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Toxicological information

Skin irritation / corrosion

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Administrative data

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 July 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP/Guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
not specified
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Light yellow, clear liquid
Details on test material:
The test substance, identified as Paraformaldehyde, oligomeric reaction products with 4-tert-butylphenol, m-phenylenebis(methylamine) (Mannich Base PTBP-MXDA), Lot #: VH 101996M1, was used. Three major components were present based on liquid chromatography analysis. 4-tert-Butylphenol (PTBP) was quantified by external standard at 45.2% w/w. The other two major components, m-xylenediamine (MXDA) and primary reaction product (PTBP-MXDA) were detected at 21.2% and 17.4% by area, respectfully. Water was detected at 0.31% w/w. The NMR and LC/MS spectra obtained were consistent with the proposed structures of the major components.

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Number of Animals: 1
Sex: Female, nulliparous and non-pregnant
Species/Strain: Rabbit/New Zealand albino.
Age/Body weight: Young adult (13 weeks)/2437 grams at experimental start.
Source: Received from Robinson Services, Inc. Clemmons, NC on June 27, 2012.

Housing: The animal was singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011)3. Litter paper was placed beneath the cage and was changed at least three times per week.
Animal Room Temperature and Relative Humidity Ranges: 21-22ºC and 69%, respectively.
Animal Room Air Changes/Hour: 12; Airflow measurements are evaluated regularly and the records are kept on file at Eurofins | Product Safety Labs.
Photoperiod: 12-hour light/dark cycle
Acclimation Period: 13 days
Feed: Harlan Teklad Certified Global High Fiber Rabbit Diet® #2031C. A designated amount of the diet was available to the rabbit (approximately 150 grams/day).
Water: Filtered tap water was supplied ad libitum by an automatic water dispensing system.
Contaminants: There were no known contaminants reasonably expected to be found in the food or water at levels which would have interfered with the results of this study. Analysis of the water is conducted regularly and the records are kept on file at Eurofins | Product Safety Labs. The most recent water analysis was conducted in July 2012. Harlan Teklad Certified Global High Fiber Rabbit Diet® #2031C, Lot Number: 2031C-053112MA, was analyzed in June 2012.

Test system

Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
Five-tenths of a milliliter of the test substance was applied to the skin of each dose site (total of 3 dose sites)
Duration of treatment / exposure:
The patches were removed at the appropriate intervals (3 minutes, 1 hour, and 4 hours).
Observation period:
All test sites were evaluated for corrosion 30-60 minutes after patch removal.
Number of animals:
1
Details on study design:
Preparation and Selection of Animal
On the day before application, a single animal was prepared by clipping the dorsal area and the trunk. On the day of dosing, but prior to application, the animal was examined for health and the skin checked for any abnormalities according to the “Primary Skin Irritation Scoring System”. One healthy naive animal (not previously tested) without pre-existing skin irritation was selected for test.

Application of Test Substance
Testing was conducted on one rabbit to determine the irritation/corrosion potential of the test substance. Three test sites, each approximately 6-cm2, were delineated on this rabbit. Five-tenths of a milliliter of the test substance was applied to the skin of each dose site and covered with a 1-inch x 1-inch, 4-ply gauze pad. The pads and entire trunk of the animal were then wrapped with semi-occlusive 3-inch Micropore™ tape to avoid dislocation of the patches. An Elizabethan collar was placed on the rabbit and it was returned to its designated cage. The patches were removed at the appropriate intervals (3 minutes, 1 hour, and 4 hours). All test sites were evaluated for corrosion 30-60 minutes after patch removal. Since corrosion was observed at the 4-hour test site for this animal, the study was terminated and no additional animals were tested.

After each exposure period, the test sites were cleansed with a 3% soap solution then tap water and a clean towel to remove any residual test substance. After 4 hours of exposure to the test substance, the 4-hour patch and Elizabethan collar were removed.

As per the Study Director, the animal was administered a 0.1 mL subcutaneous injection of a systemic analgesic (Buprenorphine Hydrochloride, i.e.: Buprenex®) at the 30-60 minute scoring interval following the 1-hour exposure to relieve potential discomfort.

Evaluation of Test Sites
Individual dose sites were scored according to the Draize scoring system at approximately 30-60 minutes after patch removal (Draize et al., 1944).

Body Weights
Body weights of the animal were recorded prior to test substance application (initial) and prior to euthanasia.

Cage-Side Observations
The animal was observed prior to test substance application.

Reference:
Draize, J.H., Woodward, G. and Calvery, H.O. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther. 1944; 82:377-390.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 1 hours
Score:
4
Remarks on result:
other: Brown discoloration and blanching in the dose site observed.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 4 hours
Score:
4
Remarks on result:
other: Blanching throughout the entire dose site with large areas of dark discoloration. Area outside of dose site appears to have destruction of the top skin layer.
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 1 hour
Score:
1
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 4 hours
Score:
2
Irritant / corrosive response data:
No visible necrosis of the skin tissue was observed at the 3-minute and 1-hour test sites. Corrosion was observed at the 4-hour test site at the 30-60 minutes scoring interval.

3-Minute and 1-Hour Exposure Sites
At 30-60 minutes after patch removal, severe erythema (score of 4) and very slight edema (score of 1) were noted at the 3-minute and 1-hour treated dose sites. Brown discoloration and blanching were also evident in the 1-hour dose site.

4-Hour Exposure Site
At 30-60 minutes after patch removal, severe erythema (score of 4) and slight edema (score of 2) were noted for the treated dose site. Blanching was also observed throughout the entire dose site with large areas of dark discoloration. The area outside of the dose site appeared to have destruction of the top skin layer.

Based on the severity of irritation observed at the 30-60 minute scoring interval, this animal was euthanized for humane reasons.
Other effects:
No additional information available.

Any other information on results incl. tables

No additional information available.

Applicant's summary and conclusion

Interpretation of results:
corrosive
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
Under the conditions of this study, Paraformaldehyde, oligomeric reaction products with 4-tert-butylphenol, m-phenylenebis(methylamine) (Mannich Base PTBP-MXDA) caused corrosion at the 4-hour exposure site for the 30-60 minute scoring interval.
Executive summary:

A primary skin irritation test was conducted with a female New Zealand albino rabbit to determine the potential for Paraformaldehyde, oligomeric reaction products with 4-tert-butylphenol, m-phenylenebis(methylamine) (Mannich Base PTBP-MXDA) to produce irritation and/or corrosion after a single topical application. Under the conditions of this study, Paraformaldehyde, oligomeric reaction products with 4-tert-butylphenol, m-phenylenebis(methylamine) (Mannich Base PTBP-MXDA) caused corrosion at the 4-hour exposure site for the 30-60 minute scoring interval. The animal was euthanized for humane reasons, the study was terminated and no additional animals were tested.

Initially, one rabbit was tested to determine the irritation/corrosion potential of the test substance. Three test sites, each approximately 6-cm2, were delineated on this animal. Five-tenths of a milliliter of the test substance was applied to the skin of each dose site and covered with a 1-inch x 1-inch, 4-ply gauze pad. The pads and entire trunk of the animal were then wrapped with semi-occlusive 3-inch Micropore™ tape to avoid dislocation of the patches. The patches were removed at the appropriate intervals (3 minutes, 1 hour, and 4 hours). All test sites were evaluated for corrosion 30-60 minutes after patch removal. All test sites were evaluated for skin irritation according to the Draize.

At 30-60 minutes after patch removal, severe erythema (score of 4) and very slight to slight edema (scores of 1 or 2) were noted at the 3-minute, 1-hour and 4-hour treated dose sites. Brown discoloration and blanching were evident at the 1- and 4- hour sites. The area outside of the 4-hour dose site also appeared to have destruction of the top skin layer. Based on the severity of the irritation observed, this animal was euthanized for humane reasons.

Due to corrosion observed at the 4-hour test site for this animal, the study was terminated and no additional animals were tested.