaction. Three other exhibited low level (±) reactions. During the challenge, four other subjects exhibited low-level (±).
- Number of subjects with positive reactions: 5/112 (faint, minimal erythema noted during challenge phase)
- Number of subjects with negative reactions: 104/112 (3 subjects had no reading during challenge phase)
HRIPT 146-2:
During the induction phase, ten subjects exhibited low-level (±) reactions. During the challenge, three subjects exhibited low-level (±) reactions.
- Number of subjects with positive reactions: 3/112 (faint, minimal erythema noted during challenge phase)
- Number of subjects with negative reactions: 106/112 (3 subjects had no reading during challenge phase)
HRIPT 146-3:
During the induction phase, no reactions were exhibited. During the challenge, two subjects exhibited low-level (±) reactions.
- Number of subjects with positive reactions: 2/112 (faint, minimal erythema noted during challenge phase)
- Number of subjects with negative reactions: 107/112 (3 subjects had no reading during challenge phase)

OTHER RESULTS:
Subject #031 (HRL #33532) received nine Induction patchings but was unable to return to HRL for the final Induction reading/scoring; she was therefore given a reading of N9R (no 9th reading).
Two subjects, #096 (HRL #22870) and #108 (HRL #35661), missed Challenge Reading 4. Both of the subjects returned to HRL on October 25, 2010 and their test sites were negative. A verbal report from these subjects stated ‘no reaction present’ at what would have been her Challenge Reading 4.
Effectivity of medical treatment:
Not applicable.
Outcome of incidence:
Not applicable.

Applicant's summary and conclusion

Conclusions:
During the Induction phase, one subject #112 (HRL #36601) out of 112 subjects, exhibited a 1-level plus edema reaction; the test site was changed. The new test site exhibited a low-level (±) reaction (faint, minimal erythema). The etiology of the edematous reaction exhibited during the Induction Phase to Test Material HRIPT 146 -1 (piperonal), by Subject #112, is unknown. Three other subjects out of 112 subjects exhibited low-level (±) reactions (faint, minimal erythema).
Executive summary:

The RIPT conducted by Harrison Research Laboratories (2011), which was conducted under the supervision of a Board-certified dermatologist, enrolled a total of 120 subjects (47 males and 73 females) to evaluate the sensitizing potential of 3 test materials: heliotropin (piperonal) (2.5% in a 1:3 ethanol:diethyl phthalate vehicle; designated HRIPT-146-1), vehicle (1:3 ethanol:diethyl phthalate; designated HRIPT-146-3), and saline (designated HRIPT-146-2). A total of 112 subjects completed the study (the other 8 subjects withdrew due to personal reasons; none withdrew due to test material reactions). In the induction phase, a volume of 0.3 mL of each test material was applied to designated 25 mm patches that were adhered occlusively to 1 side of the back of each subject (i.e., each subject received a patch of each test material). For heliotropin (piperonal), this resulted in a dose of 2,953µg/cm2. Patches were applied as such on Mondays, Wednesdays, and Fridays for 3 consecutive weeks (9 total applications), and were removed approximately 24 hours after each application (on Tuesdays, Thursdays, and Saturdays). Patches were repeatedly applied to the same sites, which were evaluated on Mondays, Wednesdays, and Fridays for possible reactions. A 2-week rest period followed the induction phase, after which subjects were challenged with a similar application of 3 patches (1 for each test material) on the opposite side of the back. During the induction phase, 3 subjects exhibited faint, minimal erythema after the first (1 subject) or second (2 subjects) application. A fourth subject exhibited faint, minimal erythema after applications 5, 6, and 7 and had erythema and edema after application 8. The application site was changed and this subject again had faint, minimal erythema after application 9. Comparatively, a total of 10 subjects exhibited faint, minimal erythema after 2 or more applications of saline. Thus, heliotropin (piperonal) demonstrated little potential to induce irritation in this study.