Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Tetsing was conducted between the 11th January 2018 and the 7th March 2018.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method

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:
2.1.1 Name Bisphenol-F(Reaction mass of 2,2’- methylenediphenol and 4,4’-methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol)
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 Content 97.4%
2.1.6 Expiration date Jun. 30, 2018
2.1.7 Storage condition Room temperature (measurement value: 18.7−20.2°C, permissible range: 15−25°C)
2.1.8 Handling instructions Wear gloves, protective clothing, and eye and face protection
2.1.9 Supplier
Name KUKDO Chemical Co., Ltd.
Address 345-35, Kasan-dong, Kumchon-gu, Seoul 08588, Republic of Korea
2.1.10 Date of receipt Dec. 1, 2017

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
2.3.3 Justification for species selection
Sprague-Dawley rats are commonly used in toxicity studies, having a large historical control database.

2.3.4 Sex, number, age and body weight range of animals at receipt Females, 13 rats, 7 weeks old, 168.6−188.0 g
2.3.5 Sex, number, age and body weight range of animals at administration Females, 12 rats, 8−9 weeks old, 184.2−214.5 g
2.3.6 Quarantine and acclimation
Upon receipt, all animals were subjected to the clinical examination. Body weights were recorded using an electronic balance (CP3202S, Sartorius, Germany).
General health examination was conducted by responsible personnel of quarantine on the last day of the quarantine-acclimation period. All animals were observed for general condition and clinical signs daily and body weights (Table 4) were recorded on Day 7 after receipt. All animals were quarantined for 4 days, moved from the quarantine room to the animal room and then acclimated for 3 days.

2.3.7 Animal and cage identification
During the acclimation period, a temporary identification number was marked on the tail using a red indelible pen. Each cage was attached with a coded cage card for the quarantine-acclimation period.
Following group assignment, the animals were uniquely identified by a blue indelible marking on the tail and a color-coded cage card was placed on each cage describing the group and dose level.


2.3.8 Group assignment
The group assignment was carried out on animals showing no abnormal clinical signs or weight gain after the completion of acclimation period (day of group assignment). Twelve animals with body weights close to the mean body weight of the day of group assignment were selected and animals were randomly assigned to four groups (three females/group; four steps). Animals of each group (Step 1: G1, Step 2: G2, Step 3: G3 and Step 4: G4) were given an animal ID number (G1: 2101−2103, G2: 2201−2203, G3: 2301−2303 and G4: 2401−2403).

2.3.9 Disposition of remaining animals
The remaining animals not selected for the study were discarded following group assignment.

2.4 Animal Husbandry

2.4.1 Quarantine room No. A315

2.4.2 Animal room No. A323

2.4.3 Type & size of cage Stainless wire mesh cage, 260W×350D×210H (mm)

2.4.4 Number of animals per cage One animal/cage (during the study)

2.4.5 Temperature Measurement value: 17.6−24.0°C, permissible range: 19.0−25.0°C

2.4.6 Relative humidity Measurement value: 36.9−58.4%, permissible range: 30.0−70.0%

2.4.7 Air changes 10−15 clean, fresh, filtered air changes per hour

2.4.8 Lighting 12 hour light/dark cycle
(7 AM−7 PM via automated timer)

2.4.9 Intensity of illumination 150−300 Lux

2.4.10 Cage washing Every two weeks
Cages and feeders were washed in a cage washer and sterilized by an autoclave.

2.5 Feed

2.5.1 Type
Pelleted rodent chow
(Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C) 2.5.2 Lot No. 2918C-100317MA


2.5.3 Manufacturer Envigo RMS, Inc., U.S.A.

2.5.4 Method of feeding
The feed was placed in feeders and provided ad libitum.

2.5.5 Analysis and confirmation of feed
The certificate of feed analysis was provided by the manufacturer, Envigo RMS, Inc. The results of feed analysis met the allowable standard of this facility.

2.6 Drinking Water

2.6.1 Type and method of water supply
Public tap water in Cheongju-si was filtered and irradiated by ultraviolet light and provided ad libitum.

2.6.2 Analysis and confirmation of drinking water
Samples of drinking water are analyzed for specified microorganisms once a month and all environmental contaminants once a year by the Research Institute of Health & Environment, ChungBuk (184, Osong saengmyeong 1(il)-ro, Osong-eup, Heungdeok- gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea) according to the Regulation of Quality Criteria for Potable Water and Test (Ministry of Environment Ordinance No. 684, Revision Dec. 30, 2016). The results of water analysis met the allowable standard of this facility.


Administration / exposure

Route of administration:
other: Oral via gastric intubation
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
The required amount of the test substance was weighed by an electronic balance (CPA224S ENTRIS423i-1S, Sartorius, Germany) and placed in a mortar. A small
amount of vehicle, corn oil, was added and mixed using a vortex mixer until suspended. The vehicle was gradually added to yield the desired concentrations (60 and 400 mg/mL). All preparations were conducted just prior to use.

MAXIMUM DOSE VOLUME APPLIED:

DOSAGE PREPARATION (if unusual):
Individual doses were calculated based on the animal’s body weight recorded just prior to dosing at a dose volume of 5 mL/kg body weight. Animals were dosed via gastric intubation with a 1- or 3-mL disposable syringe fitted with an intubation tube. Animals were fasted overnight, approximately 16 hours prior to dosing. Drinking water was provided ad libitum. Feed was provided approximately 4 hours post dosing

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:

Group Designation and Dose Levels

The starting dose level for this study was selected at 300 mg/kg because there was no available toxicity information on the test substance.
The following sequential dosing steps were based on the mortality and clinical observations of animals for 3−4 days after the previous dose level. The following dosage regimen was selected according to the TEST PROCEDURE WITH A STARTING DOSE OF 300 MG/KG BODY WEIGHT’.
The group designation is shown as follows:

Group Step Dose (mg/kg) Dose volume (mL/kg) Animals (ID No.) Deaths
G1 Step 1 300 5 3 (2101−2103) None
G2 Step 2 300 5 3 (2201−2203) None
G3 Step 3 2,000 5 3 (2301−2303) None
G4 Step 4 2,000 5 3 (2401−2403) None

Doses:
300 mg/kg and 2000 mg/kg
No. of animals per sex per dose:
Group Step Dose (mg/kg) Dose volume (mL/kg) Animals (ID No.) Deaths
G1 Step 1 300 5 3 (2101−2103) None
G2 Step 2 300 5 3 (2201−2203) None
G3 Step 3 2,000 5 3 (2301−2303) None
G4 Step 4 2,000 5 3 (2401−2403) None
Control animals:
no
Details on study design:
Parameters Evaluated

Clinical signs
All animals were observed for mortality, general condition and clinical signs (type, severity, time of onset and recovery) at 30 minutes after dosing and at 1, 2, 4 and 6 hours after dosing on Day 0 and once daily thereafter for 14 days (Day 1−Day 14).

Body weights
The body weight was recorded prior to dosing on Day 0, on Days 1, 3, 7 and on the day of necropsy (Day 14).

Necropsy
On Day 14, all surviving animals were anesthetized with CO2 and exsanguinated from the abdominal aorta. Complete gross postmortem examinations were performed on all animals in the study.

Histopathology
Since no gross findings were observed at necropsy, histopathological examination was not performed.


Classification system used:
The classification of Globally Harmonized Classification System for Chemical Substances and Mixtures (GHS) Category was estimated based on the mortality in each step (Attachment).
Statistics:
Statistical analysis was not performed. Mean scores and values were determined

Results and discussion

Preliminary study:
None performed
Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits were not performed
Mortality:
There were no deaths of animals at 300 and 2,000 mg/kg throughout the study.
Clinical signs:
No abnormality in clinical signs was observed in any animal at 300 mg/kg throughout the study.
A decrease in locomotor activity, abnormal gait, lacrimation and/or salivation were observed in 1−3 animals at 2,000 mg/kg from 0.5−6 hours after dosing. A decrease of fecal volume was observed in 2 animals at 2,000 mg/kg on Day 1. The animals returned to a normal appearance on Day 2. These signs were considered to be test substance - related temporary changes.
Body weight:
Normal body weight gain was observed in all animals at 300 and 2,000 mg/kg throughout the study.
Gross pathology:
No grossly visible findings were observed in any animal at 300 and 2,000 mg/kg.

Any other information on results incl. tables

Table - Individual Clinical Signs

 

Dose (mg/kg)

ID

 

0.5

1

2

4

6

 

Step 1

 

2101

 

 

-

 

-

 

-

 

-

 

-

300

2102

 

-

-

-

-

-

 

2103

 

-

-

-

-

-

Step 2

2201

 

-

-

-

-

-

300

2202

 

-

-

-

-

-

 

2203

 

-

-

-

-

-

Step 3

2301

Decrease in locomotor activity

+

+

+

-

-

2,000

2302

Decrease in locomotor activity

+

+

+

-

-

 

2303

Decrease in locomotor activity

+

+

+

+

+

Step 4

2401

Abnormal gait

+

+

+

+

+

2,000

 

Lacrimation

-

-

-

+

-

 

 

2402

Salivation

-

-

-

-

-

-

+

-

-

-

 

2403

 

-

-

-

-

-

 


Days after dosing

Dose(mg/kg

)        ID

 

1

2

3

4

5

6

7

8

9

10

11

12

13

14

 

Step 1

 

2101

 

 

-

 

-

 

-

 

-

 

-

 

-

 

-

 

-

 

-

 

-

 

-

 

-

 

-

 

-

300

2102

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

2103

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Step 2

2201

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

300

2202

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

2203

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Step 3

2301

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

2,000

2302

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

2303

Decrease of fecal volume

+

-

-

-

-

-

-

-

-

-

-

-

-

-

Step 4

2401

Decrease of fecal volume

+

-

-

-

-

-

-

-

-

-

-

-

-

-

2,000

2402

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

2403

 

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

Clinical sign


Table - Individual Body Weights

 

 

 

(g)

Step /

Animal

 

Days

after dosing

 

 

Gain

Dose (mg/kg)

ID

0

1

3

7

14

014

 

Step 1

 

2101

 

186.2

 

204.4

 

208.4

 

220.7

 

235.9

 

49.7

300

2102

184.2

207.3

216.4

226.4

235.1

50.9

 

2103

188.4

208.8

223.3

233.1

250.7

62.3

 

Mean

186.3

206.8

216.0

226.7

240.6

54.3

 

S.D.

2.1

2.2

7.5

6.2

8.8

7.0

 

N

3

3

3

3

3

3

Step 2

2201

187.8

202.9

210.2

218.2

228.9

41.1

300

2202

199.7

219.9

227.0

239.9

260.3

60.6

 

2203

195.2

218.9

223.1

226.2

247.1

51.9

 

Mean

194.2

213.9

220.1

228.1

245.4

51.2

 

S.D.

6.0

9.5

8.8

11.0

15.8

9.8

 

N

3

3

3

3

3

3

Step 3

2301

209.9

228.9

230.1

241.1

255.9

46.0

2,000

2302

212.9

233.2

233.8

246.3

253.0

40.1

 

2303

207.6

219.1

219.3

235.4

260.0

52.4

 

Mean

210.1

227.1

227.7

240.9

256.3

46.2

 

S.D.

2.7

7.2

7.5

5.5

3.5

6.2

 

N

3

3

3

3

3

3

Step 4

2401

213.8

224.5

236.1

241.7

258.8

45.0

2,000

2402

214.5

230.8

231.3

244.6

257.5

43.0

 

2403

210.4

222.8

233.4

243.6

256.9

46.5

 

Mean

212.9

226.0

233.6

243.3

257.7

44.8

 

S.D.

2.2

4.2

2.4

1.5

1.0

1.8

 

N

3

3

3

3

3

3

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the result of the acute oral toxicity study in Sprague-Dawley rats, the test substance, Bisphenol-F(Reaction mass of 2,2’-methylenediphenol and 4,4’- methylenediphenol and o-[(4-hydroxyphenyl)methyl]phenol), was classified to be Category 5 or Unclassified according to the GHS classification.
Executive summary:

SUMMARY

 

The purpose of this study was to assess the potential toxicity and to classify the test substance, Bisphenol-F (Reaction mass of 2,2’-methylenediphenol and 4,4’- methylenediphenol and o- [(4-hydroxyphenyl)methyl]phenol), under the category of GHS classification following a single oral administration to 8–9-week-old female Sprague-Dawley rats.

Four dose groups of three females were utilized as follows:

Groups 1 and 2 (Steps 1 and 2):             300 mg/kg of the testsubstance

Groups 3 and 4 (Steps 3 and 4):             2,000 mg/kg of the test substance

Steps 1-2: A dose of 300 mg/kg was administered and then, there was no mortality (Step 1). A second dose of 300 mg/kg was administered. Again, no mortality was observed (Step 2).

Steps 3-4: A third dose of 2,000 mg/kg was administered and no mortality was observed (Step 3). A fourth dose of 2,000 mg/kg was administered. Again, no mortality was observed (Step 4). The study was finished at that point.

All animals were monitored for clinical signs and body weight changes during the 14-day observation period after administration. They were subjected to a gross necropsy at the end of the observation period.

 

 

There were no deaths of animals at 300 mg/kg. No test substance-related effects were observed in clinical signs, body weight changes or necropsy findings in any animal at 300 mg/kg.

There were no deaths of animals at 2,000 mg/kg. A decrease in locomotor activity, abnormal gait, lacrimation and/or salivation were observed on the day of dosing and, a decrease of fecal volume was observed at 2,000 mg/kg on Day 1. These animals returned to a normal appearance on Day 2. No test substance-related effects were observed in body weight data or necropsy findings in any animal at 2,000 mg/kg.

 

 

Based on the result of the acute oral toxicity study in Sprague-Dawley rats, the test substance, Bisphenol-F(Reaction mass of 2,2’-methylenediphenol and 4,4’- methylenediphenol and o- [(4-hydroxyphenyl)methyl]phenol), was classified to be Category 5 or Unclassified according to the GHS classification.