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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:
Testing was conducted between the 20th December 2017 and the 31st March 2018.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The purpose of this study was to assess the potential acute skin irritation/corrosion of the test substance, Bisphenol-F (Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol, following a single dermal application to New Zealand White rabbits.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Regulation on Test Methods for Chemical Substances” Notification No. 2017-4, National Institute of Environmental Research, Republic of Korea (Mar. 14, 2017)
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 4,4'-methylenediphenol and 2,2'-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol
EC Number:
908-912-9
Cas Number:
1333-16-0
Molecular formula:
C39H36O6
IUPAC Name:
Reaction mass of 4,4'-methylenediphenol and 2,2'-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol
Test material form:
solid
Details on test material:
2.1.2 Lot No. KZ517047
2.1.3 CAS No. 1333-16-0
2.1.4 Appearance Light pink or light yellow solid
2.1.5 Purity 97.4%
2.1.6 Expiration date - June 30th 2018
2.1.7 Storage condition (rom temperature 17.7 - 20.2 deg C)
Specific details on test material used for the study:
Test Substance Name: Bisphenol-F(Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol

Lot No. KZ517047

CAS No. 1333-16-0

Appearance Light pink or light yellow solid

Purity 97.4%

Expiration date Jun. 30, 2018

Storage conditions Room temperature (measurement value: 18.7–20.2°C,
permissible range: 15−25°C)

Handling instructions Wear a mask, clothing, gloves and goggle

Supplier:
Name KUKDO Chemical Co., Ltd.
Address 345-35, Kasan-dong, Kumchon-gu, 08588, Republic of Korea

Date of receipt Dec. 1, 2017

Disposition of test substance Any remaining test substance is discarded.

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
Test System:
Species, strain: Rabbit, New Zealand White (Kangda:NZW) SPF

Producer Qingdao Kangda Biotechnology Co., Ltd

Supplier Raonbio Inc., Republic of Korea

Justification for species selection: New Zealand White rabbits are commonly used in skin irritation studies having a large historical control database.

Sex, number, age and body weight range of animals (at receipt) Male, 5 rabbits, 16 weeks old, 2.52–2.67 kg

Sex, number, age and body weight range of animals (at the start of treatment) Male, 3 rabbits, 16–17 weeks old, 2.71–2.82 kg

Quarantine and acclimation
Upon receipt, all animals were subjected to the clinical examination. Body weights were recorded (CP12001S, Sartorius, Germany).
During the quarantine-acclimation period, all animals were observed for clinical signs once daily for 6 days in the initial test and for 8 days in the confirmatory test.
On the last day of the quarantine-acclimation period, the measurement of body weights and examination of health condition were conducted and the results were recorded for the study by a responsible person. All animals were judged to be healthy and acceptable for use in the study.

Animal and cage identification
During the quarantine-acclimation period, a temporary identification number was recorded on the inside of the left ear using a red indelible pen. Each cage was attached with an identification card for the quarantine-acclimation period.
Following group assignment, the animals were uniquely identified by recording the inside of the right ear with a blue indelible pen. Each cage was attached with a color identification card.

Group assignment
One day before application of the test substance, the dorsal surface of the rabbits was removed using hair clippers (Oster 5-50C U.S.A., size: 40, 1/10 mm). Three rabbits with good skin condition, without cuts or scratches, were selected for the initial test (one animal) and confirmatory test (two animals).

In order to protect the skin after group assignment, elizabeth kara was installed until the end of observation, but it was not installed during the period of occlusive dressing.

Disposition of remaining animals
Remaining animals not selected for the study were euthanized under pentothal sodium (JW Pharmaceutical Co., Ltd., Republic of Korea) anesthesia and discarded.

Animal Husbandry

Room No. A227
Type & size of cage Auto flush stainless steel cages, 450W×600D×360H (mm)
Number of animals per cage One animal/cage (during the quarantine-acclimation and observation periods)
Temperature Measurement value: 20.1–21.2°C,
Permissible range: 18.0–24.0°C

Relative humidity: Measurement value: 46.9–51.8%,
Permissible range: 30.0–70.0%
Air changes 10–15 clean, fresh, filtered air changes per hour

Lighting: 12 hour light/dark cycle (7 AM to 7 PM via automated timer)

Intensity of illumination: 150–300 Lux

Change and washing of breeding materials: Cages and feeders were washed using an automatic washer and cleaned with municipal tap water.

Test system

Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
Method of application:

A foam pad (3M Reston Self-Adhering Foam Pad, 3M Co., Ltd., U.S.A.), from which a 2.5 × 2.5 cm area was cut out, was placed on the application sites. The pulverized test substance of 0.5 g was applied on the test substance site using a spatula, moistened with 0.5 mL of water for injection (Lot No.: DBA7009, JW Pharmaceutical Co., Ltd., Republic of Korea) and a 2.5 × 2.5 cm lint patch (PIP Co., Ltd., Japan) was placed over the test substance site. An untreated 2.5×2.5 cm patch was placed over the control site. All application sites were covered with gauze (DaeHan Medical Supply Co., Ltd., Republic of Korea). Animals were wrapped loosely with an elastic bandage (3M Co., Ltd., Republic of Korea) and secured with a paper tape (Masking Tape, DAESUN Com., Republic of Korea) to form a semi-occlusive dressing. The residual test substance was gently wiped off the test substance site with cotton moistened with tepid water.
In the initial test, three test substance patches were sequentially applied to one animal. The first patch was removed at 3 minutes after application. Since no skin reaction was observed, the second patch was applied at a different site and removed at 1 hour after application. Since no skin reaction was observed, the third patch was applied and removed at 4 hours after application, and the response was graded.
A negative response was observed in the initial test. Therefore, a confirmatory test was conducted using additional two rabbits. In the confirmatory test, a single patch was applied and removed at 4 hours after application.

Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
3
Details on study design:
TEST SITE
The back, dorsal surface of each animal was clipped one day prior to application of the test substance, and each site, approximately 2.5×2.5 cm, was selected as application site

REMOVAL OF TEST SUBSTANCE
The residual test substance was gently wiped off the test substance site with cotton moistened with tepid water.

OBSERVATION TIME POINTS
Dermal observations for erythema, eschar and edema formation were recorded at 1, 24, 48 and 72 hours after patch removal according to the evaluation of skin reactions (Method of Draize: 1959)1). No skin irritation was observed in both the initial and confirmatory tests at 72 hours after patch removal; therefore, no additional skin observations were conducted.
Clinical signs were observed once daily throughout the study.

SCORING SYSTEM:
The Draize scoring system was used, however any classification would be based upon GHS.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Evaluation of Skin Reactions:
In both the initial and confirmatory tests, the test substance and control sites did not reveal any sign of adverse skin reactions such as erythema or edema in any of three animals at 1, 24, 48 and 72 hours after patch removal.

Classification of Primary Skin Irritation:
The individual primary skin irritation index (Individual P.I.I.) of the test substance was ‘0’ for each animal. Therefore, the P.I.I. of the test substance was ‘0’. The degree of skin irritation of the test substance was classified as ‘Non irritant’ according to the Draize’s method1).
Other effects:
Clinical Signs
No abnormal signs were observed in any animal throughout the course of the study.


Body Weights
All animals exhibited normal body weight gain. The mean body weight gain throughout the observation period was 0.09 kg.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
In conclusion, the test substance, Bisphenol-F(Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol, did not show any evidence of skin irritation or corrosion in New Zealand White rabbits under the conditions of this study.
Executive summary:

This study was conducted to evaluate the potential skin irritation/corrosion after a single dermal application of the test substance, Bisphenol-F (Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol, in three 16–17-week-old male New Zealand White rabbits.

In the initial test, three test substance patches were sequentially applied to one animal’s clipped back. 0.5 g of pulverized test substance was placed on the test substance site and it was moistened with water for injection. In the initial test, the first patch was removed at 3 minutes after application, and the second patch at 1 hour after application and the third patch at 4 hours after application. No skin reaction was observed in the initial test, thus a confirmatory test was conducted using two additional animals. Observations of application sites for skin response were conducted at 1, 24, 48 and 72 hours after patch removal and scored according to the ‘Evaluation of skin reactions (Method of Draize: 1959)1), although classification was assessed according to GHS.

 

In both the initial and confirmatory tests, the test substance and control sites of all animals did not reveal any sign of adverse skin reactions such as erythema or edema at 1, 24, 48 and 72 hours after patch removal. The primary skin irritation index (P.I.I.) of the test substance was ‘0’. The test substance was classified as ‘Non irritant’.

During the observation period, no abnormal clinical signs or body weight gain was observed in any animal.

 

Based on the result of this study, the test substance, Bisphenol-F (Reaction mass of 2,2’-methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol, did not show any evidence of skin irritation or corrosion in New Zealand White rabbits under the conditions of this study.