Name: OECD_SIDS / SUBSTANCE : 4-chloro-m-cresol / 59-50-7 Fri, 16 Dec 2022,
14:54:39+0900 /Legal entity owner: National Institute of Health Sciences
Printing date: 2022-12-16T14:54:39.884+09:00

iTable of Contents
0/0 ............................................................................................................................. 1
National Institute of Health Science ..................................................................... 2
4-chloro-m-cresol ................................................................................................. 3
1 General information .................................................................................. 3
1.1 Identification ................................................................................. 3
Identification ............................................................................... 3
Identification ...................................................................... 3
1.10 Assessment approach (assessment entities) ................................. 5
Assessment approach (assessment entities) ................................ 5
7 Toxicological information ......................................................................... 6
7.5 Repeated dose toxicity ................................................................... 6
7.5.1 Repeated dose toxicity: oral ................................................. 6
Repeated dose toxicity: oral.001 ........................................... 6
Repeated dose toxicity: oral.002 ......................................... 15
7.6 Genetic toxicity ............................................................................ 22
7.6.1 Genetic toxicity in vitro ...................................................... 22
Genetic toxicity in vitro.001 ................................................ 22
Genetic toxicity in vitro.002 ................................................ 28
7.8 Toxicity to reproduction ............................................................... 32
7.8.1 Toxicity to reproduction ..................................................... 32
Toxicity to reproduction.001 ............................................... 32
References ................................................................................................................ 40
Reference Substances ...................................................................................... 40
4-chloro-m-cresol ....................................................................................... 40
Test Materials .................................................................................................. 41
4-Chloro-m-cresol ...................................................................................... 41
Literatures ....................................................................................................... 42
A reproduction/developmental toxicity screening test in rats treated orallywith 4-chloro-m-cresol ............................................................................... 42
In Vitro Chromosomal Aberration Test of 4-chloro-m-cresol on Cultured
Chinese Hamster Cells .............................................................................. 43
Reverse Mutation Test of 4-chloro-m-cresol on Bacteria .............................. 44
Twenty-eight-day Repeat Dose Oral Toxicity Test of 4-chloro-m-cresol in
Rats .......................................................................................................... 45
Legal Entities ................................................................................................... 46
National Institute of Health Sciences .......................................................... 46ii

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

Dossier subject
Dossier subject
4-chloro-m-cresol / 59-50-7
Public nameSubmitting legal entity
National Institute of Health Science
Dossier creation date/time
Fri, 16 Dec 2022, 14:54:39+0900
Used in category

1

LEGAL_ENTITY: National Institute of Health
Science
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General information
Legal entity nameNational Institute of Health Science24-chloro-m-cresol
General information
Identification
Identification
SUBSTANCE: 4-chloro-m-cresol

UUID: 053ede1d-07b6-42db-ba58-88a6a246d151
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Author:Date: 2022-12-16T14:54:29.214+09:00
Remarks:
Substance name4-chloro-m-cresol
Other substance identifiers
Identifier
CAS number
Identity
59-50-7
Legal entity
National Institute of Health Sciences / Kawasaki / Japan
Contact persons

Identification of substance
Reference substance
4-chloro-m-cresol / 59-50-7
EC number

EC name

CAS number

CAS name59-50-7
IUPAC nameRole in the supply chain
Manufacturer
false
Importer
false
Only representativefalse
3

Downstream user
false

4

Assessment approach (assessment entities)
FIXED_RECORD: Assessment approach
UUID: 267e5bbd-91b8-3191-b372-29ce0931a40d
Dossier UUID:
Author:Date: 2019-09-03T09:59:28.000+09:00
Remarks:5

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

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Author:Date: 2022-12-16T14:53:11.980+09:00
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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
true
Used for classification
true
Used for SDS
false
Study period
28 days
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study
Reliability 1

Data source
Reference
Twenty-eight-day Repeat Dose Oral Toxicity Test of 4-chloro-m-cresol in Rats / Ministry of Health, Laborand Welfare, Japan / study report
Data accessdata published

Materials and methods
6Test guideline
Qualifieraccording to guideline
Guideline
other: Guideline for 28-Day Repeated Dose Toxicity Test in Mammalian Species (Chemical
Substances Control Law of Japan)
Qualifierequivalent or similar to guideline
Guideline
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance
yes
Limit test
no

Test material
Test material information
4-Chloro-m-cresol
Specific details on test material used for the study- Name of test material (as cited in study report): 4-chloro-m-cresol- Purity: 99.9%- Storage condition of test material: at a cold (temperature 2-6°C) and dark place, with airtight stopper.
- Stability under test conditions: stable- Solubility and stability of the test substance in the solvent/vehicle: stable

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 Laboratories Japan Inc., Atsugi Breeding Center.
- Age at study initiation: 5 weeks old- Weight at study initiation: male 160g (145-171g), female 142g (130-153g)- Housing: Animals were individually housed in stainless wire-meshed cages (260W × 380D × 180H
mm).
- Diet: Solid feed (MR stock: Nosan Corporation) was given ad libitum.
- Water: irradiated tap water, ad libitum.
- Acclimation period: 7-8 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 22±3°C (actual temperature: 21.5-22.1°C)7- Humidity (%): 55±10% (actual humidity: 53-60%)- Air changes (per hr): more than ten times per hr- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light (light: 7:00-19:00)

Administration / exposure
Route of administration
oral: gavage
Vehicleolive oil
Details on oral exposure- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Analytical verification of doses or concentrations
yes
Duration of treatment / exposure
28 daysFrequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
15

mg/kg bw/day (actual dose received)

Dose / conc.
60

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
Control and high-dose group: 10 animals/sex/ (including recovery group of 5 animals/sex/eachgroup)
8

Low- and middle-dose group: 5 animals/sex/doseControl animals
yes, concurrent vehicle
Details on study design- Dose selection rationale: Based on the results of a 14-day preliminary study, the highest dose of1000 mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 15 mg/
kg bw/day was selected as an expected no toxic dose. The middle dose levels of 60 and 250mg/kg
bw/day were selected.
- Rationale for animal assignment (if not random): Body weight-balanced randomization- Rationale for selecting satellite groups: Reversibility of toxic effects by treatment was examined inrecovery test with control- and high-dose groups for both sexes.
- Post-exposure recovery period in satellite groups: 14 days
[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0 (olive oil), 50, 150, 100, 500 or
1000 mg/kg bw/day). At 500 mg/kg bw/day or more or 1000 mg/kg bw/day, tremor, decrease inlocomotor activity, prone position and salivation, depression body weight gain, tendency of low foodconsumption, decrease in platelet, total bilirubin, cholinesterase and urine protein, increase in total cholesterol and potassium were observed. At 1000 mg/kg bw/day, increase in relative brain weight, decr
ease in absolute spleen weight, and slight thickening of forestomach were observed.

Examinations
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes- Time schedule: every day during the administration (4 times a day) and recovery periods (at least on
ce a day)
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: Once before the start of administration, and once every week by the end of the study
period.
BODY WEIGHT: Yes- Time schedule for examinations: Before administration (on days 1, 7, 14, 21 and 28 of the adm
inistration period, days 7 and 14 of the recovery period) and the necropsy days after completion of
every period.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes. Once a week for 24-h (males: on days 5, 12, 19 and 26 of the administration
period and days 5 and 12 of the recovery period.
females: on days 4, 11, 18 and 25 of the administration period and days 4 and 11 of the recovery p
eriod)
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood: the day after completion of the administration and recovery
periods- Anaesthetic used for blood collection: ether- Animals fasted: Yes(overnight)- How many animals: all animals- Parameters examined included RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet, reti
culocyte, PT, APTT, WBC and differential WBC.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: the day after completion of the administration and recovery
periods9

- Animals fasted: Yes(overnight)- How many animals: all animals- Parameters examined included total protein, albumin, A/G ratio, total bilirubin, glucose, total cholest
erol, triglyceride, phospholipid, AST, ALT, LDH, ALP, gamma-GTP, BUN, creatinine, Na, K, Cl, Ca and IP.
URINALYSIS: Yes- Time schedule for collection of urine: On weeks 4 of the administration period and weeks 2 of therecovery period.
- Metabolism cages used for collection of urine: Yes- How many animals: All animals- Parameters examined included color, cloudy, urine volume, specific gravity, Na, K, pH, protein,
glucose, ketone body, bilirubin, occult blood and urobilinogen.
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations: Sensory motor reflexes, forelimb and hindlimb grip strengths, andmotor activity were measured on week 4 of administration period (main/recovery group animals) andweek 2 of recovery period (recovery group animals).
- Dose groups that were examined: All animals- Battery of functions tested: sensory activity (hearing reaction, eye sight reaction, sense of touch reaction, pain reaction, pupil reflex, righting reflex), grip strength, motor activity
Sacrifice and pathology
GROSS PATHOLOGY: Yes
ORGAN WEIBHT: Yes [brain, pituitary gland, thyroid, adrenal, spleen, heart, liver, kidney, thymus, testis,
epididymis, ovary]
HISTOPATHOLOGY: Yes [brain (cerebrum, cerebellum and medulla oblongata), pituitary gland, spinal
cord (cervical, thoracical, lumber), thymus, thyroid (including parathyroid), adrenal glands, spleen, heart, stomach, liver, duodenum, jejunum, ileum (including Peyer's patches), cecum, colon, rectal, mes
enteric lymph nodes, submandibular lymph nodes, trachea, lung, kidney, bladder, testis, epididymis,
prostate, seminal vesicles, ovary, uterus, vagina, eye, bone marrow (femur) and the sciatic nerve. (seetables in the study report.)]Statistics
As for parametric data (grip strength, locomotor activity, body weight, body weight gain, food consu
mption, hematology and clinical chemistry data, organ weights, quantitative urinalysis data), the va
lues of means and standard deviations were calculated per group. When more than three groups exist
in the test group, Bartlett test for variance was done, and if the variance was homogenous, ANOVA
was applied. If the variance was not homogenous or data was non-parametric (differential WBC
percentage, qualitative urinalysis data), Kruskal-Wallis rank sum test was used. Consequently, if theresult was significant, Dunnett multiple comparison or Dunnett typed method was used for detectionof statistical significance against control group. When the number of the test group was two, F-test
was used as for parametric data.
Then, student's t-test or Aspin-Welch's t-test was applied depending on the result of homogeneityof variance. While, as for non-parametric data, Man-Whitney's U-test was applied. Furthermore, as
for categorized data (incidence of abnormal findings in clinical observation, detailed observation,
sensory functional examination, necropsy and histopathology), Fischer's exact test was used. In any
tests, level of significance was set at 5%.

Results and discussion
Results of examinations
Clinical signs
effects observed, treatment-related
10Description (incidence and severity)[treatment-related effect]:
Tremor, decrease in locomotor activity, ptosis, prone/side position, soiled perineal region and saliva
tion were observed in one dead female at 1000 mg/kg bw/day.
Tremor, decrease in locomotor activity, ptosis, prone position were observed in all males and females
at 1000 mg/kg bw/day.
Soiled perineal region was observed in all females at 1000 mg/kg bw/day.
Transient prone position in three males and decreased locomotor activity in two males were observed
at 250 mg/kg bw/day.
[non-treatment-related effect]:Transient salivation was observed in all males and females at 250 mg/kg bw/day or more. This findi
ng was thought to be due to the irritancy of the test substance.
Mortality
mortality observed, treatment-related
Description (incidence)
One female animal died in the 1000 mg/kg bw/day.
Body weight and weight changes
effects observed, treatment-related
Description (incidence and severity)
Decreased body weight and depression of body weight gains were observed in the males at 1000 mg/
kg bw.
Food consumption and compound intake (if feeding study)
effects observed, treatment-related
Description (incidence and severity)
Significant decrease in food consumption were observed in the males at 1000 mg/kg bw/day.
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)
not examined
Ophthalmological findings
not examined
Haematological findings
effects observed, non-treatment-related
Description (incidence and severity)
Significant decrease in monocyte ratio in differentiation of leukocyte were observed in the females at1000 mg/kg bw/day. These variations were within ranges of historical control data. Therefore, thesechanges were considered to be incidental and not to be related to treatment of the test substance.
Significant lower hematocrit and significant higher reticulocytes were observed in the males, sign
ificant higher RBC were observed in the females at 1000 mg/kg bw/day. These variations were within
ranges of historical control data. Therefore, these changes were considered to be incidental and not
to be related to treatment of the test substance.
Clinical biochemistry findings
effects observed, treatment-related
Description (incidence and severity)[treatment-related effect]:11Significant increase in ALT levels were observed in the females at 1000 mg/kg bw.
[non-treatment-related effect]:Significant lower total bilirubin were observed in the males at 1000 mg/kg bw/day. These variations were within ranges of historical control data. Therefore, these changes were considered to be inci
dental and not to be related to treatment of the test substance.
Significant higher total bilirubin were observed in the females at 1000 mg/kg bw/day. These var
iations were within ranges of historical control data. In addition, there were no other related changes.
Therefore, these changes were considered to be incidental and not to be related to treatment of thetest substance.
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 the dosing period, an increase in relative liver weight was observed in males and females
at 1000 mg/kg bw/day.
Gross pathological findings
effects observed, treatment-related
Description (incidence and severity)[treatment-related effect]:
At the end of the dosing period, slight thickening of forestomach mucosa was observed in all males
at 1000 mg/kg bw/day.
[non-treatment-related effect]:
At the end of the recovery period, small testis (right side) was observed in one male at 1000 mg/kg
bw/day. However, it was only one case, and it was known as a spontaneous lesion of rat. Therefore,
this change was considered to be incidental and not to be related to treatment of the test substance.
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
effects observed, treatment-related
Description (incidence and severity)[treatment-related effect]:
Liver: Slight hypertrophy of centrilobular hepatocyte was observed in two male and three females at1000 mg/kg bw/day.
Forestomach: Slight hyperplasia of squamous was observed in one male and two females at 250 mg/
kg bw/day. Moderate hyperplasia of squamous was observed in all males at 1000 mg/kg bw/day.
Slight and Moderate hyperplasia of squamous was observed in females at 1000 mg/kg bw/day.
In one dead female at 1000 mg/kg bw/day, there were severe hyperplasia of squamous in forestomac
h, slight congestive edema and inflammation in lung, slight hemorrhage in thymus and slight atrophyin spleen.
[non-treatment-related effect]:
Hematoidin crystal of lung, myocardial degeneration/fibrosis of heart were observed in males at1000 mg/kg bw/day. Atrophy cortex of thymus was observed in females at 1000 mg/kg bw/day.
12

However, these findings were only for each group, and these were known as a spontaneous lesion of
rat. Therefore, these changes were considered to be incidental and not to be related to treatment of t
he test substance.
Atrophy seminiferous tuble of testis (unilateral) was observed in one male at 1000 mg/kg bw/day.
However, it was only one case, and it was known as a spontaneous lesion of rat. Therefore, thischange was considered to be incidental and not to be related to treatment of the test substance.
Histopathological findings: neoplastic
not examined

Effect levels
Key result
false
Dose descriptor
NOAEL
Effect level60

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect levelgross pathology
At the end of the dosing period, slight thickening of forestomach mucosa was observed in all males
at 1000 mg/kg bw/day.
histopathology: non-neoplastic
Liver: Slight hypertrophy of centrilobular hepatocyte was observed in two male and three females
at 1000 mg/kg bw/day. Forestomach: Slight hyperplasia of squamous was observed in one male an
d two females at 250 mg/kg bw/day. Moderate hyperplasia of squamous was observed in all males
and females at 1000 mg/kg bw/day.
organ weights and organ / body weight ratios
At the end of the dosing period, an increase in relative liver weight was observed in males and fema
les at 1000 mg/kg bw/day.
other: In one dead female at 1000 mg/kg bw/day, there were severe hyperplasia of squamous in fore
stomach, slight congestive edema and inflammation in lung, slight hemorrhage in thymus and slightatrophy in spleen.

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF59-50-7b.pdf

Applicant's summary and conclusion
Executive summary13

A 28-day repeated-dose toxicity test was performed according to the Japanese guideline (similar toOECD TG 407). Male and female rats (5 animals/sex/dose) were administered 4-chloro-m-cresol at 0,15, 60, 250, and 1,000 mg/kg bw/day. In addition, both sexes (5 animals/sex/dose) were administered
0 and 1,000 mg/kg bw/day of this substance for 28 days and examined after a 14-day recovery period.
At 1000 mg/kg bw/day, one female died during the administration period. Clinical observation revealed,decrease in locomotor activity and prone position were observed in males at 250 mg/kg bw/day, tremor,
decrease in locomotor activity, prone/side position in both sexes at 1000 mg/kg bw/day. Soiled perineal
region were also observed in females at 1000 mg/kg bw/day. Body weights, body weight gain and foodconsumption were decreased in males at 1000 mg/kg bw/day. Blood chemical examination revealed ahigh values for ALT activity in females at 1000 mg/kg bw/day. Relative liver weights were higher in males
and females at 1000 mg/kg bw/day. Gross pathology revealed slight thickening of forestomach mucosa
in males at 1000 mg/kg bw/day. Histopathological examination revealed hypertrophy of centrilobular
hepatocyte in the liver in male and females at 1000 mg/kg bw/day, hyperplasia of squamous in theforestomach in both sexes at 250 mg/kg bw/dayor more.
On the basis of these effects, NOAEL for repeated-dose toxicity was determined to be 60 mg/kg bw/
day in male and female rats.

14

ENDPOINT_STUDY_RECORD: Repeated dose toxicity: oral.002

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Author:Date: 2022-12-16T14:54:22.207+09:00
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Administrative data
Endpoint
repeated dose toxicity: oral, other screening for reproductive / developmental toxicity
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
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study
Related information
OECD / Toxicity to reproduction / Toxicity to reproduction.001 / 4-chloro-m-cresol / 59-50-7

Data source
Reference
A reproduction/developmental toxicity screening test in rats treated orally with 4-chloro-m-cresol /Ministry of Health, Labor and Welfare, Japan / study report
Data accessdata published

Materials and methods
15

Test guideline
Qualifieraccording to guideline
Guideline
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviationsno
GLP compliance
yes
Limit test
no

Test material
Test material information
4-Chloro-m-cresol
Specific details on test material used for the study- Name of test material (as cited in study report): 4-Chloro-m-cresol- Analytical purity: 99.9%- Storage condition of test material: at a cold (temperature 1-8 °C) and dark place, with airtight stopper.
- Stability under test conditions: The stability of test material was identified by analysis of the remai
nder.

Test animals
Speciesratcommon rodent species
Strainother: Crl:CD(SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charle s River Japan, Inc., Atsugi Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation: Male: 398.6 g (366 -432 g), Female: 257.2 g (235-283 g)- Housing: Animals were housed individually, except for during the acclimation (two animals by sex)
, mating (one male and one female) and lactation periods (one litter), in metallic bracket-type cageswith wire mesh floors (260W x 380D x 180H mm). From gestation day 17 to lactation day 4, individualdams and litters were reared on bedding.
- Diet: Solid feed (CRF-1: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 22±3 (actual temperature: 21-25°C)- Humidity (%): 50±20% (actual humidity: 36-62%)- Air changes (per hr): 10-15
16

- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 8:00~20:00)

Administration / exposure
Route of administration
oral: gavage
Vehiclecorn oil
Details on oral 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 or sperm in vaginal smear referred to as day 0 of pregnancy- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
Analytical verification of doses or concentrations
yes
Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating and mating periods, and thereafter 14 days(P) Females: up to 56 days including 14 days pre-mating, mating and gestation periods, and the days
until day 3 of lactation
Frequency of treatment
Once/day, 7days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
35

mg/kg bw/day (actual dose received)

Dose / conc.
150

mg/kg bw/day (actual dose received)

Dose / conc.
600

mg/kg bw/day (actual dose received)

No. of animals per sex per dose
12 animals/sex/doseControl animals
yes, concurrent vehicle17

Details on study design- Dose selection rationale: Based on the results of a 14-day preliminary study, the highest dose of 600
mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 35 mg/kg
bw/day was selected as an expected no toxic dose. The middle dose levels of 150 mg/kg bw/day
were selected.
- Rationale for animal assignment (if not random): Body weight-balanced randomization[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0 (olive oil), 35, 150, and 600 mg/kg
bw/day). At 600 mg/kg bw/day, staggering gait, soiled perineal region, yellowish white mass in thecauda epididymis were observed.

Examinations
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes- Time schedule: Males and females: 2 times/day
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes- Time schedule for examinations:
Males: Days 1, 2, 5, 7, 10, 14, 21, 28, 35, 42, and the day of necropsy
Females: Days 1, 2, 5, 7, 10, and 14; gestation days 0, 1, 3, 5, 7, 10, 14, 17, and 20; lactation days 0, 1
and 4; and the day of necropsy. For unmating females, 21 and 28 in the mating period
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes
Males: Days 1, 2, 5, 7, 10, 14, 21, 28, 35, and 42, in dosing period
Females: Days 1, 2, 5, 7, 10, and 14; gestation days 0, 1, 3, 5, 7, 10, 14, 17, and 20; lactation days 0, 1
and 4
OTHER: Females: Numbers of corpus luteum and implantation site on the day of necropsy
Sacrifice and pathology
SACRIFICE- Male animals: All surviving animals were euthanized by exsanguination under ether anesthesia on the day after the last administration.
- Maternal animals: All surviving animals were euthanized by exsanguination under ether anesthesia
on day 4 of lactation.
GROSS NECROPSY: Yes (gross necropsy consisted of external and internal examinations including
the cervical, thoracic, and abdominal viscera.)
HISTOPATHOLOGY: Yes (Male: testis, epididymis, and gross abnormal site (ileum); Female: ovary, andgross abnormal site (pituitary gland, thymus, spleen, kidney, ileum))
Other examinations
ORGAN WEIGHTS: Yes (brain, thymus, heart, liver, kidney, spleen, adrenal, testis, epididymis, ovary)
Statistics
Body weights, body weight gain, food consumption, organ weights and relative organ weights, stagesof spermatogenesis, length of the estrous cycle, number of corpora lutea, number of implantation sites, implantation index, delivery index, number of pups delivered, number of live pups, live birth index,
sex ratio, number of live pups and viability index at lactation day4 were analyzed for statistical signifi
cance in the following way: homogeneity of variance was evaluated first by Bartlett’s test. When groupvariances were homogeneous, the one-way analysis of variance was used to determine if any statist18

ical differences existed among the groups. If the analysis of variance gave a significant result, Du
nnett’s test was performed to detect any significant differences between the treated groups and their corresponding controls. When Bartlett’s test indicated that the variances were not homogeneous,the Kruskal-Wallis test was used for detecting any statistical differences and if they were significant, the Mann-Whitney U test was performed to detect any significant differences between the treatedgroups and their corresponding controls. The incidences of females with abnormal estrous cyclicity,and indices of copulation, fertility and gestation, and nursing index were analyzed by the Chi-square
test or Fisher’s exact probability test.

Results and discussion
Results of examinations
Clinical signs
effects observed, treatment-related
Description (incidence and severity)
Decrease in locomotor activity was observed in one male on day 5 and 6, in one female on day 1 at 60
0 mg/kg bw/kg.
Crawling position, lateral position and soil of perigenital fur were observed in males and females at 60
0 mg/kg bw/kg.
Mortality
no mortality observed
Body weight and weight changes
effects observed, treatment-related
Description (incidence and severity)
Significantly low value of body weight was observed in both sexes at 600 mg/kg bw/day.
Food consumption and compound intake (if feeding study)
effects observed, treatment-related
Description (incidence and severity)
Significantly low value of food consumption was observed in both sexes at 600 mg/kg bw/day.
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)
not examined
Ophthalmological findings
not examined
Haematological findings
not examined
Clinical biochemistry findings
not examined
Urinalysis findings
not examined
Behaviour (functional findings)
not examined
19

Immunological findings
not examined
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Description (incidence and severity)[treatment-related effect]:
Increases in relative kidney weight was observed in both sexes at 600 mg/kg bw/day.
[non-treatment-related]:
Increases in relative brain weight was observed in both sexes at 600 mg/kg bw/day.
However, this change was considered due to the reduction in terminal body weights. Therefore this change was no toxicological meaning.
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 level150

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
body weight and weight gain
Significantly low value of body weight was observed in both sexes at 600 mg/kg bw/day.
clinical signs
Decrease in locomotor activity was observed in one male on day 5 and 6, in one female on day 1
at 600 mg/kg bw/kg. Crawling position, lateral position and soil of perigenital fur were observed inmales and females at 600 mg/kg bw/kg.
food consumption and compound intake
Significantly low value of food consumption was observed in both sexes at 600 mg/kg bw/day.

Any other information on results incl. tables
20

Figures and Tables (in English) are available in the following full report of the study.
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF59-50-7c.pdf

Applicant's summary and conclusion
Executive summary
A reproduction/developmental toxicity screening test was performed according to OECD TG 421. Maleand female rats (12 animals/sex/dose) were administered 4 -chloro-m-cresol at 0, 35, 150, and 600 mg/
kg bw/day. Males were dosed for 42 days, including a 14 day pre-mating and mating periods. Females
were dosed for 56 days, including a 14 day pre-mating, mating, and gestation periods, and the time
until lactation day 3. Decrease in locomotor activity was observed in both sexes at 600 mg/kg bw/kg.
Crawling position, lateral position and soil of perigenital fur were observed in both sexes at 600 mg/
kg bw/kg. Significantly low value of body weight was observed in both sexes at 600 mg/kg bw/day.
Significantly low value of food consumption was observed in both sexes at 600 mg/kg bw/day. On thebasis of these effects, NOAEL for repeated-dose toxicity was determined to be 150 mg/kg bw/day inmale and female rats.

21

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

UUID: 764bbe55-ffa6-468b-b592-12facb8c9342
Dossier UUID:
Author:Date: 2022-12-12T11:32:21.719+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
true
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study
Reliability 1

Data source
Reference
Reverse Mutation Test of 4-chloro-m-cresol on Bacteria / MHLW (Ministry of Health, Labour andWelfare), Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
22

Guideline
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
in vitro gene mutation study in bacteria
Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, other
GLP compliance
yesType of assay
bacterial reverse mutation assay
in vitro gene mutation study in bacteria

Test material
Test material information
4-Chloro-m-cresol
Specific details on test material used for the study- Name of test material (as cited in study report): 4-chloro-m-cresol- CAS No.: 59-50-7
Lot No.: ASL1407- Purity: 100%
- Supplier: Wako Pure Chemical Industries, Ltd.
- Boiling point : 235°C- Melting point/Freezing point: 65.7°C- Vapor pressure: 0.05 mmHg (20°C)- Solubility: 1 g/260 mL (20°C) in water.
- Physical state: white powder- Storage condition of test material: stored at room temperature (21.1-25.3°C), light shielding

MethodSpecies / strain
Species / strain / cell typeS. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2bacteria
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
Preliminary study+/-S9 mix:1.22, 4.88, 19.5, 78.1, 313, 1250, 5000 μg/plate(growth inhibition was observed at >=313μg/plate in TA100 and TA1535 and at >=1250μg/plate in
WP2uvrA/pKM101, TA98, and TA1537)

23

Main study+/-S9 mix: 9.77, 19.5, 39.1, 78.1, 156, 313, 625 μg/plate (TA100, TA1535 strains)+/-S9 mix: 19.5, 39.1, 78.1, 156, 313, 625, 1250 μg/plate (WP2uvrA/pKM101, TA98, TA1537 strains)
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
Controls
Negative solvent / vehicle controls
yes
Positive controls
yes
Positive control substance
9-aminoacridine
9-aminoacridine hydrochloride, -S9mix: (TA1537)
sodium azide-S9 mix: (TA1535)
other: 2-(2-Furyl)-3-(5-nitro-2-furyl) acrylamide-S9mix: (TA 100, TA98 and WP2 uvrA/pKM101)
Remarks-S9mix
Negative solvent / vehicle controls
yes
Positive controls
yes
Positive control substanceother: 2-aminoanthracene(all strains)
Remarks+S9 mix
Details on test system and experimental conditions
METHOD OF APPLICATION: Preincubation
DURATION- Preincubation period: 20 min at 37°C
- Exposure duration: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.
Statistics
not used

Results and discussion
24Test results
Key result
false
Species / strain
S. typhimurium TA 100
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity +/-S9: at =>313 μg/plate
Vehicle controls validity
valid
Positive controls validity
valid
Key result
false
Species / strain
S. typhimurium TA 1535
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity +/-S9: at =>313 μg/plate
Vehicle controls validity
valid
Positive controls validity
valid
Key result
false
Species / strain
E. coli WP2 uvr A pKM 101
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9mix: at=>625 μg/plate, +S9mix: at 1250 μg/plate25

Vehicle controls validity
valid
Positive controls validity
valid
Key result
false
Species / strain
S. typhimurium TA 98
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity +/-S9mix: at =>625 μg/plate
Vehicle controls validity
valid
Positive controls validity
valid
Key result
false
Species / strain
S. typhimurium TA 1537
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity +/-S9mix: at =>625 μg/plate
Vehicle controls validity
valid
Positive controls validityvalid

Any other information on results incl. tables
Figures and Tables (in Japanese) are available in the following full report of the study. http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF59-50-7e.pdf
Tables (in English) are attachted to this document. Please download the export file to see the Tables.

26

Applicant's summary and conclusion
Conclusions
In a bacterial reverse mutation assay using Salmonella typhimurium TA100, TA1535, TA98, andTA1537, and Escherichia coli WP2uvrA/pKM101 (OECD TG 471), 4-chloro-m-cresol was negative withor without metabolic activation.

27

ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.002

UUID: 126966d5-1d1f-48a0-8437-c0fb2b9ac1e2
Dossier UUID:
Author:Date: 2022-12-12T11:32:46.026+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
true
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study
Reliability 1

Data source
Reference
In Vitro Chromosomal Aberration Test of 4-chloro-m-cresol on Cultured Chinese Hamster Cells / MHLW(Ministry of Health, Labour and Welfare), Japan / study report

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)in vitro cytogenicity / chromosome aberration study in mammalian cells
Qualifieraccording to guideline28

Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, other
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-Chloro-m-cresol
Specific details on test material used for the study- Name of test material (as cited in study report): 4-chloro-m-cresol- CAS No.: 59-50-7
Lot No.: ASL1407- Purity: 100%
- Supplier: Wako Pure Chemical Industries, Ltd.
- Boiling point : 235°C- Melting point/Freezing point: 65.7°C- Vapor pressure: 0.05 mmHg (20°C)- Solubility: 1 g/260 mL (20°C) in water.
- Physical state: white powder- Storage condition of test material: stored at room temperature (21.1-25.3°C), light shielding

MethodSpecies / strain
Species / strain / cell typeother:
Details on mammalian cell type (if applicable)
Chinese hamster lung(CHL/IU) cells
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
Preliminary study
50, 500, 5000 μg/mL (100% growth inhibition was observed at 500 μg/mL and higher)
Main study[short-term treatment (6 h)] (+/-S9 mix): 50, 100, 200, 300, 400, 500 μg/mL[continuous treatment (24 h)]: 50, 100, 150, 200, 250, 300 μg/mL
Vehicle / solvent
DMSO
29

Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substancebenzo(a)pyrene+S9 mix
mitomycin C-S9 mix
Details on test system and experimental conditions
METHOD OF APPLICATION: Exposure duration: [short-term treatment]:6 hrs + 18 hr, [continuous
treatment]: 24h
STAIN: Giemsa stain (3 v/v%) for 10 min.
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 1000 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.
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
Statistics
Not used

Results and discussion
Test results
Key result
false
Species / strainother: Chinese hamster lung(CHL/IU) cells
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity
30

Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid
Additional information on results
Figures and Tables (in Japanese) are available in the following full report of the study. http://dra
4.nihs.go.jp/mhlw_data/home/pdf/PDF59-50-7f.pdf
Tables (in English) are attachted to this document. Please download the export file to see the Tables.

Applicant's summary and conclusion
Conclusions
Negative with and without metabolic activation
Executive summary
The in vitro chromosomal aberration test using CHL/IU cells (OECD TG 473) was negative with andwithout metabolic activation.

31

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

UUID: 1bfb91e5-1962-41d1-b12b-a748fd549888
Dossier UUID:
Author:Date: 2022-12-12T11:33:32.429+09:00
Remarks:

Administrative data
Endpoint
screening for reproductive / developmental toxicity
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
Reliability 1

Data source
Reference
A reproduction/developmental toxicity screening test in rats treated orally with 4-chloro-m-cresol /Ministry of Health, Labor and Welfare, Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
32

Guideline
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviationsno
GLP compliance
yes

Test material
Test material information
4-Chloro-m-cresol
Specific details on test material used for the study- Name of test material (as cited in study report): 4-Chloro-m-cresol- Analytical purity: 99.9%- Storage condition of test material: at a cold (temperature 1-8 °C) and dark place, with airtight stopper.
- Stability under test conditions: The stability of test material was identified by analysis of the remai
nder.

Test animals
Speciesrat
Strainother: Crl:CD(SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charle s River Japan, Inc., Atsugi Breeding Center.
- Age at study initiation: 10 weeks- Weight at study initiation: Male: 398.6 g (366 -432 g), Female: 257.2 g (235-283 g)- Housing: Animals were housed individually, except for during the acclimation (two animals by sex),
mating (one male and one female) and lactation periods (one litter), in metallic bracket-type cageswith wire mesh floors (260 mm x 380 mm x 180 mm). From gestation day 17 to lactation day 4,
individual dams and litters were reared on bedding.
- Diet: Solid feed (CRF-1: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 22±3 (actual temperature: 21-25°C)- Humidity (%): 50±20% (actual humidity: 36-62%)- Air changes (per hr): 10-15- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 8:00~20:00)

Administration / exposure
Route of administration
oral: gavage
33

Vehiclecorn oil
Details on mating procedure- M/F ratio per cage: 1:1- Length of cohabitation: up to 14 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating and mating periods, and thereafter 14 days (P) Femal
es: up to 56 days including 14 days pre-mating, mating and gestation periods, and the days until day 3of lactation
Frequency of treatment
Once/day, 7days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
35

mg/kg bw/day (actual dose received)

Dose / conc.
150

mg/kg bw/day (actual dose received)

Dose / conc.
600

mg/kg bw/day (actual dose received)

No. of animals per sex per dose
12 animals/sex/doseControl animals
yes, concurrent vehicle
Details on study design- Dose selection rationale: Based on the results of a 14-day preliminary study, the highest dose of 600
mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 35 mg/kg
bw/day was selected as an expected no toxic dose. The middle dose levels of 150 mg/kg bw/day
were selected.
- Rationale for animal assignment (if not random): Body weight-balanced randomization34

[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0 (olive oil), 35, 150, and 600 mg/kg
bw/day). At 600 mg/kg bw/day, staggering gait, soiled perineal region, yellowish white mass in thecauda epididymis were observed.

Examinations
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes- Time schedule: Males and females: 2 times/day
BODY WEIGHT: Yes- Time schedule for examinations:
Males: Days 1, 2, 5, 7, 10, 14, 21, 28, 35, 42, and the day of necropsy
Females: Days 1, 2, 5, 7, 10, and 14; gestation days 0, 1, 3, 5, 7, 10, 14, 17, and 20; lactation days 0, 1 an
d 4; and the day of necropsy. For unmating females, 21 and 28 in the mating period
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes
Males: Days 1, 2, 5, 7, 10, 14, 21, 28, 35, and 42, in dosing period
Females: Days 1, 2, 5, 7, 10, and 14; gestation days 0, 1, 3, 5, 7, 10, 14, 17, and 20; lactation days 0, 1
and 4
OTHER: Females: Numbers of corpus luteum and implantation site on the day of necropsy
Oestrous cyclicity (parental animals)
Vaginal smears were collected from all females and microscopically examined every day from the day
after the start of administration until the day copulation was confirmed.
During the pre-mating administration period, vaginal smear pictures were classified as proestrus,
estrus, metestrus or diestrus and examined for the frequency of estrus and interval between estruses(estrous cycle). During the mating period, vaginal smears were examined for the presence of sperm.
Sperm parameters (parental animals)
Parameters examined in P male parental generations: testis weight, epididymis weight
Litter observations
PARAMETERS EXAMINEDThe following parameters were examined in F1 offspring:number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weig
ht.
GROSS EXAMINATION OF DEAD PUPS: Yes, for external and internal abnormalities.
Postmortem examinations (parental animals)
SACRIFICE- Male animals: All surviving animals were euthanized by exsanguination under ether anesthesia on the day after the last administration.
- Maternal animals: All surviving animals were euthanized by exsanguination under ether anesthesia
on day 4 of lactation.
GROSS NECROPSY: Yes (gross necropsy consisted of external and internal examinations including
the cervical, thoracic, and abdominal viscera.)
HISTOPATHOLOGY: Yes (Male: testis, epididymis, and gross abnormal site (ileum); Female: ovary, andgross abnormal site (pituitary gland, thymus, spleen, kidney, ileum))35

ORGAN WEIGHTS: Yes (brain, thymus, heart, liver, kidney, spleen, adrenal, testis, epididymis, ovary )Postmortem examinations (offspring)
SACRIFICE- The F1 pups were euthanized on day 4 of lactation by using carbon dioxide.
GROSS NECROPSY- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, andabdominal viscera.
Statistics
Body weights, body weight gain, food consumption, organ weights and relative organ weights, stagesof spermatogenesis, length of the estrous cycle, number of corpora lutea, number of implantation sites, implantation index, delivery index, number of pups delivered, number of live pups, live birth index,
sex ratio, number of live pups and viability index at lactation day4 were analyzed for statistical signifi
cance in the following way: homogeneity of variance was evaluated first by Bartlett’s test. When groupvariances were homogeneous, the one-way analysis of variance was used to determine if any statist
ical differences existed among the groups. If the analysis of variance gave a significant result, Du
nnett’s test was performed to detect any significant differences between the treated groups and their corresponding controls. When Bartlett’s test indicated that the variances were not homogeneous,the Kruskal-Wallis test was used for detecting any statistical differences and if they were significant, the Mann-Whitney U test was performed to detect any significant differences between the treatedgroups and their corresponding controls. The incidences of females with abnormal estrous cyclicity,and indices of copulation, fertility and gestation, and nursing index were analyzed by the Chi-square
test or Fisher’s exact probability test.
Reproductive indices
Each parameter was determined by the following equations:
Abnormal estrous cycle = (No. of female with abnormal estrous cycle/No. of females examined) ×100
Copulation index (%) = (No. of animals with successful copulation/No. of animals mated) × 100
Fertility index (%) = (No. of pregnant females/No. of pairs with successful copulation) × 100
Gestation index (%) = (No. of females with live pups/number of pregnant females) × 100
Nursing index (%) = (No. of females nursing live pups on lactation day 4/No. of females with live pupsdelivery) × 100
Implantation index (%) = (No. of implantation sites/No. of corpora lutea) × 100
Delivery index (%) = (No. of pups born/No. of implantation sites) × 100
Sex ratio = No. of live male pups/No. of live pups
Live birth index (%) = (No. of live pups on lactation day 0/No. of pups born) × 100
Offspring viability indices
Viability index on lactation day 4 = (No. of live pups on lactation day 4/No. of live pups on lactation
day 0) × 100

Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
Clinical signs
effects observed, treatment-related36

Description (incidence and severity)see 7.5.1 Repeated dose toxicity: oral.002
Mortality
no mortality observed
Body weight and weight changes
effects observed, treatment-related
Description (incidence and severity)see 7.5.1 Repeated dose toxicity: oral.002
Food consumption and compound intake (if feeding study)
effects observed, treatment-related
Description (incidence and severity)see 7.5.1 Repeated dose toxicity: oral.002
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)
not examined
Ophthalmological findings
not examined
Haematological findings
not examined
Clinical biochemistry findings
not examined
Urinalysis findings
not examined
Behaviour (functional findings)
not examined
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: oral.002
no effects on reproductive organs
Gross pathological findings
no effects observed
Description (incidence and severity)
no effects on reproductive organs
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
no effects observed37Description (incidence and severity)
no effects on reproductive organs
Histopathological findings: neoplastic
not examined

Reproductive function / performance (P0)
Reproductive function: oestrous cycle
no effects observed
Reproductive function: sperm measureseffects observed, non-treatment-related
Description (incidence and severity)
Increase number of cells on preleptotene spermatocytes at Stage VII-VIII at 600 mg/kg bw/day.
Reproductive performanceno effects observed

Effect levels (P0)
Key result
true
Dose descriptor
NOAEL
Effect level600

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female

Results: F1 generation
General toxicity (F1)Clinical signs
no effects observed
Mortality / viability
mortality observed, non-treatment-related
Description (incidence and severity)control: 2 males and 4 females died.
35 mg/kg bw/day: 2 males died.
150 mg/kg bw/day: 3 males and 2 females died.
600 mg/kg bw/day: 2 males and 1 females died.
Body weight and weight changes
no effects observed
38

Sexual maturation
not examined
Organ weight findings including organ / body weight ratios
not examined
Gross pathological findings
no effects observed
Histopathological findings
not examined

Effect levels (F1)
Key result
true
Dose descriptor
NOAEL
Generation
F1
Effect level600

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF59-50-7c.pdf

Applicant's summary and conclusion
Executive summary
A reproduction/developmental toxicity screening test was performed according to OECD TG 421. Maleand female rats (12 animals/sex/dose) were administered 4 -chloro-m-cresol at 0, 35, 150, and 600 mg/
kg bw/day. Males were dosed for 42 days, including a 14 day pre-mating and mating periods. Females
were dosed for 56 days, including a 14 day pre-mating, mating, and gestation periods, and the time
until lactation day 3. No effects of this substance on reproductive and developmental parameters wereobserved at 600 mg/kg bw/day. NOAEL for the rat reproductive/developmental toxicity of 4 -chloro-mcresol was determined to be 600 mg/kg bw/day, the highest dose tested.

39

References
Reference Substances
REFERENCE_SUBSTANCE: 4-chloro-m-cresol
UUID: fa2f9d53-ba31-416b-964a-93e8166287ef
Dossier UUID:
Author:Date: 2018-02-27T14:37:55.000+09:00
Remarks:
Reference substance name4-chloro-m-cresol

Inventory
CAS number
59-50-7

Molecular and structural information
Structural formula40Test Materials
TEST_MATERIAL_INFORMATION: 4-Chloro-m-cresol
UUID: 52e5cce7-3877-49f0-b7d7-9a7311d51401
Dossier UUID:
Author:Date: 2022-12-12T11:29:11.508+09:00
Remarks:
Name
4-Chloro-m-cresol41Literatures
LITERATURE: A reproduction/developmental toxicity
screening test in rats treated orally with 4-chloro-mcresol
UUID: 01a49291-8a84-4bfd-80d1-76819202e03a
Dossier UUID:
Author:Date: 2018-03-14T15:23:19.000+09:00
Remarks:

General information
Reference Typestudy report
Title
A reproduction/developmental toxicity screening test in rats treated orally with 4-chloro-m-cresol
Author
Ministry of Health, Labor and Welfare, Japan
Bibliographic source
available in the web of Japan Existing Chemical Data Bae (JCEDB) at
Testing facility
Safety Research Institute for Chemical Compounds Co., Ltd.
Report number
SR08135

42

LITERATURE: In Vitro Chromosomal Aberration Test of 4chloro-m-cresol on Cultured Chinese Hamster Cells
UUID: 073bdd8b-cbe0-45d4-92e8-d80334293bb1
Dossier UUID:
Author:Date: 2018-02-27T16:54:46.000+09:00
Remarks:

General information
Reference Typestudy report
Title
In Vitro Chromosomal Aberration Test of 4-chloro-m-cresol on Cultured Chinese Hamster Cells
AuthorMHLW (Ministry of Health, Labour and Welfare), Japan
Year
2007
Bibliographic source
Japan Existing Chemical Data Base (JECDB) http://dra4.nihs.go.jp/mhlw_data/jsp/SearchPage
ENG.jsp
Testing facility
Mitsubishi Safety Institute Ltd.
Report number
B06031343

LITERATURE: Reverse Mutation Test of 4-chloro-mcresol on Bacteria
UUID: 6c7ed821-3dcf-4cf8-84b3-97085910a4cb
Dossier UUID:
Author:Date: 2018-02-27T16:44:27.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Reverse Mutation Test of 4-chloro-m-cresol on Bacteria
AuthorMHLW (Ministry of Health, Labour and Welfare), Japan
Year
2007
Bibliographic source
Japan Existing Chemical Data Base (JECDB) http://dra4.nihs.go.jp/mhlw_data/jsp/SearchPageE
NG.jspTesting facility
Mitsubishi Safety Institute Ltd.
Report number
B06031244

LITERATURE: Twenty-eight-day Repeat Dose Oral Toxicity
Test of 4-chloro-m-cresol in RatsUUID: 4e3fff29-f57b-43c3-a2f7-968da6f2a134
Dossier UUID:
Author:Date: 2018-03-17T12:37:49.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Twenty-eight-day Repeat Dose Oral Toxicity Test of 4-chloro-m-cresol in Rats
Author
Ministry of Health, Labor and Welfare, Japan
Bibliographic source
available in the web of Japan Existing Chemical Data Bae (JCEDB) at
Testing facility
Research Institute for Animal Science in Biochemistry and Toxicology
Study number
06-08745

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 systemIUCLID446

ID
16558402024DIV750

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