Name: COMPLETE / SUBSTANCE : 2-Nitro-p-cresol / 4-methyl-2-nitrophenol / 119-33-5 Fri,
16 Dec 2022, 14:32:16+0900 /Legal entity owner: National Institute of Health Sciences
Printing date: 2022-12-16T14:32:16.767+09:00

iTable of Contents
0/0 ............................................................................................................................. 1
National Institute of Health Science ..................................................................... 2
2-Nitro-p-cresol .................................................................................................... 3
CORE .......................................................................................................... 3
1 General information .......................................................................... 3
1.10 Assessment approach (assessment entities) ......................... 3
Assessment approach (assessment entities) ........................ 3
OECD .......................................................................................................... 4
D Health Effects .................................................................................. 4
60 Acute toxicity: oral .................................................................. 4
Acute toxicity: oral.001 ........................................................ 4
67 Repeated dose toxicity: oral .................................................... 8
Repeated dose toxicity: oral.001 ........................................... 8
Repeated dose toxicity: oral.002 ......................................... 1570 Genetic toxicity in vitro ......................................................... 21
Genetic toxicity in vitro.001 ................................................ 21
Genetic toxicity in vitro.002 ................................................ 2571 Genetic toxicity in vivo .......................................................... 29
Genetic toxicity in vivo.001 ................................................ 29
73 Toxicity to reproduction ........................................................ 33
Toxicity to reproduction.001 ............................................... 33
DOMAIN .................................................................................................... 40
Substance ......................................................................................... 40
Substance ................................................................................ 40
References ................................................................................................................ 41
Reference Substances ...................................................................................... 41
2-nitro-p-cresol .......................................................................................... 41
Test Materials .................................................................................................. 43
2-Nitro-p-cresol .......................................................................................... 43
2-Nitro-p-cresol .......................................................................................... 44
Literatures ....................................................................................................... 45
A reproduction/developmental toxicity screening test in rats treated orallywith 2-nitro-p-cresol ................................................................................... 45
In Vitro Chromosomal Aberration Test of 2-nitro-p-cresol on Cultured
Chinese Hamster Cells. ............................................................................. 46
Micronucleous test of 2-nitro-p-cresol on mouse ......................................... 47
Reverse mutation test of 2-nitro-p-cresol in Bacteria .................................... 48
Single Dose Oral Toxicity Test of 2-nitro-p-cresol in Rats .............................. 49
Twenty-eight-day Repeat Dose Oral Toxicity Test of 2-Nitro-p-cresol in
Rats .......................................................................................................... 50
Legal Entities ................................................................................................... 51
National Institute of Health Sciences .......................................................... 51

ii

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2-Nitro-p-cresol / 4-methyl-2-nitrophenol / 119-33-5
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LEGAL_ENTITY: National Institute of Health
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General information
Legal entity nameNational Institute of Health Science2

2-Nitro-p-cresol
CORE
General information
Assessment approach (assessment entities)
FIXED_RECORD: Assessment approach

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OECD
Health Effects
Acute toxicity: oral
ENDPOINT_STUDY_RECORD: Acute toxicity: oral.001

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Administrative data
Endpoint
acute 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
Reliability 1

Data source
Reference
Single Dose Oral Toxicity Test of 2-nitro-p-cresol in Rats / MHLW, japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
4Guideline
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance
yes
Test type
acute toxic class method
Limit test
yes

Test material
Test material information
2-Nitro-p-cresol
Specific details on test material used for the study
CAS; 119-33-5

Test animals
Speciesratcommon species
Strain
Crj: CD(SD)rat
Sex
femaleDetails on test animals or test system and environmental conditions- Source: Charles River Japan Inc.
- Age at the time of purchase: 7 weeks old- Weight at dosing: Females, 190 - 192 g- Fasting period before study: Approximately 16 hrs- Housing: One animal/cage- Diet (e.g. ad libitum): Ad libitum except fasting period for 16 hrs before
administration to 3 hrs after administration- Water (e.g. ad libitum): Ad libitum- Acclimation period: more than one week
ENVIRONMENTAL CONDITIONS- Temperature (°C): 21-24- Humidity (%): 36-59- Ventilation (per hr): Approximately > 12 times- Photoperiod (hrs light / hrs dark): 12/12

Administration / exposure
Route of administration
oral: gavage
Vehiclecorn oil
Details on oral exposure
Test substance5-Lot no.: FBR01-Purity: 99.8%
VEHICLE- Lot no.: V6K0677 produced by Nacalai Tesque, INC..
MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw
Doses
2000 mg/kg bw
No. of animals per sex per doseFirst time of administration: 3 females /dose
Second time of administration: 3 females /doseControl animals
noDetails on study design- Duration of observation period following administration: 14 days
- Frequency of observations: Day 1 (day of administration): within 30 minutes and 1, 2, 3, 4, 5 and 6 hrs
after administration. After day 2: once a day- Frequency of weighing: on the day of administration (before administration), and 1, 3, 7, and 14 days
after administration.
- Necropsy of survivors performed: Yes
The starting administration dose was set as 2000 mg/kg bw. No deaths were observed in the firstadministration; therefore, the second dose was also set as 2000 mg/kg bw.
Statistics
No

Results and discussion
Effect levels
Key result
true
Sex
female
Dose descriptor
LD50
Effect level>2000

mg/kg bw

Based onact. ingr.
Mortality
No deaths were observed in first and second times.
Clinical signs
other: Decreased spontaneous movement was observed 30 min-4 hrs after administration in all animals.
Gross pathology
No changes related to the test substance were observed in first and second times.
6

Applicant's summary and conclusion
Conclusions
The LD50 value was considered to be more than 2000 mg/kg bw for female rats.

7

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

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Author:Date: 2022-12-16T14:25:48.717+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
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
other: The study was conducted in accordance with Test Guidelines and under GLP
Cross-reference
Reason / purpose for cross-reference
reference to other study
Remarks
7.5.1 Repeated dose toxicity: oral.002

Data source
Reference
Twenty-eight-day Repeat Dose Oral Toxicity Test of 2-Nitro-p-cresol in Rats / MHLW, Japan / publication
Data accessdata published

Materials and methods
8Test guideline
Qualifieraccording to guideline
Guideline
other: other guideline: 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

Test material
Test material information
2-Nitro-p-cresol

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.
- Age at study initiation: 5 weeks old- Weight at study initiation: male 161 g (146-173 g), female 144 g (130-154 g)- Housing: Animals were individually housed in a metallic cage with wire mesh bottoms- Diet: Solid feed (MR stock: Nosan Corporation) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation and quarantine period:7-8 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 22±3 (actual temperature: 22.0-22.6 ℃)- Humidity (%): 55±10% (actual humidity: 55-62%)- Air changes (per hr): 10-15- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 7:00~19:00)

Administration / exposure
Route of administration
oral: gavage
Vehicleolive oil9Analytical verification of doses or concentrations
yes
Duration of treatment / exposure
28 daysFrequency of treatment
once a day
Doses / concentrations
Remarks
Doses / Concentrations:0, 15, 60, 250, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose
10/sex (0, 1000 mg/kg bw/day)
5/sex (15, 60, 250 mg/kg bw/day)Control animals
yes, concurrent vehicle
Details on study design- Dose selection rationale: Doses in this test were set based on the results of the following study: 14day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0 (olive oil), 10, 30, 100, 250, 500 or 1000
mg/kg bw/day). At 500 mg/kg/day and higher, sedation and salivation, and tendency of urine oxidatio
n were observed in both sexes. At 1000 mg/kg/day, anemia and changes in liver functions wereobserved. At 250 mg/kg/day and higher, an increasing tendency on the liver weight was observed inboth sexes. On the basis of these effects, a dose level of 1000 mg/kg was selected as the maximum
dose expecting to induce the toxic changes, and then dose levels of 250, 60 and 15 mg/kg bw/day
were selected, in accordance with a common ratio of approximately 4.
- Rationale for animal assignment (if not random): Body weight-balanced randomization- Post-exposure recovery period in satellite groups: 14 days

Examinations
Observations and examinations performed and frequency
CLINICAL OBSERVATIONS: Yes- Time schedule: every day during the administration (4 times a day) and recovery periods (at least
once a day)
DETAILED CLINICAL OBSERVATIONS: Yes
The functional observational battery testing (FOB) was performed on all animals. Among the me
asures in the FOB, detailed clinical observations were made before the initiation of dosing. Thereafter,
detailed clinical observations were made once a week in dosing and recovery periods.
Sensory motor reflexes, forelimb and hindlimb grip strengths, and motor activity were measured
on week 4 of administration period (main/recovery group animals) and week 2 of recovery period(recovery group animals).
BODY WEIGHT: Yes- Time schedule for examinations: Before administration (on days 1, 7, 14, 21 and 28 of the admi
nistration period, days 7 and 14 of the recovery period) and the necropsy days after completion of every period.
10

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 administ
ration period and days 4 and 11 of the recovery period)
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood: the after completion of the administration and recovery perio
ds- Anaesthetic used for blood collection: ether- Animals fasted: Yes (overnight)- How many animals: all animals
CLINICAL CHEMISTRY: 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
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
NEUROBEHAVIOURAL EXAMINATION: No
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), the values 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, urinalysis data),
Kruskal-Wallis rank sum test was used. Consequently, if the result was significant, Dunnett multiple
comparison or Dunnett-typed method was used for detection of 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 homogeneity of 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 signi
ficance was set at 5%.

Results and discussion
11

Results of examinations
Clinical signs
effects observed, treatment-related
Description (incidence and severity)(see Details on results)
Mortality
mortality observed, treatment-related
Description (incidence)(see Details on results)
Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
Haematological findings
effects observed, treatment-related
Description (incidence and severity)(see Details on results)
Clinical biochemistry findings
effects observed, treatment-related
Description (incidence and severity)(see Details on results)
Urinalysis findings
effects observed, treatment-related
Description (incidence and severity)(see Details on results)
Behaviour (functional findings)
no effects observed
Description (incidence and severity)(see Details on results)
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Description (incidence and severity)(see Details on results)
Gross pathological findings
effects observed, treatment-related
Description (incidence and severity)(see Details on results)
Histopathological findings: non-neoplastic
effects observed, treatment-related
Description (incidence and severity)(see Details on results)
Details on results
CLINICAL SIGNS AND MORTALITY12

At 250 mg/kg bw/day and higher, sedation and ptosis were observed in both sexes.
Transient salivation was observed in both sexes at 1,000 mg/kg bw/day. Soiled fur in one female andreddish tear in one male were observed at 1,000 mg/kg bw/day.
NEUROBEHAVIOUR
Clinical signs in detailed observation: No effects.
Sensory/reflex function test: No effects.
Grip strength: In the recovery period, high value of hindlimb strength in males and low value of
forelimb strength in female were observed. (These were within background date.)
Motor activity: No effects.
BODY WEIGHT AND WEIGHT GAIN: No effects.
FOOD CONSUMPTION: No toxicological effects.
HAEMATOLOGY
At 1,000 mg/kg bw/day, low values of Hb, Ht and MCHC, and high values of Ret were observed inmales and females, and high value of APTT was observed in females. At the end of recovery period,
high values of MCV and MCH, and low value of MCHC were observed in males.
CLINICAL CHEMISTRY
At 1,000 mg/kg bw/day, high values of Alb, A/G, T-Cho, and K in males, and high values of γ-GTP
and T-Bil in females were observed. At the end of recovery period, high value of Na was observed inmales.
URINALYSIS
Pale yellow color was observed at 250 mg/kg bw/day and higher in males and females. At 1,000 mg/
kg bw/day, low value of pH were observed in males and females. In the recovery period, low value of
specific gravity was observed in males.
ORGAN WEIGHTSAt 250 mg/kg bw/day and higher, sedation and ptosis were observed in both sexes. Increase in theliver weight was observed at 250 mg/kg bw/day and higher in females and at 1,000 mg/kg bw/day
in males. Furthermore, increases in the kidney weight in males and spleen weight in both sexes wereobserved at 1,000 mg/kg bw/day.
GROSS PATHOLOGY
At 1,000 mg/kg bw/day, blackish color of the spleen was observed in males and females at the endsof administration and recovery periods.
HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological examinations revealed hypertrophy of hepatocytes at 250 mg/kg bw/day and higher
in females. At 1,000 mg/kg bw/day, increase in the extramedullary hematopoiesis and brown pigmentation in the spleen was observed in both sexes. Additionally in males, hypertrophy of hepatocyt
es in the liver was observed at 1,000 mg/kg bw/day. Moreover, an increase in hyaline droplets contai
ning α2u-globulin in the renal proximal tubular epithelium in the kidney was observed in males at thesame dose. These changes, except brown pigmentation in the spleen, tended to resolve after the recovery period.
(See tables in the full report for more details)

Effect levels
Key result
false
Dose descriptor
NOAEL
13

Effect level60

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
other: see 'Remark'At 250 mg/kg bw/day and higher, sedation and ptosis were observed in both sexes. Increase in theliver weight was observed at 250 mg/kg bw/day and higher in females and at 1,000 mg/kg bw/day
in males. Histopathological examinations revealed hypertrophy of hepatocytes at 250 mg/kg bw/
day and higher in females.

Target system / organ toxicity
Key result
false
Critical effects observed
not specified

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/PDF119 -33 -5b.pdf

Applicant's summary and conclusion
Executive summary
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 2-nitro-p-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
250 mg/kg bw/day and higher, sedation and ptosis were observed in both sexes. Increase in the liver
weight was observed at 250 mg/kg bw/day and higher in females and at 1,000 mg/kg bw/day in males.
Furthermore, increases in the kidney weight in males and spleen weight in both sexes were observed at
1,000 mg/kg bw/day. Histopathological examinations revealed hypertrophy of hepatocytes at 250 mg/
kg bw/day and higher in females. At 1,000 mg/kg bw/day, increase in the extramedullary hematopoiesis
and brown pigmentation in the spleen was observed in both sexes. Additionally in males, hypertrophy ofhepatocytes in the liver was observed at 1,000 mg/kg bw/day. Moreover, an increase in hyaline droplets
containing α2u-globulin in the renal proximal tubular epithelium in the kidney was observed in males atthe same dose. These changes, except brown pigmentation in the spleen, tended to resolve after therecovery period. 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

UUID: IUC5-c2b1b0b7-0568-4483-b21c-54cfa1d1f5a7
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Author:Date: 2022-12-16T14:27:08.815+09:00
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Administrative data
Endpoint
repeated dose toxicity: oral combined repeated dose and reproduction / developmental screening
deactivated phrase
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
other: GLP guideline study
Cross-reference
Reason / purpose for cross-reference
reference to same study
Remarks
7.8.1 Toxicity to reproduction.001

Reason / purpose for cross-reference
reference to other study
Remarks
7.5.1 Repeated dose toxicity: oral.001

Data source
Reference
A reproduction/developmental toxicity screening test in rats treated orally with 2-nitro-p-cresol / MHLW,Japan / study report15

Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
other: OECD TG 421: Reproduction/developmental toxicity screening test
Deviationsno
GLP compliance
yes
Limit test
no

Test material
Test material information
2-Nitro-p-cresol

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. Tsukuba- Age at study initiation: 10 weeks- Weight at study initiation: Males: 392-474 (average 427) g; Females: 238-297 (average 270) g- Housing: Steel wire-mesh cage (250 mm x 350 mm x 200 mm )- Diet: ad libitum- Water: ad libitum- Acclimation period: 19 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 20-24- Humidity (%): 33-69- Air changes: 10-15 times / hr
- Photoperiod: 12 hrs dark / 12 hrs light (07:00-19:00)

Administration / exposure
16Route of administration
oral: gavage
Vehicleolive oilAnalytical 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) Femal
es: 42-47 days including 14 days pre-mating, mating and gestation periods, and the days until day 4 oflactation. Infertile females: 40-53 days
Frequency of treatment
Once/day, 7days/week
Doses / concentrations
Remarks
Doses / Concentrations:
0 (vehicle), 60, 250, and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose
12 animals/sex/doseControl animals
yes, concurrent vehicle
Details on study design- Dose selection rationale: Doses in this test were set based on the results of the following study: 28day repeated dose oral toxicity test (doses: 0, 15, 60, 250, and 1000 mg/kg bw/day). At 250 mg/kg
bw/day and higher, sedation and ptosis were observed in both sexes. Increase in the liver weight
was observed at 250 mg/kg bw/day and higher in females and at 1,000 mg/kg bw/day in males.
Furthermore, increases in the kidney weight in males and spleen weight in both sexes were observed
at 1,000 mg/kg bw/day. Histopathological examinations revealed hypertrophy of hepatocytes at 250
mg/kg bw/day and higher in females. At 1,000 mg/kg bw/day, increase in the extramedullary hema
topoiesis and brown pigmentation in the spleen was observed in both sexes. Additionally in males, hy
pertrophy of hepatocytes in the liver was observed at 1,000 mg/kg bw/day. Moreover, an increase in
hyaline droplets containing α2u-globulin in the renal proximal tubular epithelium in the kidney was observed in males at the same dose. These changes, except brown pigmentation in the spleen, tended
to resolve after the recovery period.
On the basis of these effects, a dose level of 1000 mg/kg was selected as the maximum dose exp
ecting to induce the toxic changes, and then dose levels of 250 and 60 mg/kg bw/day were selected
as a middle dose and a minimum dose levels, respectively, in accordance with a common ratio of
approximately 4.
- 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: 3 times/day
17

BODY WEIGHT: Yes- Time schedule for examinations:
Males: Days 1, 4, 8, 11, 15, 22, 25, 29, 32, 36, 39, 42, and the day of necropsy
Females: Twice a week during the precopulation period (days 1, 4, 8, 11, and 15); gestation days 0, 4,
7, 11, 14, 17, and 20; lactation days 0 and 4; and the day of necropsy. For unmating females, 18, 22
and 25 in the mating period
FOOD CONSUMPTION: Yes
Males: Days 1, 4, 8, 11, 15, 32, 36, 39, and 42 in dosing period
Females: Days 1, 4, 8, 11, and 15; gestation days 1, 4, 7, 11, 14, 17, and 20; lactation days 2 and 4
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
Sacrifice and pathology
GROSS PATHOLOGY: Yes (see tables)
HISTOPATHOLOGY: Yes (epididymis, prostate, seminal vesicle, testis, ovary, uterus, vagina, and grossabnormal sites)
Other examinations
Organ weight: Testes and epididymides
Statistics
3 or more groups: The data were analyzed for homogeneity of variance by the Bartlett test. If variances were homogeneous, data was analyzed by the Dunnett test, whereas heterogeneous data wasanalyzed by the steel test (p<0.05, two-sided).
2 groups: The data were analyzed for homogeneity of variance by the F test. If variances were homog
eneous, data was analyzed by the Student t test, whereas heterogeneous data was analyzed by the
Aspin-Welch t test (p<0.05, two-sided).

Results and discussion
Results of examinations
Clinical signs
effects observed, treatment-related
Description (incidence and severity)
At 1,000 mg/kg bw/day, ptosis and decreased locomotor activity were observed in both sexes.
Mortality
mortality observed, treatment-related
Description (incidence)
At 1,000 mg/kg bw/day, ptosis and decreased locomotor activity were observed in both sexes.
Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
18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
Organ weight findings including organ / body weight ratios
no effects observed
Gross pathological findings
effects observed, treatment-related
Description (incidence and severity)
see tables in the full report.
Histopathological findings: non-neoplastic
effects observed, treatment-related
Description (incidence and severity)
see tables in the full report.
Histopathological findings: neoplastic
not examined
Details on results
At 1,000 mg/kg bw/day, histopathological examinations revealed centrilobular hypertrophy ofhepatocytes in the liver and increased extramedullary hematopoiesis in the spleen in both sexes.

Effect levels
Key result
false
Dose descriptor
NOAEL
Effect level250

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
19Basis for effect level
other: see 'Remark'At 1,000 mg/kg bw/day, ptosis and decreased locomotor activity were observed in both sexes. At
the same dose, histopathological examinations revealed centrilobular hypertrophy of hepatocytes in
the liver and increased extramedullary hematopoiesis in the spleen in both sexes.

Target system / organ toxicity
Key result
false
Critical effects observed
not specified

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/PDF119 -33 -5c.pdf

Applicant's summary and conclusion
Conclusions
In this study, NOAEL for repeated-dose toxicity was determined to be 250 mg/kg bw/day in male andfemale rats.
Executive summary
A reproduction/developmental toxicity screening test was performed according to OECD TG 421. Maleand female rats (12 animals/sex/dose) were administered 2-nitro-p-cresol at 0, 60, 250, and 1,000 mg/
kg bw/day. Males were dosed for 42 days, including a 14 day pre-mating and mating periods. Females
were dosed for 42–47 days, including a 14 day pre-mating, mating, and gestation periods, and the time
until lactation day 4. At 1,000 mg/kg bw/day, ptosis and decreased locomotor activity were observedin both sexes. At the same dose, histopathological examinations revealed centrilobular hypertrophy ofhepatocytes in the liver and increased extramedullary hematopoiesis in the spleen in both sexes. On
the basis of these changes, NOAEL for repeated-dose toxicity was determined to be 250 mg/kg bw/day
in male and female rats.

20

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

UUID: IUC5-052223da-12ec-41a9-9c66-24acf10465ce
Dossier UUID:
Author:Date: 2022-12-16T14:28:45.851+09:00
Remarks:

Administrative data
Endpoint
in vitro gene mutation study in bacteria Type of genotoxicity: gene mutation
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
other: GLP guideline study

Data source
Reference
Reverse mutation test of 2-nitro-p-cresol in Bacteria / MHLW, Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
in vitro gene mutation study in bacteria
GLP complianceyes21Type of assay
bacterial reverse mutation assay
in vitro gene mutation study in bacteria

Test material
Test material information
2-Nitro-p-cresol

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
Test concentrations with justification for top dose
Dose–range finding test (–S9 mix and +S9 mix): 0 (vehicle), 1.22, 4.88, 19.5, 78.1, 313, 1250, and 5000
μg/plate;
Main bacterial reverse mutation test (–S9 mix and +S9 mix): 0 (vehicle), 39.1-5000 μg/plate [1st].
0 (vehicle), 19.5-5000 μg/plate [2nd]. 0 (vehicle), 19.5-1250 μg/plate [3rd, TA98].
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle: The test substance was soluble in DMSO, but not in water.
Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controls
yes tests without all strains
Positive controls
yes
Positive control substancesodium azide
benzo(a)pyrene
furylfuramide
other: 2-aminoanthracene, 2-methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino]acridine-2HCl
Details on test system and experimental conditions
METHOD OF APPLICATION: Preincubation
DURATION- Preincubation period: 20 min
22

- Exposure duration: ca. 50 hours
NUMBER OF REPLICATIONS: 3
DETERMINATION OF CYTOTOXICITY- Method: Cell growth
Evaluation criteria
Criteria for determining a positive result were as follows; A 2–fold or more increase in the numberof revertant colonies compared with the solvent control, a concentration–related increase in the nu
mber of revertant colonies, and a reproducible increase in the number of revertant colonies.
Statistics
No statistic method was used for judging of results.

Results and discussion
Test results
Key result
false
Species / strain
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity see tables.
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid
Key result
false
Species / strain
E. coli WP2 uvr A
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity see tables.
23

Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid
Additional information on results
TEST-SPECIFIC CONFOUNDING FACTORS- Precipitation: Precipitation was not observed on any plates with/without metabolic activation.
- Other effects: coloring was observed on plates with concentration of 1250 μg/plate or more with/w
ithout metabolic activation in range-finding studies.
RANGE-FINDING/SCREENING STUDIES:
In range-finding studies, growth inhibition was observed on plates with concentration of 1250 μg/
plate or more in all S. typhimurium strains with/without metabolic activation and on plates withconcentration of 5000 μg/plate in all E.coli strains with/without metabolic activation.
COMPARISON WITH HISTORICAL CONTROL DATA:
In all test conditions and in all tested strains, the number of revertant colonies of solvent controls andpositive controls were within the range of historical control data.
Remarks on result
other: all strains/cell types tested Migrated from field 'Test system'.

Overall remarks, attachments
Overall remarks

Figures and Tables (in Japanease) are available in the following full report of the study.
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF119 -33 -5e.pdf
Tables (in English) are attachted to this document. Please download the export file to see the Tables.
Attachments
Attached (sanitised) documents for publication
119-33-5_Ames Tables.xlsx / 40.077 KB (application/vnd.openxmlformatsofficedocument.spreadsheetml.sheet)

Applicant's summary and conclusion
Conclusions
Interpretation of results (migrated information):negative
Executive summary
In a bacterial reverse mutation assay using S. typhimuriumTA100, TA1535, TA98, and TA1537 and E.
coli WP2uvrA (OECD TG 471), 2-nitro-p-cresol was negative with or without metabolic activation.

24

ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.002

UUID: IUC5-05fb6ad5-c084-4f39-96a2-3ec8deffac01
Dossier UUID:
Author:Date: 2022-12-16T14:29:34.047+09:00
Remarks:

Administrative data
Endpoint
in vitro cytogenicity / chromosome aberration study in mammalian cells Type of genotoxicity:
chromosome aberration
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
other: OECD Test Guideline study under GLP condition

Data source
Reference
In Vitro Chromosomal Aberration Test of 2-nitro-p-cresol on Cultured Chinese Hamster Cells. / MHLW,Japan / study report
Data accessdata published

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
25

Deviations
no
Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
Deviationsno
GLP compliance
yesType of assay
in vitro mammalian chromosome aberration test
chromosome aberration

Test material
Test material information
2-Nitro-p-cresol

MethodTarget gene
Chromosome
Species / strain
Species / strain / cell typeother: Chinese hamster lung(CHL/IU) cells
Metabolic activation
with and without
Metabolic activation system
rat liver, induced by phenobarbital and 5,6-benzoflavone
Test concentrations with justification for top dose
-S9 mix (short-term treatment): 0, 25.0, 50.0, 100, 200, 400 ug/mL+S9 mix (short-term treatment): 0, 25.0, 50.0, 100, 200, 400 ug/mL+S9 mix (short-term treatment, confirmation test): 0, 300, 400, 500, 600, 700, 800 ug/mL-S9 mix (continuous treatment, 24 h): 0, 25.0, 50.0, 100, 200, 400 ug/mL-S9 mix (continuous treatment, 48 h): 0, 25.0, 50.0, 100, 200, 400 ug/mL
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes26

True negative controlsnoPositive controls
yes
Positive control substancecyclophosphamide
mitomycin C
Remarks
mitomycin C (without S9 mix), cyclophosphamide (with S9 mix)
Details on test system and experimental conditions
METHOD OF APPLICATION: Exposure duration: [continuous treatment]: 24, 48 hrs [short-term treatment]:6 hrs + 18 hr
SPINDLE INHIBITOR: Colcemid
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 200 cells / dose
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 cells with chromosomal aberrations: Negative (-): < 5%; equivocal (±): 5-10%;
positive (+): > 10%.
Finally, the substance is positive when the incidence is considered to be dose-related and repro
ducible.
Statistics
not used.

Results and discussion
Test results
Key result
false
Species / strainother: Chinese hamster lung (CHL/IU) cells
Metabolic activation
with
Genotoxicity
positive structural aberration
Cytotoxicity / choice of top concentrations
cytotoxicity 50% cell growth inhibition: 190.0 ug/mL (short)
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid

27

Key result
false
Species / strainother: Chinese hamster lung (CHL/IU) cells
Metabolic activation
without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity 50% cell growth inhibition: 192.3 ug/mL (short), 252.6 ug/mL (24h continuous) and
200.0 ug/mL (48h continuous)
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
validOverall remarks, attachments
Overall remarks
Figures and Tables (in English) are available in the following full report of the study.
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF119 -33 -5f.pdf

Applicant's summary and conclusion
Executive summary
An in vitro chromosomal aberration test using CHL/IU cells (OECD TG 473) showed positive result withmetabolic activation.

28

Genetic toxicity in vivo
ENDPOINT_STUDY_RECORD: Genetic toxicity in vivo.001

UUID: IUC5-40365d06-5dac-40cf-a914-51fc7eacba50
Dossier UUID:
Author:Date: 2022-12-16T14:30:38.531+09:00
Remarks:

Administrative data
Endpoint
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus Type of genotoxicity:
chromosome aberration
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
other: OECD Guideline study under GLP condition

Data source
Reference
Micronucleous test of 2-nitro-p-cresol on mouse / MHLW, Japan / study report

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Deviations
not specified
Qualifieraccording to guideline
29

Guideline
other: Testing Methods for New Chemical Substances etc.
Deviations
not specified
GLP complianceyes (incl. QA statement)
Type of assay
micronucleus assay
chromosome aberration

Test material
Test material information
2-Nitro-p-cresol

Test animals
Speciesmouse
Strainother: Crlj: CD1(ICR)
Sexmale
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Laboratories Japan, Inc. Atsugi Farm Center- Age at study initiation: 8 weeks old- Weight at study initiation: 31.2-36.1 g- Assigned to test groups randomly: yes- Housing: White flake (Charles River Japan, Inc.) in plastic cage (W 155 x K 245 x H 150mm: Clea
Japan, Inc.)- Diet: ad libitum- Water: ad libitum- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS- Temperature (°C):21-23- Humidity (%):47-67- Air changes: 10-15/h- Photoperiod: 12 h dark/ 12 h light (light time: 7:00 to 19:00)

Administration / exposure
Route of administration
oral: gavage
Vehicle- Vehicle(s)/solvent(s) used: olive oil- Concentration of test material in vehicle: 0, 25, 50, and 100 mg/mL- Amount of vehicle (if gavage or dermal): 10 mL/kg bw- Lot/batch no. (if required): 0420, 0929

30

Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared by dissolving the test substance in olive oil. They were used within 6
days.
Duration of treatment / exposure
24 hFrequency of treatment
Twice, 24 h interval
Doses / concentrations
Remarks
Doses / Concentrations:
0 (vehicle), 250, 500, and 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose
5 males/doseControl animals
yes, concurrent vehicle
Positive control(s)Mitomycin C (MMC)- Justification for choice of positive control: MMC is widely used in the micronucleus test and is oneof the positive control materials exemplified and recommended in the applicable guidelines.
- Route of administration: intraperitoneal injection- Doses / concentration: 1 mg/kg bw

Examinations
Tissues and cell types examined
Polychromatic erythrocytes from the femur bone marrow
Details of tissue and slide preparation
TREATMENT AND SAMPLING TIMES (in addition to information in specific fields): Cells for specimen
were collected 24 h after the administration.
DETAILS OF SLIDE PREPARATION: Cell suspensions were expanded on the slide glass and dried.
The expanded cells were stained using a cover glass with a small amount of acridine orange solution(40ug/mL).
METHOD OF ANALYSIS: fluorescence microscopy, blind method
Evaluation criteria
Criterion for determining a positive result: A dose-related increase in the number of micronucleatedcells.
Statistics
The number of micronucleated polychromatic erythrocytes was determined by the Kastenbaum andBowman method, and Cochran Armitage test;
Ratio of polychromatic erythrocytes to whole erythrocytes by Bartlett's test and Dunnett's test31

Results and discussion
Test results
Key result
false
Sex
male
Genotoxicity
negative
Vehicle controls validity
valid
Positive controls validity
valid
Additional information on results
RESULTS OF RANGE-FINDING STUDY- Dose range: 250, 500, 1000, 2000 mg/kg bw for males and females- Clinical signs of toxicity in test animals: Death was observed in one male and one female at 2000
mg/kg bw. Colored urine and lowered body weight were observed in all animals dosed.
- Harvest times: 24 h after the treatment
RESULTS OF DEFINITIVE STUDY- Induction of micronuclei (for Micronucleus assay): Males: The number of micronucleated cells in all
dosed groups was within the range of control. Females: The study was not conducted because no sex differences were found in the preliminary study.
- Ratio of PCE/NCE (for Micronucleus assay): Ratios for dose levels, 0, 250, 500, and 1000 mg/kg bw/
day: 0.13%, 0.13%, 0.16%, and 0.11%; Positive control: 2.54%

Overall remarks, attachments
Overall remarks
Figures and Tables (in English) are available in the following full report of the study.
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF119 -33 -5g.pdf

Applicant's summary and conclusion
Conclusions
Interpretation of results (migrated information): negative
The test substance did not produce micronuclei in the immature erythrocytes of the test species.
Executive summary
The result of an in vivo micronucleus study (OECD TG 474) was negative up to the maximum tolerated
dose (1,000 mg/kg bw/day for 2 days) in mice.

32

Toxicity to reproduction
ENDPOINT_STUDY_RECORD: Toxicity to reproduction.001

UUID: IUC5-8f5a4886-495c-4d75-a80e-240dc9bce661
Dossier UUID:
Author:Date: 2022-12-16T14:31:56.759+09:00
Remarks:

Administrative data
Endpoint
screening for reproductive / developmental toxicity based on test type (migrated information)
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
other: OECD Test Guideline study under GLP condition
Cross-reference
Reason / purpose for cross-reference
reference to same study
Remarks
7.5.1 Repeated dose toxicity: oral.002

Data source
Reference
A reproduction/developmental toxicity screening test in rats treated orally with 2-nitro-p-cresol / MHLW,Japan / study report
Data accessdata published

Materials and methods
33

Test guideline
Qualifieraccording to guideline
Guideline
other: OECD TG 421: Reproduction/developmental toxicity screening test
Deviationsno
GLP compliance
yes
Limit test
no

Test material
Test material information
2-Nitro-p-cresol

Test animals
Speciesrat
Strainother: Crl:CD(SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Laboratories Japan, Inc. Tsukuba- Age at study initiation: 10 weeks- Weight at study initiation: Males: 392-474 (average 427) g; Females: 238-297 (average 270) g- Housing: Steel wire-mesh cage (250 mm x 350 mm x 200 mm )- Diet: ad libitum- Water: ad libitum- Acclimation period: 19 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 20-24- Humidity (%): 33-69- Air changes: 10-15 times / hr
- Photoperiod: 12 hrs dark / 12 hrs light (07:00-19:00)

Administration / exposure
Route of administration
oral: gavage
34

Vehicleolive oil
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
Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating and mating periods, and thereafter 14 days (P) Femal
es: 42-47 days including 14 days pre-mating, mating and gestation periods, and the days until day 4 oflactation. Infertile females: 40-53 days
Frequency of treatment
Once/day, 7days/week
Doses / concentrations
Remarks
Doses / Concentrations:
0 (vehicle), 60, 250, and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose
12 animals/sex/doseControl animals
yes, concurrent vehicle

Examinations
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes- Time schedule:
Males and females: 3 times/day
BODY WEIGHT: Yes- Time schedule for examinations:
Males: Days 1, 4, 8, 11, 15, 22, 25, 29, 32, 36, 39, 42, and the day of necropsy
Females: Twice a week during the precopulation period (days 1, 4, 8, 11, and 15); gestation days 0, 4,
7, 11, 14, 17, and 20; lactation days 0 and 4; and the day of necropsy. For unmating females, 18, 22
and 25 in the mating period
FOOD CONSUMPTION: Yes
Males: Days 1, 4, 8, 11, 15, 32, 36, 39, and 42 in dosing period
Females: Days 1, 4, 8, 11, and 15; gestation days 1, 4, 7, 11, 14, 17, and 20; lactation days 2 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 in the main groups 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,
35

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: testes weight, epididymides weight
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].
GROSS EXAMINATION OF DEAD PUPS: Yes, for external and internal abnormalities.
Postmortem examinations (parental animals)
SACRIFICE:
Male animals: Rats were euthanized by exsanguination under ether anesthesia on the day after the last administration.
Maternal animals: Rats were euthanized by exsanguination under ether anesthesia on day 4 of lactati
on.
GROSS PATHOLOGY: Yes (see tables)
HISTOPATHOLOGY: Yes (epididymis, prostate, seminal vesicle, testis, ovary, uterus, vagina, and grossabnormal sites)
ORGAN WEIGHTS, Yes: Testes and epididymis
Postmortem examinations (offspring)
GROSS NECROPSY- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, andabdominal viscera.
Statistics
The data were analyzed for homogeneity of variance by the Bartlett test. If variances were
homogeneous, data was analyzed by the Dunnett test, whereas heterogeneous data was analyzed by
the Steel test (p<0.05, two-sided).
2 groups: The data were analyzed for homogeneity of variance by the F test. If variances were homogeneous, data was analyzed by the Student t test, whereas heterogeneous data was analyzed by the
Aspin-Welch t test (p<0.05, two-sided).
Especially,
Implantation index, Stillborn index, Liveborn index, External abnormalities, Viability index: the Steeltest (p<0.05 and <0.01, two-sided)
Copulation index, Fertility index, Insemination index, Delivery index: Fisher's exact test (p<0.05 and<0.01, two-sided)
Reproductive indices
Each parameter was determined by the following equations:
Copulation index (%) = (No. of copulated animals/No. of co-housed animals) × 100
Fertility index (%) = (No. of pregnant females/No. of copulated females) × 100
Insemination index (%) = (No. of pregnant females/No. of copulated males) × 100
Duration of gestation (days) = day 0 of lactation – day 0 of gestation
Delivery index (%) = (No. of females delivered liveborn pups/No. of pregnant females) × 100
Implantation index (%) = (No. of implantation sites/No. of corpora lutea) × 100
Stillborn index (%) = (No. of stillborn pups/Total No. of pups born) × 100
Liveborn index (%) = (No. of liveborn pups/Total No. of pups born) × 100
External abnormalities (%) = (No. of pups with external abnormalities/No. of liveborn pups) × 100
Sex ratio = No. of liveborn male pups/(No. of liveborn male pups + No. of liveborn female pups)
Offspring viability indices
Viability index (%) = (No. of surviving pus on day 4 after birth/No. of liveborn pups on day 0 after birth)
× 100
36

Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
Clinical signs
effects observed, treatment-related
Description (incidence and severity)see 7.5.1 Repeated dose toxicity: oral.002
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
Organ weight findings including organ / body weight ratios
no effects observed
Description (incidence and severity)
on reproductive organs
Gross pathological findings
no effects observed
Description (incidence and severity)
on reproductive organs
Histopathological findings: non-neoplastic
no effects observed
Description (incidence and severity)
on reproductive organs

Reproductive function / performance (P0)
Reproductive function: oestrous cycle
no effects observed
Reproductive function: sperm measures
not examined
Reproductive performanceno effects observed
Description (incidence and severity)
on reproductive organs

Effect levels (P0)37Key result
false
Dose descriptor
NOAEL
Effect level250

mg/kg bw/day (actual dose received)

Sexmale/female

Results: F1 generation
General toxicity (F1)Clinical signs
no effects observed
Mortality / viability
no mortality observed
Body weight and weight changes
no effects observed
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
false
Dose descriptor
NOAEL
Generation
F1
Effect level1000

mg/kg bw/day (actual dose received)

Sexmale/female
Basis for effect level
other: the highest dose tested

Overall reproductive toxicity
38

Key result
false
Reproductive effects observed
not specified

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/PDF119 -33 -5c.pdf

Applicant's summary and conclusion
Conclusions
NOAEL for the rat reproductive/developmental toxicity of 4-chlorobenzaldehyde was determined to be
200 mg/kg bw/day.

Executive summary
In the reproduction/developmental toxicity screening test (0, 60, 250, and 1,000 mg/kg bw/day) (OECDTG 421), no effects of this substance on reproductive and developmental parameters were observed
at 1,000 mg/kg bw/day. NOAEL for the rat reproductive/developmental toxicity of 2-nitro-p-cresol was
determined to be 1,000 mg/kg bw/day, the highest dose tested.

39

DOMAIN
Substance
SUBSTANCE: 2-Nitro-p-cresol
UUID: IUC5-b0a94a30-717c-4d02-af0c-412c12b4d472
Dossier UUID:
Author:Date: 2022-12-16T14:32:04.949+09:00
Remarks:
Substance name
2-Nitro-p-cresol
Legal entity
National Institute of Health Sciences / Kawasaki / Japan

Identification of substance
Reference substance
2-nitro-p-cresol / 4-methyl-2-nitrophenol / 119-33-5 / 204-315-6
EC number

EC name204-315-6

EC Inventory

CAS number

CAS name

119-33-5
IUPAC name
4-methyl-2-nitrophenol

Role in the supply chain
Manufacturer
false
Importer
false
Only representativefalse
Downstream user
false

40

References
Reference Substances
REFERENCE_SUBSTANCE: 2-nitro-p-cresol
UUID: ECB5-4c8b7908-3640-47d4-b274-fae78201d6fd
Dossier UUID:
Author:Date: 2018-08-27T10:55:22.000+09:00
Remarks:
Reference substance name
2-nitro-p-cresol
IUPAC name
4-methyl-2-nitrophenol

Inventory
Inventory number
Inventory name
2-nitro-p-cresol
Inventory
EC Inventory
Inventory number
204-315-6
CAS number
119-33-5
Molecular formula
C7H7NO3
Description
CAS number
119-33-5

Synonyms
Synonyms
Identity
2-nitro-p-cresol
Identity
Phenol, 4-methyl-2-nitro-

Molecular and structural information
41

Molecular formula
C7H7NO3
Molecular weight
153.1354
SMILES notation
Cc1ccc(O)c(c1)[N+](=O)[O-]
InChl
InChI=1/C7H7NO3/c1-5-2-3-7(9)6(4-5)8(10)11/h2-4,9H,1H3
Structural formula

Related substancesGroup / category information
OECD Category: m,p - Cresols
USEPA Category: Phenols

42Test Materials
TEST_MATERIAL_INFORMATION: 2-Nitro-p-cresol
UUID: 122b9bdd-68e3-3539-adbb-7378661ed03e
Dossier UUID:
Author:Date: 2022-12-15T09:17:52.446+09:00
Remarks:Name
2-Nitro-p-cresol

Composition
Composition
Type
Constituent
Reference substance
2-nitro-p-cresol / 4-methyl-2-nitrophenol / 119-33-5 / 204-315-6
EC number

EC name204-315-6

EC Inventory

CAS number

CAS name

119-33-5
IUPAC name
4-methyl-2-nitrophenol

Other characteristics
Details on test material- Name of test material (as cited in study report): 2-nitro-p-cresol- Purity: 99.6%- Lot/batch No.: FHD01- Stability under test conditions: Stable- Storage condition of test material: a cool (3-6 °C) and dark place (in a refrigerator), with an airtightstopper- Dosing solution storage condition: under a cool (3-6 °C) place (in a refrigerator), in a brown glass bottle- Other: The dosing solution was used within 7 days of preparation.

43

TEST_MATERIAL_INFORMATION: 2-Nitro-p-cresol
UUID: 5bf89a9f-610d-3117-9884-daae68efa128
Dossier UUID:
Author:Date: 2022-12-15T09:16:41.786+09:00
Remarks:Name
2-Nitro-p-cresol

Composition
Composition
Type
Constituent
Reference substance
2-nitro-p-cresol / 4-methyl-2-nitrophenol / 119-33-5 / 204-315-6
EC number

EC name204-315-6

EC Inventory

CAS number

CAS name

119-33-5
IUPAC name
4-methyl-2-nitrophenol

Other characteristics
Details on test material- Name of test material (as cited in study report): 2-Nitro-p-cresol- Analytical purity: 99.8%- Lot No.: FBR01- Storage condition of test material: at a cold (temperature 2-6 ℃) and dark place, with airtightstopper.
- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

44

Literatures
LITERATURE: A reproduction/developmental toxicity
screening test in rats treated orally with 2-nitro-p-cresol
UUID: cdbb7871-31c4-3a0d-8a4b-bf954b375559
Dossier UUID:
Author:Date: 2017-02-15T15:43:40.000+09:00
Remarks:

General information
Reference Typestudy report
Title
A reproduction/developmental toxicity screening test in rats treated orally with 2-nitro-p-cresol
Author
MHLW, Japan
Year
2012
Bibliographic source
available in the web of Japan Existing Chemical Data Base (JECDB) at http://dra4.nihs.go.jp/
mhlw_data/jsp/SearchPageENG.jsp
Testing facility
BoZo Research Center

45

LITERATURE: In Vitro Chromosomal Aberration Test of 2nitro-p-cresol on Cultured Chinese Hamster Cells.
UUID: 8a48dba7-f670-3547-8ad5-6a6f48a27e32
Dossier UUID:
Author:Date: 2017-02-15T15:41:24.000+09:00
Remarks:

General information
Reference Typestudy report
Title
In Vitro Chromosomal Aberration Test of 2-nitro-p-cresol on Cultured Chinese Hamster Cells.
Author
MHLW, Japan
Year
2007
Bibliographic source
available in the web of Japan Existing Chemical Data Base (JECDB) at http://dra4.nihs.go.jp/
mhlw_data/jsp/SearchPageENG.jsp
Testing facility
BoZo Research Center46

LITERATURE: Micronucleous test of 2-nitro-p-cresol on
mouse
UUID: 322a5a3a-eb01-3870-ada3-90cdba50efff
Dossier UUID:
Author:Date: 2017-02-15T15:42:10.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Micronucleous test of 2-nitro-p-cresol on mouse
Author
MHLW, Japan
Year
2011
Bibliographic source
available in the web of Japan Existing Chemical Data Base (JECDB) at http://dra4.nihs.go.jp/
mhlw_data/jsp/SearchPageENG.jsp
Testing facility
Bozo Research Center47

LITERATURE: Reverse mutation test of 2-nitro-p-cresol in
Bacteria
UUID: 99e619c7-c952-31c2-9687-ca7d8c11d691
Dossier UUID:
Author:Date: 2022-12-15T09:31:25.733+09:00
Remarks:

General information
Reference Typestudy report
Title
Reverse mutation test of 2-nitro-p-cresol in Bacteria
Author
MHLW, Japan
Year
2007
Bibliographic source
available in the web of Japan Existing Chemical Data Base (JECDB) at http://dra4.nihs.go.jp/
mhlw_data/jsp/SearchPageENG.jsp
Testing facility
Bozo Research Center Inc.

48

LITERATURE: Single Dose Oral Toxicity Test of 2-nitro-pcresol in RatsUUID: c35179d9-e9d1-4f83-8fea-4e8e3cfe7be7
Dossier UUID:
Author:Date: 2018-08-24T16:59:16.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Single Dose Oral Toxicity Test of 2-nitro-p-cresol in Rats
Author
MHLW, japan
Bibliographic source
Single Dose Oral Toxicity Test of 2-nitro-p-cresol in Rats

49

LITERATURE: Twenty-eight-day Repeat Dose Oral Toxicity
Test of 2-Nitro-p-cresol in RatsUUID: 498a7463-633b-3f3e-93d5-83ac8e71b5bd
Dossier UUID:
Author:Date: 2022-12-15T09:31:07.197+09:00
Remarks:

General information
Reference Typepublication
Title
Twenty-eight-day Repeat Dose Oral Toxicity Test of 2-Nitro-p-cresol in Rats
Author
MHLW, Japan
Year
2011
Bibliographic source
available in the web of Japan Existing Chemical Data Base (JECDB) at http://dra4.nihs.go.jp/
mhlw_data/jsp/SearchPageENG.jsp
Testing facility
Research institute for animal science in biochemistry and toxicology (RIAS)

50

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 systemIUCLID451

ID
16558402024DIV750

52