Name: OECD_SIDS / SUBSTANCE : 4,4&#39;-Bis(chloromethyl)-1,1&#39;-biphenyl /1667-10-3 Tue, 29 Nov 2022, 14:54:11+0900 /Legal entity owner: National Institute of Health Sciences
Printing date: 2022-11-29T14:54:11.863+09:00

iTable of Contents
0/0 ............................................................................................................................. 1
National Institute of Health Science ..................................................................... 2
4,4'-Bis(chloromethyl)-1,1'-biphenyl ....................................................................... 3
1 General information .................................................................................. 3
1.1 Identification ................................................................................. 3
Identification ............................................................................... 3
Identification ...................................................................... 3
7 Toxicological information ......................................................................... 4
7.5 Repeated dose toxicity ................................................................... 4
7.5.1 Repeated dose toxicity: oral ................................................. 4
Repeated dose toxicity: oral. 001 .......................................... 4
7.6 Genetic toxicity ............................................................................ 13
7.6.1 Genetic toxicity in vitro ...................................................... 13
Genetic toxicity in vitro.001 ................................................ 13
Genetic toxicity in vitro.002 ................................................ 20
7.8 Toxicity to reproduction ............................................................... 24
7.8.1 Toxicity to reproduction ..................................................... 24
Toxicity to reproduction. 001 .............................................. 24
References ................................................................................................................ 34
Reference Substances ...................................................................................... 34
4,4’-bis(chloromethyl)-1,1’-biphenyl ............................................................. 34
Test Materials .................................................................................................. 35
4,4’-bis(chloromethyl)-1,1’-biphenyl ............................................................. 35
Literatures ....................................................................................................... 36
Combined repeated dose toxicity study with the reproductive/
developmental toxicity screening test of 4,4’-bis(chloromethyl)-1,1’biphenyl by oral administration in rats ........................................................ 36
In Vitro Chromosomal Aberration Test of on 4,4’-bis(chloromethyl)-1,1’biphenyl Cultured Chinese Hamster Cells. ................................................... 37
Reverse Mutation Test of 4,4’-bis(chloromethyl)-1,1’-biphenyl on Bacteria. ..... 38
Legal Entities ................................................................................................... 39
National Institute of Health Sciences .......................................................... 39ii

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Dossier header
Dossier submission type
Name
OECD SIDS
Versioncore 7.0
Name (given by user)

Dossier subject
Dossier subject
4,4'-Bis(chloromethyl)-1,1'-biphenyl / 1667-10-3
Public nameSubmitting legal entity
National Institute of Health Science
Dossier creation date/time
Tue, 29 Nov 2022, 14:54:11+0900
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LEGAL_ENTITY: National Institute of Health
Science
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General information
Legal entity nameNational Institute of Health Science2

4,4'-Bis(chloromethyl)-1,1'-biphenyl
General information
Identification
Identification
SUBSTANCE: 4,4'-Bis(chloromethyl)-1,1'-biphenyl

UUID: 3ee00742-ccec-4b17-adfe-16029fd9fc15
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Author:Date: 2022-11-29T14:30:05.957+09:00
Remarks:
Substance name
4,4'-Bis(chloromethyl)-1,1'-biphenyl
Legal entity
National Institute of Health Sciences / Kawasaki / Japan

Identification of substance
Reference substance
4,4’-bis(chloromethyl)-1,1’-biphenyl / 1667-10-3
EC number

EC name

CAS number

CAS name

1667-10-3
IUPAC nameRole in the supply chain
Manufacturer
false
Importer
false
Only representativefalse
Downstream user
false

3

Toxicological information
Repeated dose toxicity
Repeated dose toxicity: oral
ENDPOINT_STUDY_RECORD: Repeated dose toxicity: oral. 001

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Administrative data
Endpoint
short-term repeated dose toxicity: oral
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study OECD Test Guideline study under GLP condition
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study 7.8.1 Toxicity to reproduction: Toxicity to reproduction. 001
Related information
OECD / Toxicity to reproduction / Toxicity to reproduction. 001 / 4,4&#39;-Bis(chloromethyl)-1,1&#39;biphenyl / 1667-10-3

Data source
Reference
Combined repeated dose toxicity study with the reproductive/developmental toxicity screening test of /Ministry of Health, Labour and Welfare (MHLW), Japan / study report
Data accessdata published4Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction /Developmental Toxicity Screening Test)
Deviationsno
GLP compliance
yes
Limit test
no

Test material
Test material information
4,4’-bis(chloromethyl)-1,1’-biphenyl
Specific details on test material used for the study- Name of test material (as cited in study report): 4,4’-bis(chloromethyl)-1,1’-biphenyl- Analytical purity: 99.8%- Storage condition of test material: Room temperature, shading, airtightness, moisture proof- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

Test animals
Speciesratcommon rodent species
Strainother: Crl:CD (SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Japan, Inc., Hino Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation:
Males (main study groups): 325-367 g, females (main study groups): 223-258 g, females (mating stu
dy groups): 222-259 g- Housing: Animals were individually housed in stainless steel suspension cage (240W × 380D × 200Hmm), from gestation day 18 to lactation day 4, Dams were bred individually or with individual litte
rmates in plastic cages (310W x 360D x 175H mm) and bedding.
- Diet: Solid feed (CRF-1: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: Males (main study groups): 18 days, females (main study groups): 19 days,
females (mating study groups): 18 days
5

ENVIRONMENTAL CONDITIONS- Temperature (°C): 20-26°C (actual temperature: 22.5-24.8°C)- Humidity (%): 40.0-70.0% (actual humidity: 40.7-60.4%)- Air changes (per hr): 12- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 6:00~18:00)

Administration / exposure
Route of administration
oral: gavage
Vehiclemethylcellulose 0.5 w/v% methylcellulose
Details on oral exposure- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
Test suspensions at each concentration to be used for males in main group and females matinggroup in day 1 of administration were analyzed by HPLC method. Results showed that the concentrat
ion of test article in each concentration was 102.7 to 106.7% of the nominal concentration andboth values were within the acceptable range (concentration: percentage of nominal concentration,
100±10%)Duration of treatment / exposure
Males: 28 days including 14 days pre-mating
Females (main study groups): 28 days
Females (mating groups): 42-46 days including 14 days pre-mating, mating and gestation periods andthe days until day 4 of lactation
Frequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
62.5

mg/kg bw/day (actual dose received)

Dose / conc.
250

mg/kg bw/day (actual dose received)

Dose / conc.
1000

mg/kg bw/day (actual dose received)

6

No. of animals per sex per dose
- Main study groups:
Control- and high-dose groups: 12 males and 10 females per group (half of both sexes assigned as t
he treatment groups, and the remaining half assigned as the recovery groups)
Low- and middle-dose groups: 12 males and 5 females per group (half of males assigned as thetreatment groups, and the remaining half assigned as the recovery groups)- Mating groups:
12 females per dose
Control animals
yes, concurrent vehicle
Details on study design- Dose selection rationale: Based on the results of a 14-day preliminary study, the high dose was set to1000 mg/kg bw/day, which is the upper limit in OECD TG422, and the intermediate dose and low dosewere set to 250 mg/kg bw/day and 62.5 mg/kg bw/day, respectively.
[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0, 200, 500 or 1000 mg/kg bw/day).
In males at 1000 mg/kg bw/day, decrease tendencies in body weight and decrease in food cons
umption were observed. In females at 1000 mg/kg bw/day, increase in A/G and relative liver weights
were observed.
- Rationale for animal assignment (if not random): Body weight-balanced randomization.

Examinations
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes- Time schedule:
Males and females (main study groups): 2 times/day (before administration, 54-137 minutes afteradministration) during the administration period. Once a day during the recovery period.
Females (mating groups): 2 times/day (before administration, 60-138 minutes after administration) during the administration period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Males and females (main study groups): on day of grouping, on days 7, 14, 21 and 27 of admin
istration period.
Females (mating groups): on day of grouping, on days 7 and 14 of administration period, on days 1, 8
and 15 of gestation period, on day 4 of lactation period.
BODY WEIGHT: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (On days 1, 4, 8, 11, 15, 18, 22, 25, 28 and 29 of administration period, on days 1, 4, 8, 11
and 14 of recovery period).
Females (mating groups): Twice a week (On days 1, 4, 8, 11, 15 and 18 of administration period, ondays 0, 7, 14 and 20 of gestation period, on days 0, 4 and 5 of lactation period).
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (Males: On days 2, 5, 9 and 12 of administration period, on days 2, 5, 9 and 12 of reco
very period; Females: On days 2, 5, 9, 12, 16, 19, 23 and 26 of administration period, on days 2, 5, 9 and
12 of recovery period).
7

Females (mating groups): Twice a week (On days 2, 5, 9 and 12 of administration period, on days 2, 9,
16 and 20 of gestation period, on days 2 of lactation period).
WATER INTAKE: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (Males: On days 2, 5, 9 and 12 of administration period, on days 2, 5, 9 and 12 of recove
ry period; Females: On days 2, 5, 9, 12, 16, 19, 23 and 26 of administration period, on days 2, 5, 9 and
12 of recovery period).
Females (mating groups): Twice a week (On days 2, 5, 9 and 12 of administration period, on days 2, 9,
16 and 20 of gestation period, on days 2 of lactation period).
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood:
Males and females (main study groups): At the end of administration period, or at the end of recovery
period in both sexes- Anaesthetic used for blood collection: Pentobarbital sodium- Animals fasted: Yes- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters examined: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte per
centage, platelet count, white blood cell count, differential white blood cell count, prothrombin time,
activated partial thromboplastin time, fibrinogen.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood:
Males and females (main study groups): At the end of administration period, or at the end of recovery
period in both sexes- Animals fasted: Yes- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0 and 1000 mg/kg bw/day)- Parameters checked: ALP, total cholesterol, triglyceride, total bilirubin, glucose, urea nitrogen,creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, albumin, A/G
ratio, AST, ALT, γ-GT
BLOOD HORMONE: Yes- Time schedule for collection of serum:
Males and females (main study groups): At the end of administration period in both sexes- Animals fasted: Yes- How many animals:
6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0, 62.5, 250, 1000 mg/kg bw/day)- Parameters checked: Triiodothyronine (T3), Thyroxin (T4), and thyroid stimulating hormone (TSH)
URINALYSIS: Yes- Time schedule for collection of urine:
Males and females (main study groups): Before the end of the administration period (day 23 of admin
istration period) and before the end of recovery (days 12 of recovery period).
- Metabolism cages used for collection of urine: Yes

8

A urine collector to collect fresh urine samples under fasting but ad libitum drinking conditions,followed by collection of 24-hour urine samples under ad libitum feeding and drinking conditions.
- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters checked:
Fresh urine: Color, pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen, sediment24-urine: Specific gravity, urine volume (24-hour volume)
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations:
Males and females (main study groups): Final week of administration (Manipulative test and measur
ement of grip strength: Day 27 of administration, measurement of motor activity: Day 26 of administr
ation)- Dose groups that were examined: Autopsy animals after the end of the administration period- Battery of functions tested:
1) Manipulative Test. Pupillary reflex, approaching behavior, response to touch, auditory reflex, painreflex2) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb
were measured by CPU gauge (San Diego Instruments Inc.).
3) Measurement of Spontaneous Motor Activity. Spontaneous motor activity (Ambulatory and verticalcounts) was measured by Activity Monitor (MED Associates Inc.).
The measurements were collected at 10-minute intervals from 1 hour to 2 hours after administration.
Sacrifice and pathology
GROSS PATHOLOGY: Yes
ORGAN WEIGHT: Yes [main study groups: brain, pituitary, salivary glands, thyroids, adrenal gland, thymus, spleen, heart, liver, kidney, testes, epididymides, ventral prostate, seminal vesicles, ovaries,
uterus; females in mating groups: ovary, uterus]
HISTOPATHOLOGY: Yes, [main study groups: heart, lung, trachea, liver, pancreas, sublingual gland, submandibular gland, esophagus, stomach, duodenum, jejunum, ileum (including Peyer’s patch),cecum, colon, rectum, thymus, spleen, mandibular lymph nodes, mesenteric lymph nodes, kidney,urinary bladder, testis, epididymis, ventral prostate, seminal vesicles (including coagulating gland),ovaries, uterus, vagina, pituitary, adrenal glands, thyroid (including parathyroid), cerebrum, cerebellum,
pons, spinal cord, sciatic nerve, eye ball, Harderian gland, sternum and femur (including bone marrows), muscle (rectus femoris), mammary gland; females in mating groups: ovaries, uterus, vagina]
Statistics
For quantitative data, homogeneity of variance was tested using Bartlett method first. If the variance
was homogenous, statistical difference between each treatment group and the control group was
analyzed using Dunnett method. If not homogenous, statistical difference between each treatmentgroup and the control group was tested using Steel method. For comparison of quantitative data be
tween two groups in the recovery test, homogeneity of variance was analyzed by F-test. Then, if homo
genous, student's t-test was applied. If not homogenous, Aspin-Welch's t-test was used.
For histopathological findings, statistical analysis was carried out in combination with Steel-test a
nd Cochran-Armitage trend test. Regarding clinical observation (except for frequency of urination, defecation, rearing and grooming) and sensory reactivity, Steel test was applied.

Results and discussion
Results of examinations
9

Clinical signs
no effects observed
Mortality
no mortality observed
Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)no effects observed
Ophthalmological findings
not examined
Haematological findings
effects observed, treatment-related
Description (incidence and severity)[At the end of administration period]:
Prolongation of PT was observed in males at 1000 mg/kg bw/day.
[At the end of recovery period]:
There were no changes related to the test substance in any groups.
Clinical biochemistry findings
effects observed, treatment-related
Description (incidence and severity)
Including blood hormones (T3, T4, TSH)
CLINICAL BIOCHEMISTRY:[At the end of administration period]:
Increase in ALT and decrease in triglyceride were observed in males at 1000 mg/kg bw/day. Increase
in A/G was observed in females of main study group at 250 mg/kg bw/day and above.
[At the end of recovery period]:
Increase in ALT was observed in males at 1000 mg/kg bw/day.
BLOOD HORMONES:
There were no changes related to the test substance in any groups at the end of administration andrecovery periods.
Urinalysis findings
no effects observed
Behaviour (functional findings)
no effects observed
Immunological findings
not examined
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Description (incidence and severity)[At the end of administration period]:10

Increases in absolute and relative thyroids weights, increase in relative liver weight and increase t
endencies in absolute liver weight were observed in females of main study group at 1000 mg/kg bw/
day.
[At the end of recovery period]:
Increase in relative liver weight and increase tendency in absolute liver weight were observed inmales at 1000 mg/kg bw/day.
Gross pathological findings
no effects observed
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
no effects observed
Histopathological findings: neoplastic
not examined

Effect levels
Key result
true
Dose descriptor
NOAEL
Effect level250

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
male
Basis for effect level
clinical biochemistry
At 1000 mg/kg bw/day, increase in ALT and decrease in triglyceride were observed in males.
Key result
true
Dose descriptor
NOAEL
Effect level
62.5

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
female11

Basis for effect level
clinical biochemistry
At 250 mg/kg bw/day, increase in A/G was observed in non-mating females (main study groups)

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF1667-10-3d.pdf

Applicant's summary and conclusion
Conclusions
The NOAELs for the repeated dose toxicity were 250 mg/kg bw/day in males based on increased ALT
and decreased TG at 1000 mg/kg bw/day and 62.5 mg/kg bw/day in females based on increased A/
G at 250 mg/kg bw/day.
Executive summary
In the combined repeated dose and reproductive/developmental screening test (OECD TG422), SD rats
were treated orally with the test substance at the doses of 0, 62.5, 250 and 1000 mg/kg bw/day. Males(12 animals/dose: 6 animals were treated as a recovery group) were dosed for 28 days including a 14 day
pre-mating period. Females (12 animals/dose) were dosed for 42-46 days including 14 day premating,mating, and gestation periods and days until day 4 of lactation. In addition, as the main study group of
females, 5 or 10 females/group was dosed for 28 days without mating (5 females at 0 and 1000 mg/
kg bw/day were treated as recovery groups).
The following findings were observed in examination at the end of administration period. In thehematological examination, prolongation of PT was observed in males at 1000 mg/kg bw/day. In theclinical chemistry, an increase in ALT and a decrease in triglyceride were observed in males at 1000 mg/
kg bw/day, an increase in A/G was observed in females of main study group at 250 mg/kg bw/day andabove. In the organ weights, increases in absolute and relative thyroids weights, increase in relative liver
weight and increase tendency in absolute liver weight were observed in females of main study groupat 1000 mg/kg bw/day.
Based on the above results, NOAELs for the repeated dose toxicity of 4,4’-bis(chloromethyl)-1,1’-biphenyl
were determined to be 250 mg/kg bw/ day in male rats and 62.5 mg/kg bw/day in female rats.

12

Genetic toxicity
Genetic toxicity in vitro
ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.001

UUID: 42637a34-e7bc-4ab4-8ac0-ed16cb012d88
Dossier UUID:
Author:Date: 2021-03-15T16:13:55.000+09:00
Remarks:

Administrative data
Endpoint
in vitro gene mutation study in bacteria
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study under GLP condition
Reliability 1

Data source
Reference
Reverse Mutation Test of 4,4’-bis(chloromethyl)-1,1’-biphenyl on Bacteria. / Ministry of Health, Labourand Welfare (MHLW), Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
13

Guideline
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
in vitro gene mutation study in bacteria
Deviations
no
Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, otherDeviationsno
GLP compliance
yesType of assay
bacterial reverse mutation assay
in vitro gene mutation study in bacteria

Test material
Test material information
4,4’-bis(chloromethyl)-1,1’-biphenyl
Specific details on test material used for the study
Purity: 99.8%

MethodSpecies / strain
Species / strain / cell typeS. typhimurium TA 1535, TA 1537, TA 98 and TA 100
bacteria
Species / strain / cell type
E. coli WP2 uvr A
bacteria
Metabolic activation
with and without
Metabolic activation system
S9 mix: SD male rat liver, induced by phenobarbital and 5,6-benzoflavone
Test concentrations with justification for top dose
-S9 mix:
0.05, 0.15, 0.5, 1.5, 5, 15, 50, 150, 500, 1500, 5000 μg/plate (TA 1535, TA 98 and TA 100 strains)
50, 150, 500, 1500, 5000 μg/plate (TA1537and WP2uvrA strain)+S9 mix:
5, 15, 50, 150, 500, 1500, 5000 μg/plate (TA 98 and TA 100 strains)
15, 50, 150, 500, 1500, 5000 μg/plate (TA 1535 strain)14

50, 150, 500, 1500, 5000 μg/plate (TA1537 and WP2uvrA strain)
Maximum concentration was established based on the result of the preliminary test at concentration
up to 5000 ug/plate. In this test, the growth inhibition was not observed for all strains with or without
S9 mix.
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substance
9-aminoacridine
9-amimoacridine hydrochloride (9AA): -S9 mix: (TA1537)
sodium azide
NaN3: -S9 mix: (TA1535)
furylfuramide2-(2-Furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2): -S9 mix: (TA100, TA98, WP2 uvrA)
other: 2-aminoanthracene (2AA)+S9 mix: (TA1535, TA100, TA98, TA1537 and WP2 uvrA)
Details on test system and experimental conditions
METHOD OF APPLICATION: Preincubation
DURATION- Preincubation period: 20 min at 37°C
- Exposure duration: ca.48 hrs
NUMBER OF PLATES: 3
NUMBER OF REPLICATIONS: 2
DETERMINATION OF CYTOTOXICITY- Method: other: growth inhibition
Evaluation criteria
A chemical was judged to be mutagenic when the mean number of revertant colonies per plateincreased more than twice that of the negative control and when the dose-related and reproducible increase was observed.
StatisticsnoResults and discussion
Test results
Key result
true
15Species / strain
S. typhimurium TA 1535
bacteria
Metabolic activation
with and without
Genotoxicity
positive
Cytotoxicity / choice of top concentrations
no cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
True negative controls validity
not examined
Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 1537
bacteria
Metabolic activation
with
Genotoxicity
positive
Cytotoxicity / choice of top concentrations
no cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
True negative controls validity
not examined
Positive controls validity
valid
Key result
false
Species / strain
S. typhimurium TA 1537
bacteria
16

Metabolic activation
without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
no cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
True negative controls validity
not examined
Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 98
bacteria
Metabolic activation
with and without
Genotoxicity
positive
Cytotoxicity / choice of top concentrations
no cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
True negative controls validity
not examined
Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 100
bacteria
Metabolic activation
with and without
Genotoxicity
positive
17

Cytotoxicity / choice of top concentrations
no cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
True negative controls validity
not examined
Positive controls validity
valid
Key result
trueSpecies / strain
E. coli WP2 uvr A
bacteria
Metabolic activation
with and without
Genotoxicity
positive
Cytotoxicity / choice of top concentrations
no cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
True negative controls validity
not examined
Positive controls validity
valid
Additional information on results
The maximum specific activity of mutation was 142666.7 revertants/mg/plate, which was obse
rved in plates of Salmonella typhimurium TA100 treated with the test article at 1.5 μg/plate without
metabolic activation.

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF1667-10-3e.pdf

Applicant's summary and conclusion
Conclusions
Positive with or without metabolic activation
18

Executive summary
In a bacterial reverse mutation assay using Salmonella typhimurium TA100, TA1535, TA98, and TA
1537, and Escherichia coli WP2uvrA/pKM101 (OECD TG 471), 4,4’-bis(chloromethyl)-1,1’-biphenyl was
positive for TA100, TA1535, TA98 and Escherichia coli WP2uvrA with or without metabolic activation,
positive for TA1537 with metabolic activation. The maximum specific activity of mutation was 142666.7
revertants/mg/plate, which was observed in plates of Salmonella typhimurium TA100 treated with thetest article at 1.5 μg/plate without metabolic activation.

19

ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.002

UUID: ce367ab8-29bb-4af3-aee0-bbd090bcba9c
Dossier UUID:
Author:Date: 2021-03-15T16:14:34.000+09:00
Remarks:

Administrative data
Endpoint
in vitro cytogenicity / chromosome aberration study in mammalian cells
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study under GLP condition
Reliability 1

Data source
Reference
In Vitro Chromosomal Aberration Test of on 4,4’-bis(chloromethyl)-1,1’-biphenyl Cultured Chinese Ham /Ministry of Health, Labour and Welfare (MHLW), Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 473 (In Vitro Mammalian Chromosomal Aberration Test)in vitro cytogenicity / chromosomal aberration study in mammalian cells (from 26 September 2014)20

Deviations
no
Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, otherDeviationsno
GLP compliance
yesType of assay
in vitro mammalian chromosome aberration testin vitro cytogenicity / chromosome aberration study in mammalian cells

Test material
Test material information
4,4’-bis(chloromethyl)-1,1’-biphenyl
Specific details on test material used for the study
Purity: 99.8%

MethodSpecies / strain
Species / strain / cell type
Chinese hamster lung (CHL/IU)
mammalian cell line
Cytokinesis block (if used)colcemid
Metabolic activation
with and without
Metabolic activation system
S9 mix: SD male rat liver, induced by phenobarbital and 5,6-benzoflavone
Test concentrations with justification for top dose
Cell growth inhibition study-S9 mix (short-term treatment): 20.3, 40.6, 81.3, 162.5, 325, 650, 1300, 2600 ug/mL+S9 mix (short-term treatment): 20.3, 40.6, 81.3, 162.5, 325, 650, 1300, 2600 ug/mL-S9 mix (continuous treatment, 24hr): 20.3, 40.6, 81.3, 162.5, 325, 650, 1300, 2600 ug/mL
Main study-S9 (short-term treatment): 5, 10, 20, 40 ug/mL+S9 (short-term treatment): 12.5, 25, 50, 100 ug/mL-S9 mix (continuous treatment, 24hr): 2.5, 5, 10, 20 ug/mL
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
21

Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceN-dimethylnitrosamine+S9
mitomycin C-S9Details on test system and experimental conditions
METHOD OF APPLICATION: Exposure duration: [short-term treatment]:6 hrs + 18 hr, [continuous
treatment]: 24 hrs
SPINDLE INHIBITOR: Colcemid
STAIN: Giemsa stain (2 v/v%) for 15 min.
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 100 + 100 cells /concentration
DETERMINATION OF CYTOTOXICITY- Method: relative total growth
Evaluation criteria
For the evaluation of the frequencies of structural aberrations and of polyploidy induced, the following
criteria were employed. Appearance incidence of cell with chromosomal aberrations: Negative (-):
less than 5%, Equivocal(±): 5% or more and less than 10%, Positive(+): 10% or more
StatisticsnoResults and discussion
Test results
Key result
trueSpecies / strain
Chinese hamster lung (CHL/IU)
mammalian cell line
Metabolic activation
with and without
Genotoxicity
positive structural aberration, D20: 0.0011 mg/mL, TR: 9300
Cytotoxicity / choice of top concentrations
no cytotoxicity
22

Vehicle controls validity
valid
Untreated negative controls validity
not examined
True negative controls validity
not examined
Positive controls validityvalid

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF1667-10-3e.pdf

Applicant's summary and conclusion
Conclusions
Positive with or without metabolic activation
Executive summary
In an in vitro chromosomal aberration test using CHL/IU cells (OECD TG 473), 4,4’-bis(chloromethyl)-1,1’biphenyl induced structural chromosomal aberrations but did not induce chromosome numericalaberrations under the conditions of this study.

23

Toxicity to reproduction
Toxicity to reproduction
ENDPOINT_STUDY_RECORD: Toxicity to reproduction. 001

UUID: 85eab845-8249-48de-9a6b-4acc2e41e5a6
Dossier UUID:
Author:Date: 2022-11-17T16:49:30.411+09:00
Remarks:

Administrative data
Endpoint
reproductive toxicity, other A combined repeated dose/reproductive developmental toxicity study
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study OECD Test Guideline study under GLP condition
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study 7.5.1 Repeated dose toxicity: oral: Repeated dose toxicity: oral. 001
Related information
OECD / Repeated dose toxicity: oral / Repeated dose toxicity: oral. 001 / 4,4&#39;Bis(chloromethyl)-1,1&#39;-biphenyl / 1667-10-3

Data source
Reference
Combined repeated dose toxicity study with the reproductive/developmental toxicity screening test of /Ministry of Health, Labour and Welfare (MHLW), Japan / study report
Data accessdata published

Materials and methods
24Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction /Developmental Toxicity Screening Test)
Deviationsno
GLP compliance
yes
Limit test
no

Test material
Test material information
4,4’-bis(chloromethyl)-1,1’-biphenyl
Specific details on test material used for the study- Name of test material (as cited in study report): 4,4’-bis(chloromethyl)-1,1’-biphenyl- Analytical purity: 99.8%- Storage condition of test material: Room temperature, shading, airtightness, moisture proof- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

Test animals
Speciesrat
Strainother: Crl:CD(SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Japan, Inc., Hino Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation: Males in main group male: 325-367 g, females in main group: 223-258 g,
females in mating group: 222-259 g- Housing: Animals were individually housed in stainless steel suspension cage (240W × 380D × 200Hmm), from gestation day 18 to lactation day 4, Dams were bred individually or with individual littermat
es in plastic cages (310W x 360D x 175H mm) and bedding.
- Diet: Solid feed (CRF-1: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: Males in main group: 18 days, females in main group: 19 days, females in matinggroup: 18 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 20-26°C (actual temperature: 22.5-24.8°C)- Humidity (%): 40.0-70.0% (actual humidity: 40.7-60.4%)- Air changes (per hr): 12- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 6:00~18:00)
25

Administration / exposure
Route of administration
oral: gavage
Vehicleother: 0.5 w/v% methylcellulose
Details on exposure- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Details on mating procedure- M/F ratio per cage:1/1- Length of cohabitation: up to 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
Concentrations of the test suspensions using administration on day 1 were analyzed with HPLC.
Analytical concentrations of the test suspensions were all within the range of 102.7-106.7% of thenominal concentrations and both values were within the acceptable range (concentration: percentage
of nominal concentration, 100±10%).
Duration of treatment / exposure
Males: 28 days including 14 days pre-mating
Females (main study groups): 28 days
Females (mating groups): 42-46 days including 14 days pre-mating, mating and gestation periods andthe days until day 4 of lactation
Frequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
62.5

mg/kg bw/day (actual dose received)

Dose / conc.
250

mg/kg bw/day (actual dose received)

Dose / conc.
1000

mg/kg bw/day (actual dose received)

No. of animals per sex per dose
- Main study groups:
26

Control- and high-dose groups: 12 males and 10 females per group (half of both sexes assigned as t
he treatment groups, and the remaining half assigned as the recovery groups)
Low- and middle-dose groups: 12 males and 5 females per group (half of males assigned as thetreatment groups, and the remaining half assigned as the recovery groups)- Mating groups:
12 females per dose
Control animals
yes, concurrent no treatment
Details on study design- Dose selection rationale: Based on the results of a 14-day preliminary study, the high dose was set to1000 mg/kg bw/day, which is the upper limit in OECD TG422, and the intermediate dose and low dosewere set to 250 mg/kg bw/day and 62.5 mg/kg bw/day, respectively.
[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0, 200, 500 or 1000 mg/kg bw/day).
Males in the 1000 mg/kg bw/day group tended to have lower body weights and significantly lower
food intakes, females in the 1000 mg/kg bw/day group had significantly higher A/G and significantly
higher relative liver weights.
- Rationale for animal assignment (if not random): Body weight-balanced randomization

Examinations
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes- Time schedule:
Males and females (main study groups): 2 times/day (before administration, 54-137 minutes afteradministration) during the administration period. Once a day during the recovery period.
Females (mating groups): 2 times/day (before administration, 60-138 minutes after administration) during the administration period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Males and females (main study groups): on day of grouping, on days 7, 14, 21 and 27 of admin
istration period.
Females (mating groups): on day of grouping, on days 7 and 14 of administration period, on days 1, 8
and 15 of gestation period, on day 4 of lactation period.
BODY WEIGHT: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (On days 1, 4, 8, 11, 15, 18, 22, 25, 28 and 29 of administration period, on days 1, 4, 8, 11
and 14 of recovery period).
Females (mating groups): Twice a week (On days 1, 4, 8, 11, 15 and 18 of administration period, ondays 0, 7, 14 and 20 of gestation period, on days 0, 4 and 5 of lactation period).
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (Males: On days 2, 5, 9 and 12 of administration period, on days 2, 5, 9 and 12 of reco
very period; Females: On days 2, 5, 9, 12, 16, 19, 23 and 26 of administration period, on days 2, 5, 9 and
12 of recovery period).

27

Females (mating groups): Twice a week (On days 2, 5, 9 and 12 of administration period, on days 2, 9,
16 and 20 of gestation period, on days 2 of lactation period).
WATER INTAKE: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (Males: On days 2, 5, 9 and 12 of administration period, on days 2, 5, 9 and 12 of recove
ry period; Females: On days 2, 5, 9, 12, 16, 19, 23 and 26 of administration period, on days 2, 5, 9 and
12 of recovery period).
Females (mating groups): Twice a week (On days 2, 5, 9 and 12 of administration period, on days 2, 9,
16 and 20 of gestation period, on days 2 of lactation period).
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood:
Males and females (main study groups): At the end of administration period, or at the end of recovery
period in both sexes- Anaesthetic used for blood collection: Pentobarbital sodium- Animals fasted: Yes- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters examined: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte per
centage, platelet count, white blood cell count, differential white blood cell count, prothrombin time,
activated partial thromboplastin time, fibrinogen.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood:
Males and females (main study groups): At the end of administration period, or at the end of recovery
period in both sexes- Animals fasted: Yes- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0 and 1000 mg/kg bw/day)- Parameters checked: ALP, total cholesterol, triglyceride, total bilirubin, glucose, urea nitrogen,creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, albumin, A/G
ratio, AST, ALT, γ-GT
BLOOD HORMONE: Yes- Time schedule for collection of serum:
Males and females (main study groups): At the end of administration period in both sexes- Animals fasted: Yes- How many animals:
6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0, 62.5, 250, 1000 mg/kg bw/day)- Parameters checked: Triiodothyronine (T3), Thyroxin (T4), and thyroid stimulating hormone (TSH)
URINALYSIS: Yes- Time schedule for collection of urine:
Males and females (main study groups): Before the end of the administration period (day 23 of admin
istration period) and before the end of recovery (days 12 of recovery period).
- Metabolism cages used for collection of urine: Yes

28

A urine collector to collect fresh urine samples under fasting but ad libitum drinking conditions,followed by collection of 24-hour urine samples under ad libitum feeding and drinking conditions.
- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters checked:
Fresh urine: Color, pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen, sediment24-urine: Specific gravity, urine volume (24-hour volume)
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations:
Males and females (main study groups): Final week of administration (Manipulative test and measur
ement of grip strength: Day 27 of administration, measurement of motor activity: Day 26 of administr
ation)- Dose groups that were examined: Autopsy animals after the end of the administration period- Battery of functions tested:
1) Manipulative Test. Pupillary reflex, approaching behavior, response to touch, auditory reflex, painreflex2) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb
were measured by CPU gauge (San Diego Instruments Inc.).
3) Measurement of Spontaneous Motor Activity. Spontaneous motor activity (Ambulatory and verticalcounts) was measured by Activity Monitor (MED Associates Inc.).
The measurements were collected at 10-minute intervals from 1 hour to 2 hours after administration.
Oestrous cyclicity (parental animals)
Vaginal smears were collected from all females in the mating study groups and microscopicallyexamined every day from the day after the start of administration until the day copulation was c
onfirmed.
Sperm parameters (parental animals)
Parameters examined in all P male parental generations: testis, epididymis and seminal vesicle weight, histopathological examinations for testes, epididymides, seminal vesicle and ventral prostate.
Litter observations
PARAMETERS EXAMINED: The following parameters were examined in F1 offspring: Number and sexof pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, and weight gain.
GROSS EXAMINATION OF DEAD PUPS: Yes, for external and internal abnormalities.
Postmortem examinations (parental animals)
METHOD OF SACRIFICED: All animals were sacrificed by exsanguination under pentobarbital sodium
anesthesia.
SACRIFICE: Males and females (main study groups): On next day after the last administration,
Maternal animals: on Day 5 of lactation, and males and females recovery group: on Day 14 of recovery.
GROSS PATHOLOGY: Yes
ORGAN WEIGHT: Yes [main study groups: brain, pituitary, salivary glands, thyroids, adrenal gland,
thymus, spleen, heart, liver, kidney, testes, epididymides, ventral prostate, seminal vesicles, ovaries, ut
erus; females in mating group: ovary, uterus]
HISTOPATHOLOGY: Yes, [main study groups: heart, lung, trachea, liver, pancreas, sublingual gland,
submandibular gland, esophagus, stomach, duodenum, jejunum, ileum (including Peyer’s patch),cecum, colon, rectum, thymus, spleen, mandibular lymph nodes, mesenteric lymph nodes, kidney,urinary bladder, testis, epididymis, ventral prostate, seminal vesicles (including coagulating gland),29

ovaries, uterus, vagina, pituitary, adrenal glands, thyroid (including parathyroid), cerebrum, cerebellum, pons, spinal cord, sciatic nerve, eye ball, Harderian gland, sternum and femur (including bone marrows), muscle (rectus femoris), mammary gland; females in mating group: ovaries, uterus, vagina ]Postmortem examinations (offspring)
SACRIFICE- The F1 offsprings were euthanized on PND4 by exsanguination under 20%Isoflurane anesthesia.
GROSS NECROPSY: Yes- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, andabdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS- Not examined.
Statistics
For quantitative data, homogeneity of variance was tested using Bartlett method first. If the variance
was homogenous, statistical difference between each treatment group and the control group was
analyzed using Dunnett method. If not homogenous, statistical difference between each treatmentgroup and the control group was tested using Steel method. For comparison of quantitative data be
tween two groups in the recovery test, homogeneity of variance was analyzed by F-test. Then, if homo
genous, student's t-test was applied. If not homogenous, Aspin-Welch's t-test was used.
For histopathological findings, statistical analysis was carried out in combination with Steel-test a
nd Cochran-Armitage trend test. Regarding clinical observation (except for frequency of urination, defecation, rearing and grooming) and sensory reactivity, Steel test was applied. Regarding implantat
ion index, delivery index, birth index, live birth index, viability index, sex ratio and external abnormalities, Steel test was performed between administration groups and control groups. Regarding copulation,
fertility index, and gestation index, Fisher's test was applied.
Reproductive indices
Each parameter was determined by the following equations:
Copulation index (%) = (No. of pairs with successful copulation / No. of pairs) × 100
Fertility index (%) = (No. of pregnant females / No. of pairs with successful copulation) × 100
Gestation index (%) = (No. of dams having live pups / No. of pregnant dams) × 100
Length of gestation (days)
Implantation index (%) = (No. of implantation scars / No. of corpora lutea) × 100
Delivery index (%) = (No. of pups born / No. of implantation scars) × 100
Birth index (%) = (No. of live pups born / No. of implantation scars) × 100
Live birth index (%) = (No. of live pups born / No. of pups born) × 100
Sex ratio on Day 4 of lactation = No. of male pups / No. of female pups
External abnormalities (%) = (No. of pups with external abnormalities / No. of live pups) × 100
Offspring viability indices
Viability index (%) = (No. of live pups on Day 4 of lactation/ No. of live pups born) × 100

Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
Clinical signs
no effects observed
Mortality
no mortality observed
30Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)no effects observed
Ophthalmological findings
not examined
Haematological findings
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity. 001
Clinical biochemistry findings
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity. 001
Urinalysis findings
no effects observed
Behaviour (functional findings)
no effects observed
Immunological findings
not examined
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity. 001
Gross pathological findings
no effects observed
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
no effects observed
Histopathological findings: neoplastic
not examined

Reproductive function / performance (P0)
Reproductive function: oestrous cycle
no effects observed31

Reproductive function: sperm measures
no effects observed
Reproductive performanceno effects observed

Details on results (P0)General toxicity: See 7.5.1 Repeated dose toxicity. 001
Reproductive function / performance: There were no effects on reproductive parameters up to 1000
mg/kg bw/day.

Effect levels (P0)
Key result
false
Dose descriptor
NOAEL
Effect level1000

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Remarks on result
other: There were no effects on reproductive parameters up to 1000 mg/kg bw/day.

Results: F1 generation
General toxicity (F1)Clinical signs
no effects observed
Mortality / viability
no mortality observed
Body weight and weight changes
no effects observed
Gross pathological findings
no effects observed

Details on results (F1)
There were no effects on developmental parameters up to 1000 mg/kg bw/day.

Effect levels (F1)32

Key result
true
Dose descriptor
NOAEL
Generation
F1
Effect level1000

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
other: There were no effects on developmental parameters up to 1000 mg/kg bw/day.

Overall reproductive toxicity
Key result
true
Reproductive effects observednoAny other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF1667-10-3d.pdf

Applicant's summary and conclusion
Conclusions
In the combined repeated oral dose toxicity study with the reproduction/developmental toxicity
screening test (OECD TG 422) described above, there were no effects on the reproductive and dev
elopmental parameters up to 1000 mg/kg bw/day. The NOAEL for the rat reproductive/developmental
toxicity of 4,4’-bis(chloromethyl)-1,1’-biphenyl was regarded as 1000 mg/kg bw/day, the highest dosetested.

33

References
Reference Substances
REFERENCE_SUBSTANCE: 4,4’-bis(chloromethyl)-1,1’biphenyl
UUID: 7e71486c-3f27-4c3d-93ee-5b14b41905c6
Dossier UUID:
Author:Date: 2020-12-24T13:27:13.000+09:00
Remarks:
Reference substance name4,4’-bis(chloromethyl)-1,1’-biphenyl

Inventory
CAS number
1667-10-3

Molecular and structural information
Molecular formula
C14H12Cl2
Molecular weightca. 251.15

34

Test Materials
TEST_MATERIAL_INFORMATION: 4,4’bis(chloromethyl)-1,1’-biphenyl
UUID: 757212f2-5e32-4874-89c5-f2c6d7e985cd
Dossier UUID:
Author:Date: 2020-12-24T13:28:24.000+09:00
Remarks:Name
4,4’-bis(chloromethyl)-1,1’-biphenyl

Composition
Composition
Type
Constituent
Reference substance
4,4’-bis(chloromethyl)-1,1’-biphenyl / 1667-10-3
EC number

EC name

CAS number

CAS name

1667-10-3
IUPAC nameConcentration
99.8% (w/w)

Other characteristics
Test material form
solid: crystalline

35

Literatures
LITERATURE: Combined repeated dose toxicity study
with the reproductive/developmental toxicity screening
test of 4,4’-bis(chloromethyl)-1,1’-biphenyl by oral
administration in rats
UUID: 41bada24-1592-4bf3-b1bd-e21062c1a849
Dossier UUID:
Author:Date: 2020-12-24T13:15:44.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Combined repeated dose toxicity study with the reproductive/developmental toxicity screening test of4,4’-bis(chloromethyl)-1,1’-biphenyl by oral administration in rats
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Year
2011
Bibliographic source
available in the web of Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/
mhlw_data/home/pdf/PDF1667-10-3d.pdf
Testing facility
Nihon Bioresearch Inc.
Report number
10063036

LITERATURE: In Vitro Chromosomal Aberration Test of
on 4,4’-bis(chloromethyl)-1,1’-biphenyl Cultured Chinese
Hamster Cells.
UUID: fcb1e260-3f6a-4179-8167-ed926c3f7785
Dossier UUID:
Author:Date: 2021-03-15T16:14:31.000+09:00
Remarks:

General information
Reference Typestudy report
Title
In Vitro Chromosomal Aberration Test of on 4,4’-bis(chloromethyl)-1,1’-biphenyl Cultured Chinese
Hamster Cells.
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Year
2011
Bibliographic source
Japan Existing Chemical Data Base (JECDB)
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF1667-10-3e.pdf
Testing facility
Nihon Bioresearch Inc.
Report number
97103037

LITERATURE: Reverse Mutation Test of 4,4’bis(chloromethyl)-1,1’-biphenyl on Bacteria.
UUID: 88df2882-f6cc-4ab8-8657-609ba7f82941
Dossier UUID:
Author:Date: 2021-03-10T13:39:13.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Reverse Mutation Test of 4,4’-bis(chloromethyl)-1,1’-biphenyl on Bacteria.
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Year
2011
Bibliographic source
Japan Existing Chemical Data Base (JECDB)
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF1667-10-3e.pdf
Testing facility
Nihon Bioresearch Inc.
Report number
90143038

Legal Entities
LEGAL_ENTITY: National Institute of Health Sciences
UUID: IUC4-b036ff75-0f3c-323b-b200-ed5f46cf5101
Dossier UUID:
Author:Date: 2022-11-07T15:49:29.000+09:00
Remarks:

General information
Legal entity nameNational Institute of Health Sciences
Remarks
Disclaimer: The contents in this document were created based on the MHLW (Ministry of Health,Labour and Welfare) peer reviewed study reports (in Japanese) in JECDB (Japan Existing Chemical
Database) at http://dra4.nihs.go.jp/mhlw_data/jsp/SearchPageENG.jsp. Authorship is in the Divisionof Risk Assessment, the National Institute of Health Sciences, and the contents do not reflect any official MHLW opinions or any other regulatory policies.

Address
Address 1
Tonomachi 3-25-26
Address 2
Kawasaki-ku
Postal code
210-9501
Town
KawasakiRegion / State
Kanagawa
CountryJapan
JP

Identifiers
Other IT system identifiers
IT system
LEO
ID
10767
IT systemIUCLID439

ID
16558402024DIV750

40