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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Remarks:
Human patch test information
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
5th August to 20th September 1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is a well-documented study in humans. The study was subject to a Quality Assurance review. The reliability is reduced as the study is being used for read-across purposes.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
A Repeated Insult Patch Test with the test material was conducted by Hill Top Research, Inc., for Chevron Research and Technology Company. The test site location for this study was Norwood, Ohio.

The objective of this study was to evaluate the test article for the induction of contact sensitization by repetitive applications to the skin of human volunteers and to report any irritation observed with the test article. The design utilized was an adaptation of the Draize Patch Test.

The testing design consisted of the following:
A. INDUCTION PERIOD - Repetitive application of test article to the same site on the skin for approximately three weeks.
B. REST PERIOD - Following the induction period, the subjects did not receive any application of test article for approximately two weeks.
C. CHALLENGE - Application of test article to a naive site to test for reactions indicative of contact sensitization.

The two test articles listed below were tested simultaneously in this study employing the referenced concentrations, dose quantities, and patch types:
HTR Code Sponsor Code Patch Type Concentration Method and Quantity of Application Patch
A Mineral Oil, U.S.P. * Undiluted 0.1 ml dispensed using an Eppendorf® Semi-Automatic pipette
B Chevron test material * Undiluted 0.1 ml dispensed using a 2.5 cc syringe
C Chevron tes material * 50% w/w in Mineral Oil 0.1 ml dispensed using a 2.5 cc syringe
*Semi-occluded using Webril® pads (Professional Medical Products, Inc.) secured on two opposing sides with hypoallergenic tape (Blenderm®). Patches for the main phase of this study were occluded patches instead of semi-occluded.

Each test article was applied to sites on the skin of the deltoid region of the upper arm for a contact period of 24 (±1) hours per application. Induction applications were made three times per week for three successive weeks. The nine applications made during these three weeks were termed Induction Application Nos. 1 through 9, respectively. During the fourth week (on Monday), any subject who was absent for one of the regularly scheduled induction applications received a make-up induction application.

All induction applications for an individual test article were made to the same site (the site receiving the original test article at Induction Application No. 1) unless reactions become so strong as to make this inadvisable. Assessment of a score of Grade 2 or greater is considered to be a strong reaction. In this case, subsequent applications of the offending test article was made to an adjacent area, and a second change of site was made if a second strong reaction occurred. If a third strong reaction to the test article was manifested, patches of this test article were discontinued until after the rest period has been completed. The use of a first and second adjacent site was identified on the source document as M and M-1 sites, respectively, to indicate movement of test site from the original (O) application site.

A 10 to 17-day rest period followed the final induction application. Following the rest period, on the sixth week, a challenge application of the test articles were made to each subject. During the challenge application, the test articles remained in contact with the skin for a period of 24 (±1) hours. Challenge consisted of application to a naive site located away from the original (O) application site on the opposite arm. Observations at a naive site provided a basis for an interpretation of contact sensitization.

The study protocol was followed.

In the opinion of the Investigator, none of the deviations that occurred affected the integrity of the study.
GLP compliance:
no
Remarks:
Not applicable, however, the study was reviewed by the Quality Assurance Department of the test facility.
Type of study:
patch test
Justification for non-LLNA method:
This study was conducted (as all the studies in this category for this endpoint) some time before the choice of LLNA as default animal testing method was brought into guidance and regulation. The information from this human study was considered to be reliable, and is supported by all of the additional animal studies which exist (and are included), so the weight of evidence with all of the data suggests that the result of this key study is correct and should be used as they key information for hazard and risk assessment. With all the information available, no justification for further LLNA testing can be presented.

Test material

Constituent 1
Reference substance name:
122384-87-6
Cas Number:
122384-87-6
IUPAC Name:
122384-87-6
Details on test material:
CAS# 122384-87-6/68784-26-9/122384-86-5/68784-25-8. Phenol, tetrapropenyl-, sulfurized, carbonates, dodecyl-, sulfurized, carbonates,
calcium salts, overbased. Test material purity not provided

In vivo test system

Test animals

Species:
human
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
Prior to entrance into the study, written informed consent was obtained from each subject. Urine pregnancy tests were given to all females of childbearing potential at study start, week three, and study end.

One hundred forty-six (115 females and 31 males) subjects were enrolled in the study.

Twenty-six subjects dropped from the study.

A total of twenty-four (24) subjects completed the pilot phase. Eleven (11) subjects tested Test Article B, and thirteen (13) subjects tested Test Article C.

A total of ninty-six subjects completed the main phase of this study. One hundred twenty subjects completed the study.

Twenty-four subjects (17 females and 7 males) completed the pilot phase of this study. One hundred and four subjects (84 females and 20 males) completed the main phase of this study. All subjects were between the ages of 25 and 60.

Study design: in vivo (non-LLNA)

Induction
Route:
epicutaneous, occlusive
Vehicle:
other: Mineral Oil used in pilot study
Concentration / amount:
Pilot Study: 0.1 ml of mineral oil, undiluted test material & 50% diluted test material in mineral oil
Main Study Induction phase: 0.1 ml of mineral oil & undiluted test material
Main Study Challenge phase: 0.1 ml of mineral oil & undiluted test material
Challenge
Route:
epicutaneous, occlusive
Vehicle:
other: Mineral Oil used in pilot study
Concentration / amount:
Pilot Study: 0.1 ml of mineral oil, undiluted test material & 50% diluted test material in mineral oil
Main Study Induction phase: 0.1 ml of mineral oil & undiluted test material
Main Study Challenge phase: 0.1 ml of mineral oil & undiluted test material
No. of animals per dose:
Human Pilot Study: 24 total (17 females, 7 males)
Main Study: 104 (84 females, 20 males)
Details on study design:
The study was a human repeat insult patch study.

No chemical analysis of dosing solution was performed.

For the pilot study a semi occluded Webril patch was used.
For the main studies occluded Webril patches were used.

During the pilot study the test material was tested diluted 50% in mineral oil and undiluted. Mineral oil served as a negative control. Testing was
conducted under semi-occluded patch conditions. Twenty-four subjects were tested; one half with each formulation. The pilot study included both induction and challenge phases.

The main study included 104 subjects. Each subjects was exposed to 100% concentration of the test material. Mineral oil served as the negative
control. Testing was conducted under occluded patch conditions.

The test material was applied to the skin of the deltoid region of the upper arm for 24 hours/application. Induction applications were made three
times/week for three successive weeks. During the fourth week any subject who was absent for one regularly scheduled induction application
received a make-up induction application. A 10 to 17 day rest period followed the last induction application. Following the rest period a challenge
application remained in contact with a naive skin site, on the opposite arm, for 24 hours.

Challenge controls:
yes
Positive control substance(s):
not required

Results and discussion

Positive control results:
n/a

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
other: 1 challenge after repeated topical inductions
Group:
test chemical
Dose level:
100% (undiluted) test substance
No. with + reactions:
0
Total no. in group:
104
Clinical observations:
small incidence of mild erythema following initial induction, no evidence of sensitisation responses after challenge in either dose level
Remarks on result:
no indication of skin sensitisation
Group:
negative control
Remarks on result:
not measured/tested
Group:
positive control
Remarks on result:
not measured/tested

Any other information on results incl. tables

A total of 24 subjects completed the pilot study. 11 of 24 were exposed to the undiluted test material, 13 of 24 were exposed to the 50% concentration of the test material. All subjects were exposed to the mineral oil negative control. A small incidence of mild (+1) erythema was noted in response to all three materials during induction. Responses were sporadic and transient. Following challenge there was no evidence of contact sensitization.

A total of 104 subjects completed the main phase of the study. All subjects tested the undiluted test material and the mineral oil negative control. A small incidence of mild (+1) erythema was noted in response to the test material and the negative control during the challenge phase. Responses were sporadic and transient. Following challenge there was no evidence of contact sensitization.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
The test material was non-irritating and non-sensitizing under the conditions of this study.
Executive summary:

A standard Repeated Insult Patch Test was conducted on the test material. This was preceded by a Pilot Phase to select a proper concentration of the test material. The test material was tested undiluted and diluted to 50% in Mineral Oil. The negative control was Mineral Oil. The testing was conducted under semi-occluded patch conditions.

A total of 24 subjects was tested; one half to undiluted test material and one half to 50% test material in mineral oil. Only minimal reactions were noted during the inductions and challenge so that undiluted test material was selected for testing in the Main Phase.

A total of 104 additional subjects completed the Main Phase. The test material was tested undiluted. The negative control was Mineral Oil. The testing was conducted under occluded patch conditions. Only mild to moderate responses were noted during the main phase of the study, and it is concluded that the test material is non-irritating and non-sensitizing under the condition of this test.

The study is being used as read across to a structurally similar substance (the registration material).