Name: COMPLETE / SUBSTANCE : 4-sec-Butyl-2,6-di-tert-butylphenol / 4-sec-butyl-2,6-ditert-butylphenol / 17540-75-9 Fri, 16 Dec 2022, 14:48:49+0900 /Legal entity owner: National Institute of Health Sciences
Printing date: 2022-12-16T14:48:49.464+09:00

iTable of Contents
0/0 ............................................................................................................................. 1
National Institute of Health Science ..................................................................... 2
4-sec-Butyl-2,6-di-tert-butylphenol ......................................................................... 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
67 Repeated dose toxicity: oral .................................................... 4
Repeated dose toxicity: oral.001 ........................................... 470 Genetic toxicity in vitro ......................................................... 12
Genetic toxicity in vitro.001 ................................................ 12
Genetic toxicity in vitro.002 ................................................ 16
73 Toxicity to reproduction ........................................................ 20
Toxicity to reproduction.001 ............................................... 20
DOMAIN .................................................................................................... 29
Substance ......................................................................................... 29
Substance ................................................................................ 29
References ................................................................................................................ 30
Reference Substances ...................................................................................... 30
4-sec-butyl-2,6-di-tert-butylphenol ............................................................... 30
Test Materials .................................................................................................. 32
4-sec-butyl-2,6-di-tert-butylphenol ............................................................... 32
Literatures ....................................................................................................... 33
In Vitro Chromosomal Aberration Test of 4-sec-butyl-2,6-di-tert-butylphenol
on Cultured Chinese Hamster Cells. ........................................................... 33
Reproduction/Developmental Toxicity Screening Test on 4-sec-butyl-2,6-ditert-butylphenol ......................................................................................... 34
Reverse Mutation Test of 4-sec-butyl-2,6-di-tert-butylphenol on Bacteria. ....... 35
Twenty-eight-day Repeated Dose Oral Toxicity Test of 4-sec-Butyl-2,6-ditert-butylphenol in Rats .............................................................................. 36
Legal Entities ................................................................................................... 37
National Institute of Health Sciences, Japan .............................................. 37ii

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4-sec-Butyl-2,6-di-tert-butylphenol / 4-sec-butyl-2,6-di-tert-butylphenol / 17540-75-9
Public name4-sec-Butyl-2,6-di-tert-butylphenol
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National Institute of Health Science
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Fri, 16 Dec 2022, 14:48:49+0900
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LEGAL_ENTITY: National Institute of Health
Science
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General information
Legal entity nameNational Institute of Health Science24-sec-Butyl-2,6-di-tert-butylphenol
CORE
General information
Assessment approach (assessment entities)
FIXED_RECORD: Assessment approach

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OECD
Health Effects
Repeated dose toxicity: oral
ENDPOINT_STUDY_RECORD: Repeated dose toxicity: oral.001

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Administrative data
Endpoint
short-term repeated dose toxicity: oral
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
other: The study was conducted in accordance with Test Guidelines and under GLP

Data source
Reference
Twenty-eight-day Repeated Dose Oral Toxicity Test of 4-sec-Butyl-2,6-di-tert-butylphenol in Rats /Ministry of Health, Labour and Welfare (MHLW), Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
4Guideline
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviationsno
GLP compliance
yes
Limit test
no

Test material
Test material information
4-sec-butyl-2,6-di-tert-butylphenol
Specific details on test material used for the study- Analytical purity: 99.0%- Storage condition of test material: Stored in a refrigerator (2 - 9°C)
- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

Test animals
Speciesratcommon rodent species
Strainother: Crl:CD(SD)Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Japan, Inc., Atsugi Breeding Center.
- Age at study initiation: 5 weeks old- Weight at study initiation: male 175.0 g (163-185 g), female 147.7 g (131-162 g)- Housing: Animals were individually housed in bracket-type metallic wire-mesh cages (260W × 380D ×
170H mm)- Diet: Solid feed (CRF-1: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation and quarantine period: male 5 days, female 6 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 22±3 (actual temperature: 21-24°C)- Humidity (%): 50±20% (actual humidity: 38-54%)- 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
Vehiclecorn oil5

Details on oral exposure- Amount of vehicle (if gavage): 10 mL/kg- Dosing volume: 10 mL/kg
Analytical verification of doses or concentrations
yes
Duration of treatment / exposure
28 daysFrequency of treatment
once a day
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)

No. of animals per sex per dose
Control and high-dose group: 12 animals/sex/ (including recovery group of 6 animals/sex/eachgroup)
Low- and middle-dose group: 6 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 250
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 mg/kg bw/day wereselected.
[14-day preliminary study]
In a dose finding study for a 28 day study, Crl:CD(SD) rats were given 4-sec-Butyl-2,6-di-tert-butylphenol at 0 (corn oil), 15, 60, 250 or 1000 mg/kg bw/day for 14 days. At 250 mg/kg bw/day andhigher, increase in the liver weights were observed. At 1000 mg/kg bw/day, tendency decreased bodyweight gain, tendency decreased food consumption, increase in total bilirubin and BUN, soft stool,
dilatation of gastrointestinal tract, dark reddish change of cauda epididymis were observed.
6

- 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

Examinations
Observations and examinations performed and frequency
CLINICAL OBSERVATIONS: Yes- Time schedule: every day during the administration (twice a day: am and pm) and recovery periods(twice a day: am and pm).
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: Once prior to dosing and once during each study week (administration days 7, 14,
21, 28 and recovery days 7, 14).
BODY WEIGHT: Yes- Time schedule for examinations: Before administration (on days 1, 4, 7, 14, 21 and 28 of the administ
ration 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. Before administration (on days 1, 4, 7, 14, 21 and 28 of the administration
period and days 7 and 14 of the recovery period)
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood: the after completion of the administration and recovery periods- Anaesthetic used for blood collection: ether- Animals fasted: Yes (16-19 hours)- How many animals: all animals- Parameters examined included RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet, reticul
ocyte, PT, APTT, WBC and differential WBC.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: the day after completion of the administration and recovery p
eriods- Animals fasted: Yes- How many animals: all animals- Parameters examined included total protein, protein fraction, albumin, A/G ratio, total bilirubin,
glucose, total cholesterol, triglyceride, AST, ALT, ALP, gamma-GTP, BUN, creatinine, Na, K, Cl, Ca andIP.
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- Animals fasted: No- How many animals: all animals- Parameters examined included color, urine volume, specific gravity, pH, protein, glucose, ketone bo
dy, bilirubin, occult blood and urobilinogen.
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations: On week 4 of administration period and week 2 of recovery period.
- Dose groups that were examined: All animals- Battery of functions tested:71) Sensory/Reflex test: Visual reactivity, touch reactivity, auditory reactivity, pain reactivity, pro
prioceptive reactivity and aerial righting reflex.
2) Measurement of Grip Strength. Grip strength of forelimb and hind limb was measured by CPU
gauge (Aikoh Engineering Co., Ltd.).
3) Measurement of Motor Activity.Motor activity was measured by a motor activity sensor for experim
ental animals SUPERMEX & CompAct (Muromachi Kikai Co., Ltd.). The measurement was conducted
for 1 hour, and measured values at 10-minute intervals and from 0 to 60 minutes was collected.
Sacrifice and pathology
GROSS PATHOLOGY: Yes
ORGAN WEIBHT: Yes [brain, pituitary gland, thyroid, adrenal, spleen, heart, liver, kidney, thymus, testis,
epididymis, prostate, seminal vescles (including coagulation gland), ovary, uterus]
HISTOPATHOLOGY: Yes [brain (cerebrum, cerebellum and medulla oblongata), pituitary gland, spinal
cord, thymus, thyroid, parathyroid, adrenal glands, spleen, heart, tongue, esophagus, stomach, liver,pancreas, duodenum, jejunum, ileum (including Peyer's patches), cecum, colon, rectal, mesenteric ly
mph nodes, submandibular lymph nodes, trachea, lung, kidney, bladder, testis, epididymis, prostate,seminal vesicles (including coagulation glands) , ovary, uterus, vagina, eye, Harder gland, femur (including bone marrow, right) and the sciatic nerve. (see tables in the study report.)]Statistics
The homoscedasticity was analyzed by Bartlett’s test for data of grip strength, motor activity, bodyweight, body weight gain, food consumption, urine volume, hematological test, biochemical test, org
an weight and organ weight ratio. When homogeneity was recognized, one-way analysis of variance(homogeneous data) or kruskal-wallis (non-homogenous data) was conducted. If a significant dif
ference was detected, as the result of oneway analysis of variance, Dunnett’s method was applied forcomparisons between control and individual treatment groups. And in the case of a significant diffe
rence was detected on kruskal-wallis, Mann-Whitney’s U-test was applied for the same purpose. The tr
end by the group was analyzed by Kruskal-Wallis for general appearance, detailed clinical observation,
qualitative items of urinary findings, and urine specific gravity. If a significant difference was detected
as the result of kruskal-wallis, Mann-Whitney’s U-test as applied for comparisons between control and individual treatment groups.

Results and discussion
Results of examinations
Clinical signs
effects observed, treatment-related
Mortality
no mortality observed
Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)
not examined
Ophthalmological findings
not examined
8

Haematological findings
effects observed, treatment-related
Clinical biochemistry findings
effects observed, treatment-related
Urinalysis findings
effects observed, treatment-related
Behaviour (functional findings)
no effects observed
Immunological findings
not examined
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Gross pathological findings
effects observed, treatment-related
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
effects observed, treatment-related
Details on results
CLINICAL SIGNS AND MORTALITY[At the dosing period]
Soft feces was observed in both sexes receiving 250 mg/kg bw/day.
[At the recovery period]
There were no changes related to the test substance in any groups.
BODY WEIGHT AND WEIGHT GAIN
There were no changes related to the test substance in any groups during the dosing.
FOOD CONSUMPTION
There were no changes related to the test substance in any groups during the dosing.
HAEMATOLOGY[At the end of the dosing period]
Prothrombin time was prolonged in males receiving 60 mg/kg bw/day and above. Increased activatedpartial thromboplastin time was observed in males receiving 60 mg/kg/day and above and females
receiving 250 mg/kg bw/day.
[At the end of the recovery period]
There were no changes related to the test substance in any groups.
CLINICAL CHEMISTRY[At the end of the dosing period]
An increase in total cholesterol was observed in females receiving 15 mg/kg bw/day and above and inmales receiving 60 mg/kg bw/day and above. An increase in total bilirubin was observed in both sexes receiving 250 mg/kg bw/day, increases in AST, ALT, ALP and BUN, and decreases in K and IP wereobserved in males receiving 250 mg/kg bw/day, and increases in alfa1-globulin protein fraction% andcreatinine were observed in females receiving 250 mg/kg bw/day.
[At the end of the recovery period]
There were no changes related to the test substance in any groups.
URINALYSIS[At the dosing period]
A decrease in urine pH was observed in females receiving 250 mg/kg bw/day.
9

[At the recovery period]
There were no changes related to the test substance in any groups.
NEUROBEHAVIOUR
There were no changes related to the test substance in any groups during the dosing.
ORGAN WEIGHTS[At the end of the dosing period]
An increase in relative liver weight was observed in females receiving 15 mg/kg bw/day and above, anincrease in absolute liver weight was observed in females receiving 250 mg/kg bw/day.
[At the end of the recovery period]
An increase in relative liver weight was observed in females receiving 250 mg/kg bw/day.
GROSS PATHOLOGY[At the end of the dosing period]
Cecum: Watery contents were observed in males receiving 60 mg/kg bw/day and above and in fe
males receiving 250 mg/kg bw/day.
[At the end of the recovery period]
There were no changes related to the test substance in any groups.
HISTOPATHOLOGY: NON-NEOPLASTIC[At the end of the dosing period]
Liver: Slightly centrilobular hypertrophy of hepatocytes were observed in females receiving 250 mg/kg
bw/day.
[At the end of the recovery period]
There were no changes related to the test substance in any groups.

Effect levels
Key result
true
Dose descriptor
NOAEL
Effect level15

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
male
Basis for effect levelgross pathology
Watery contents of cecum were observed in males receiving 60 mg/kg bw/day and above.

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF17540-75-9b.pdf

10Applicant's summary and conclusion
Conclusions
Based on the findings in haematological examination, clinical chemistry, organ weight, and gross pathology, the NOAEL for repeated-dose toxicity of 4-sec-butyl-2,6-di-tert-butylphenol was determined to
be 15 mg/kg bw/day.
Executive summary
The repeated-dose toxicity of 4-sec-butyl-2,6-di-tert-butylphenol was assessed with the use of rats. Maleand female rats (6 animals/sex/dose) were administered with 0 [vehicle: corn oil], 15, 60, and 250 mg/kg
bw/day of 4-sec-butyl-2,6-di-tert-butylphenol for 28 days. Six of the 12 animals/sex that have received
0 and 250 mg/kg bw/day were selected to be part of a 14-day recovery group.
No treatment-related deaths were noted for both sexes. Clinical signs have shown that the doses did
not affect the manipulative test, body weight, and food consumption. In general appearance, the maleand female groups receiving 250 mg/kg bw/day had soft feces. The urinalysis shows the urine pH infemales receiving 250 mg/kg bw/day was significantly decreased. Hematological parameters, such asprothrombin time in males in the ≥ 60 mg/kg bw/day group as well as activated partial thromboplastin
time in males in the ≥ 60 mg/kg bw/day group and in females in the 250 mg/kg bw/day group, weresignificantly prolonged. Blood chemistry analysis has shown that total cholesterol level in females
receiving ≥ 15 mg/kg bw/day and in males receiving ≥ 60 mg/kg bw/day and total bilirubin level in both
sexes receiving 250 mg/kg bw/day significantly increased. Contrarily, the levels of potassium (K) andinorganic phosphorus (IP) significantly decreased in male rats receiving 250 mg/kg bw/day. A grosspathological examination has shown watery content of cecum in males receiving 60 mg/kg bw/day andin both sexes receiving 250 mg/kg bw/day. Soft feces, watery content of cecum, and decreases of K and
IP levels were discovered, suggesting that the digestive tract is affected. There has been significantly
increase in the relative weight of the liver of females receiving ≥ 15 mg/kg bw/day and the absoluteweight of the liver of females receiving 250 mg/kg bw/day. Histopathological findings declared a slight
hypertrophy of centrilobular hepatocytes in females receiving 250 mg/kg bw/day. These changes wereno longer observed after the recovery period, showing that they were reversible. Founded on theseeffects of the cecum at 60 mg/kg bw/day in males, the no-observed-adverse-effect level (NOAEL) for
repeated-dose toxicity of 4-sec-butyl-2,6-di-tert-butylphenol was 15 mg/kg bw/day in rats.

11

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

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Author:Date: 2020-03-26T15:44:02.000+09:00
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Administrative data
Endpoint
in vitro gene mutation study in bacteria
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
other: OECD Test Guideline study under GLP condition

Data source
Reference
Reverse Mutation Test of 4-sec-butyl-2,6-di-tert-butylphenol on 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
12Deviations
no
Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, otherDeviationsno
GLP compliance
yesType of assay
bacterial reverse mutation assay
in vitro gene mutation study in bacteria

Test material
Test material information
4-sec-butyl-2,6-di-tert-butylphenol
Specific details on test material used for the study
Purity 99.0%

MethodSpecies / strain
Species / strain / cell typeS. typhimurium TA 1535, TA 1537, TA 98 and TA 100
bacteria
Species / strain / cell type
E. coli WP2 uvr A pKM 101
bacteria
Metabolic activation
with and without
Metabolic activation system
S9 mix; SD male rat liver, induced by phenobarbital and 5,6-benzoflavone
Test concentrations with justification for top dose
-S9 mix:
156, 313, 625, 1250, 2500, 5000 μg/plate (TA100, TA1535, TA98, TA1537 strains)
156, 313, 625, 1250, 2500, 5000 μg/plate (WP2uvrA/pKM101 strain)+S9 mix:
156, 313, 625, 1250, 2500, 5000 μg/plate (TA100, TA1535, TA98, TA1537 strains)
156, 313, 625, 1250, 2500, 5000 μg/plate (WP2uvrA/pKM101 strain)
Maximum concentration was established based on the result of the preliminary test at concentration
up to 5000 ug/plate. In this test, no growth inhibition was observed at any dose.
13

Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceother:
Remarks-S9 mix: 2-(2-Furyl)-3-(5-nitro-2-furyl) acrylamide (TA 100, TA98 and WP2 uvrA/pKM101), sodium
azide (TA1535) and 9-aminoacridine hydrochloride monohydrate (TA1537). +S9 mix: 2-am
inoanthracene (TA100, TA1535, WP2 uvrA/pKM101, TA98 and TA1537)
Details on test system and experimental conditions
METHOD OF APPLICATION: Preincubation
DURATION- Preincubation period: 20 min at 37°C
- Exposure duration:49 hrs
NUMBER OF PLATES: 3
NUMBER OF REPLICATIONS: 2
DETERMINATION OF CYTOTOXICITY- Method: other: growth inhibition
Evaluation criteria
A chemical was judged to be mutagenic when the mean number of revertant colonies per plateincreased more than twice that of the negative control and when the dose-related and reproducible increase was observed.
StatisticsnoResults and discussion
Test results
Key result
trueSpecies / strainother: S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 bacterias
Metabolic activation
with and without
Genotoxicity
negative
14

Cytotoxicity / choice of top concentrations
no cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid
Key result
trueSpecies / strain
E. coli WP2 uvr A pKM 101
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
no cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
validRemarks on result
other: all strains/cell types tested Migrated from field 'Test system'.

Any other information on results incl. tables
Figures and Tables (in Japanese) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF17540-75-9e.pdf
Please also see the attached files (Tables in English)

Applicant's summary and conclusion
Conclusions
Interpretation of results (migrated information): negative
In a bacterial reverse mutation assay using Salmonella typhimurium TA100, TA1535, TA98, and TA
1537, and Escherichia coli WP2uvrA/pKM101 (OECD TG 471), 4-sec-butyl-2,6-di-tert-butylphenol was
negative with or without metabolic activation.

15

ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.002

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Author:Date: 2020-03-17T14:56:12.000+09:00
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Administrative data
Endpoint
in vitro cytogenicity / chromosome aberration study in mammalian cells
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
other: OECD Test Guideline study under GLP condition

Data source
Reference
In Vitro Chromosomal Aberration Test of 4-sec-butyl-2,6-di-tert-butylphenol on Cultured Chinese Hams /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
Deviationsno16

Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, otherDeviationsno
GLP compliance
yesType of assay
other: in vitro mammalian chromosome aberration test

Test material
Test material information
4-sec-butyl-2,6-di-tert-butylphenol
Specific details on test material used for the study
Purity 99.0%

MethodSpecies / strain
Species / strain / cell typeother: 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
Cell growth inhibition study-S9 mix (short-term treatment): 10.2, 20.5, 40.9, 81.9, 164, 328, 655, 1310, 2620 ug/mL (IC50=15.1 ug/
mL)+S9 mix (short-term treatment): 10.2, 20.5, 40.9, 81.9, 164, 328, 655, 1310, 2620 ug/mL (IC50=29.0
ug/mL)-S9 mix (continuous treatment, 24hr): 10.2, 20.5, 40.9, 81.9, 164, 328, 655, 1310, 2620 ug/mL (IC50=14.4 ug/mL)
Main study-S9 (short-term treatment): 2.5, 5, 10, 13.3, 16.7 20 ug/mL+S9 (short-term treatment): 5, 10, 20, 26.7, 33.3 ug/mL+S9 (short-term treatment) (confirmatory test): 10, 20, 26.7, 33.3, 40 ug/mL-S9 (continuous treatment, 24hr): 2.5, 5, 10, 13.3, 16.7, 20 ug/mL-S9 (continuous treatment, 24hr) (confirmatory test): 4, 6, 8, 10, 11, 12, 13, 14, 15 ug/mL
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
17

Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceother: [-S9]: mitomycin C; [+S9]: benzo(a)pyrene
Details on test system and experimental conditions
METHOD OF APPLICATION: Exposure duration: [short-term treatment]: 6 hrs + 18 hr, [continuous
treatment]: 24 hr
SPINDLE INHIBITOR: Colcemid
STAIN: Giemsa stain (2 v/v%) for 20 min.
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 100 + 100 cells /concentration
DETERMINATION OF CYTOTOXICITY- Method: relative total growth
Evaluation criteria
For the evaluation of the frequencies of structural aberrations and of polyploidy induced, the following
criteria were employed. Appearance incidence of cell with chromosomal aberrations: Negative (-):
less than 5%, Equivocal(±): 5% or more and less than 10%, Positive(+): 10% or more
StatisticsnoResults and discussion
Test results
Key result
trueSpecies / strainother: Chinese hamster lung (CHL/IU) cells
Metabolic activation
without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
18

Positive controls validity
valid
Key result
trueSpecies / strainother: Chinese hamster lung (CHL/IU) cells
Metabolic activation
with
Genotoxicity
other: equivocal
Cytotoxicity / choice of top concentrations
cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid
Additional information on results
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF17540-75-9f.pdf

Applicant's summary and conclusion
Conclusions
Interpretation of results (migrated information):equivocal with metabolic activation
negative without metabolic activation
The in vitro chromosomal aberration test using CHL/IU cells (OECD TG 473) was equivocal with met
abolic activation.

19

Toxicity to reproduction
ENDPOINT_STUDY_RECORD: Toxicity to reproduction.001

UUID: f2efea51-6b6b-4539-a905-c1f8ce22b37a
Dossier UUID:
Author:Date: 2022-12-16T14:48:14.279+09:00
Remarks:

Administrative data
Endpoint
screening for reproductive / developmental toxicity
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
Reproduction/Developmental Toxicity Screening Test on 4-sec-butyl-2,6-di-tert-butylphenol / MHLW,Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP complianceyes
20Test material
Test material information
4-sec-butyl-2,6-di-tert-butylphenol
Specific details on test material used for the study- Analytical purity: 99.0%- Storage condition of test material: Stored in a refrigerator (3 - 9°C)
- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

Test animals
Speciesrat
Strainother: Crl:CD(SD)Sexmale/female
Details on test animals or test system and environmental conditions
Sixty two male and 62 female Note) Sprague-Dawley strain SPF rats [Crl:CD(SD), Atsugi Breeding
Center, Charles River Laboratories Japan, Inc.] were purchased at 8 weeks of age and quarantined/
acclimated for 18 days counting the day of receipt as day 1 of acclimation and including the quarantine period of 3 days.
The body weight range at the start of administration was 405 to 494 g (mean body weight: 451 g) for
males and 227 to 272 g (mean body weight: 244 g) for females.
Animals were housed individually and subsequently in male-female pairs during the mating period inbracket-type metallic wire-mesh cages (W 254 × D 350 × H 170 mm: Lead Engineering Co., Ltd.) in an
animal room (Room No. 905) where the temperature was maintained at 23 ± 3°C (measured values:
21-25°C), the relative humidity at 50 ± 20% (measured values: 42-65%), the air ventilation at 10 to 15
times per hour and 12-hour lighting per day (07:00 to 19:00). From day 17 of gestation to day 4 oflactation, animals were housed in the unit of litter in plastic Econ cages (W 340 × D 400 × H 185 mm:
CLEA Japan, Inc.) with bedding (Whiteflakes: Charles River Laboratories Japan, Inc.).

Administration / exposure
Route of administration
oral: gavage
Vehiclecorn oil
Details on exposure
Corn oil was selected as the vehicle since the stability of the test article in corn oil was favorable inthe study for validation of the analytical method for determination of the test article concentration in
test solutions and stability (Study No. A-2262) which was conducted before this study.
Details on mating procedure
Males and females in the same dose group of the main groups were co-housed overnight on a oneto-one basis after the end of the pre-mating administration period. Copulation was consideredsuccessful if the formation of vaginal plugs or presence of sperm in vaginal smears was confirmed the following morning. The length of the mating period for the same male and female was 14 days at
maximum.
21

Delivery and delivery/lactation status: All copulated females were allowed to deliver spontaneously
and examined for any abnormality of delivery. Dams which completed delivery were observed forclearance of placenta and amnion, and the end of delivery was designated as day 0 of lactation. D
ams were then allowed to nurse their liveborn pups until day 4 of lactation and examined for lactation
status using the gathering of pups, nesting and lactating as indicators.
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
For the test solutions at all dose concentrations to be used for administration in week 1 or week 6 ofadministration, dose concentrations were verified by the HPLC method at Gotemba Laboratory, Bozo
Research Center Inc. before use for administration. In the results, the percentage of the test article
concentration in each dose concentration to the nominal concentration was in the range from 94.2 to102.1%, which was within the acceptable range (concentration: within 100.0 ± 10.0% of the nominal
value)
Duration of treatment / exposure
Males: 42 days Females: 42-46 days from 14 days before mating to day 4 of lactation
Frequency of treatment
Once a day
Doses / concentrations
Dose / conc.
0mg/kg bw/day

Dose / conc.
12

mg/kg bw/day

Dose / conc.
60

mg/kg bw/day

Dose / conc.
300

mg/kg bw/day

No. of animals per sex per dose
The number of animals per group was 12 animals of each sex
Control animals
yes, concurrent vehicle
Details on study design
The dose levels of this study were selected based on the results of the previously conducted study (dose-finding study). In the dose-finding study, death occurred at 1000 mg/kg and effects on general22condition, hematology and blood chemistry examinations at 300 mg/kg and a high value in liver
weight at 100 mg/kg and above. At 100 and 300 mg/kg, there were no clear effects from administ
ration of the test article on body weight or food consumption. In the dose-finding study, there weremortalities in 1000 mg/kg group. In the 300 mg/kg group, some changes were observed in clinicalobservation, hematological examination and blood chemistry examination, and organ weight of
the liver showed high value in the 100 mg/kg group and above. In the 100 and 300 mg/kg groups,
there were no changes which were thought to be effects from administration of the test article inbody weight or food consumption. Based on these results, the high dose in this reproduction/developmental toxicity screening test was set at 300 mg/kg, and the lower doses were set at 60 and 12
mg/kg using the common ratio of approximately 5.
Positive controlnoExaminations
Parental animals: Observations and examinations
Clinical observation performed and frequency: General condition was observed 3 times a day during
the administration period (before dosing, and immediately after and approximately 2 hours after
dosing).
Body weights were determined on days 1 (before dosing), 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 42 ofadministration for males and on days 1, 4, 8, 11, 15 of administration, days 0, 4, 7, 11, 14, 17 and 20 of
gestation, days 0 and 4 of lactation for females and the day of necropsy in males and females.
Food consumption was determined on days 1, 4, 8, 11, 15, 32, 36, 39 and 42 of administration formales and on days 1, 4, 8, 11 and 15 of administration and on days 1, 4, 7, 11, 14, 17 and 20 of gestati
on and days 2 and 4 of lactation in females, but it was not determined during the mating period formales and females.
Oestrous cyclicity (parental animals)
Vaginal smear pictures were classified as proestrus, estrus, metestrus and diestrus and examined forthe frequency of estrus and interval between estruses (estrous cycle).
Postmortem examinations (parental animals)
Dams which delivered pups were exsanguinated on day 5 of lactation. The numbers of corpora lutea
and implantation sites were counted.
Necropsy: Detailed macroscopic examination was conducted on the organs/tissues throughout the b
ody of each animal, including the external appearance, head, thorax and abdomen.
Measurement of organ weighs: The testis and epididymis were determined.
Histopathological examination: The testis, epididymis, prostate and seminal vesicle in males at 0 and
300 mg/kg groups, the ovary, uterus and vagina in females at 0 and 300 mg/kg groups In addition, allsubject organs/tissues of dead animals, all the animals that had not delivered by day 25 of gestation,
dams with total litter loss during the lactation period and all gross pathological lesions of all animals
were examined.
Postmortem examinations (offspring)Examination of liveborn pups: The numbers of liveborn pups and stillborn pups were counted on the
day of birth. After liveborn pups were examined for any external abnormality, sexed and weighed,dams were allowed to nurse their pups. Liveborn pups were observed for mortality once daily until
day 4 after birth. All liveborn pups were exsanguinated after measurement of body weight on day
4 after birth, necropsied and examined for any abnormality in organs/tissues, including those in thehead, thorax and abdomen. Individual body weights of liveborn pups were recorded, and the average
body weight per litter was calculated by sex.
Pathological examination were performed.
Statistics
Dunnett's test for continuous data and Dunnett-type mean rank test for quantal data were used.
23

Reproductive indicesno. of copulated animals, no. of males impregnated females, no. of pregnant females, no. of females
that delivered liveborn pups, estrous cycle, gestational length, no.of corpora lutea, no. of implantationsites, total no. of liveborn and stillborn pups, no. of liveborn pups, sex ratio on day 0 and day 4 after birth, copulation index (no. of copulated animals / no. of animals housed together x 100), insemin
ation index (no. of males that impregnated females / no. of copulated males x 100), fertility index (no.
of pregnant females / no. of copulated females x 100)
Offspring viability indicesdelivery index (no. of females delivered liveborn pups / no. of pregnant females x 100), implantationindex (no. of implantation sites / no. of corpora lutea x100), stillbirth index (no. of stillborn pups / tot
al no. of liveborn and stillborn pups x 100), index of external abnormalities (no. of pups with external
abnormalities / no. of liveborn pups x 100), live birth index (no. of liveborn pups / no. of implantationsites x 100), and viability index on day 4 after birth (no. of surviving pups on day 4 after birth / no. of liveborn pups x 100)Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
Clinical signs
effects observed, treatment-related
Description (incidence and severity)
In males in the 300 mg/kg group, soft feces were observed in 5-8 animals sporadically from week 4of administration onward, and fracture of incisors in 1 animal in week 6 of administration. In females of the 300 mg/kg group, there were no abnormalities in clinical signs during the pre-mating admini
stration period, but soft feces were observed sporadically in 1-3 animals from day 9 of gestation
onward and one female each died on day 22 and day 23 of gestation showing hypothermia and/or
emaciation. One female showed pale skin on day 1 of lactation and soft feces and emaciation on day
2 of lactation and another female showed soft feces on day 0 of lactation, hypothermia and emaciati
on on day 1 of lactation and pale skin and hemorrhage from the vaginal opening on day 2 of lactation
and all pups of these two females died by day 2 of lactation.
Mortality
mortality observed, treatment-related
Description (incidence)In the 300 mg/kg group, 1 female died on day 22 and day 23 of gestation.
Body weight and weight changes
effects observed, treatment-related
Description (incidence and severity)
In males in the 300 mg/kg group, body weight was lower than that of the control group from day 8 ofadministration, and the body weight on days 36, 39 and 42 of administration was significantly lower
than that of the control group and body weight gain during the administration period was significantly
lower than that of the control group.
Food consumption and compound intake (if feeding study)
effects observed, treatment-related
Description (incidence and severity)
Females in the 300 mg/kg group showed a significantly low value compared to that of the control
group on day 8 of administration, a significantly high value on day 4 and a significantly low value on d24

ay 20 of gestation, but there were no significant differences in food consumption between the control
group and this group during the lactation period.
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Description (incidence and severity)
Males showed low body weight on the day of necropsy and males and females showed a high value
in the weight of the liver in the 300 mg/kg group, and males showed a high value in the weight of theliver in the 60 mg/kg group.
Gross pathological findings
effects observed, treatment-related
Description (incidence and severity)
In the females in the 300 mg/kg group that died, a female showed undernourishment, dilatation of
the cecum, enlargement of the liver and small thymus, but the other female showed no macroscopic
abnormalities. Both females had implantations. For the dams that had total litter loss in the 300 mg/
kg group, undernourishment, pale skin, dilatation of the cecum, dark coloration of the kidney, small
thymus, dark red focus in the eye, dark coloration of Harderian gland, dark coloration of the lung, sm
all sublingual gland and submandibular gland, dark red focus in the forestomach and small spleen
were observed. In males that were necropsied on schedule, dilatation of the cecum was observedin the 300 mg/kg group. In females that were necropsied on schedule, enlargement of the liver wasobserved in the 300 mg/kg group.
Histopathological findings: non-neoplastic
effects observed, treatment-related
Description (incidence and severity)
Dead animals showed mild hypertrophy of centrilobular hepatocytes and minimal vacuolation ofcentriolbular hepatocytes in the liver, minimal hypertrophy of bile duct epithelial cells and severe
atrophy of the thymus. Among the dams that had total litter loss, the dams in the 300 mg/kg group
showed hypertrophy of bile epithelium, vacuolation of centrilobular hepatocytes and necrosis of c
entrilobular hepatocytes in the liver, acute tubular necrosis, interstitial inflammatory cell infiltrationand glomerular thrombus in the kidney, atrophy of the thymus, diffuse mucosal hyperplasia of thececum, ulcer and hyperplasia of squamous epithelium in the forestomach, increased porphyrin in H
ardelian gland, atrophy of submandibular gland, atrophy of the spleen, cell infiltration and thrombus
in the lung, and focal retinal hemorrhage in the eye. In the animals that were sacrificed on schedule,
males and females showed hypertrophy of centrilobular hepatocytes in the liver in the 60 and 300
mg/kg groups and bile duct epithelial cell hypertrophy in the liver in the 300 mg/kg group. Otherwise
the animal in the 300 mg/kg group showed single cell necrosis and diffuse hyperplasia in cecum
mucosa.

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

Effect levels (P0)
Key result
false
Dose descriptor
NOAEL
25

Effect level12

mg/kg bw/day (nominal)

Based ontest mat.
Sex
male
Basis for effect level
organ weights and organ / body weight ratios
increased liver weight
histopathology: non-neoplastic
hypertrophy of centrilobular hepatocytes in the liver
Key result
true
Dose descriptor
NOAEL
Effect level60

mg/kg bw/day (nominal)

Based ontest mat.
Sex
femaleBasis for effect level
reproductive performance
A tendency of lowing in the delivery index, the number of liveborn, and live birth index and the ten
dency of high stillborn rate were observed in 300 mg/kg bw/day group. The tendency of low viability
index on postnatal day 4 was seen in the 300 mg/kg bw/day group.
Key result
false
Dose descriptor
NOAEL
Effect level300

mg/kg bw/day

Based ontest mat.
Sex
male
Basis for effect level
reproductive performanceno effects

Results: F1 generation
26

General toxicity (F1)Mortality / viability
no mortality observed
Body weight and weight changes
no effects observed
Gross pathological findings
no effects observed

Effect levels (F1)
Key result
false
Dose descriptor
NOAEL
Generation
F1
Effect level300

mg/kg bw/day

Based ontest mat.
Sexmale/female
Basis for effect level
other: no effects on development

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study. https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF17540-75-9c.pdf

Applicant's summary and conclusion
Conclusions
There was no effect of the test substance in the parental males and pup at 300 mg/kg bw/day, the
NOAEL of paternal and developmental toxicities was 300 mg/kg bw/day group. On the other hand, as
seen on the effects on general condition of dams and delivery at 300 mg/kg bw/day, the NOAEL of
the maternal toxicity was 60 mg/kg bw/day. In conclusion, the overall NOAEL for the reproductive/dev
elopmental toxicity of4-sec-butyl-2,6-di-tert-butylphenolin this study was 60 mg/kg bw/day.
Executive summary
The reproduction/developmental toxicity screening test of 4-sec-butyl-2,6-di-tert-butylphenol wasassessed in rats in accordance to the OECD test guideline (TG) 421. In this study, 4-sec-butyl-2,6-ditert-butylphenol was administered via gavage at 0 [vehicle: corn oil], 12, 60 and 300 mg/kg bw/day.
27

Males (12/dose) were then treated for 42 days, which include a 14-day premating period and subsequentmating period, while females (12/dose) were treated for 42–46 days, including 14-day premating,mating, and gestation periods until lactation day 4. There were no effects on fertility but a tendency oflowing in the delivery index, the number of liveborn, and live birth index and the tendency of high stillborn
rate were observed in 300 mg/kg bw/day group. The tendency of low viability index on postnatal day
4 was seen in the 300 mg/kg bw/day group. Because there was no effect of the test substance in theparental males and pup at 300 mg/kg bw/day, the NOAEL of paternal and developmental toxicities was
300 mg/kg bw/day group. On the other hand, as seen on the effects on general condition of dams anddelivery at 300 mg/kg bw/day, the NOAEL of the maternal toxicity was 60 mg/kg bw/day. In conclusion,
the overall NOAEL for the reproductive/developmental toxicity of 4-sec-butyl-2,6-di-tert-butylphenolin
this study was 60 mg/kg bw/day.

28

DOMAIN
Substance
SUBSTANCE: 4-sec-Butyl-2,6-di-tert-butylphenol
UUID: b2fce83d-cfa7-43d6-a1fc-c5819c7f46d7
Dossier UUID:
Author:Date: 2022-12-16T14:48:26.652+09:00
Remarks:
Substance name4-sec-Butyl-2,6-di-tert-butylphenol
Public name4-sec-Butyl-2,6-di-tert-butylphenol
Legal entity
National Institute of Health Sciences, Japan
Contact persons

Identification of substance
Reference substance
4-sec-butyl-2,6-di-tert-butylphenol / 4-sec-butyl-2,6-di-tert-butylphenol / 17540-75-9 / 241-533-0
EC number

EC name241-533-0

EC Inventory

CAS number

CAS name

17540-75-9
IUPAC name4-sec-butyl-2,6-di-tert-butylphenol

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

29

References
Reference Substances
REFERENCE_SUBSTANCE: 4-sec-butyl-2,6-di-tertbutylphenol
UUID: ECB5-4be93424-903c-4590-bb54-0a3185f73206
Dossier UUID:
Author:Date: 2007-05-10T18:00:00.000+09:00
Remarks:
Reference substance name4-sec-butyl-2,6-di-tert-butylphenol
IUPAC name4-sec-butyl-2,6-di-tert-butylphenol

Inventory
Inventory number
Inventory name4-sec-butyl-2,6-di-tert-butylphenol
Inventory
EC Inventory
Inventory number
241-533-0
CAS number
17540-75-9
Molecular formula
C18H30O
Description
CAS number
17540-75-9

Synonyms
Synonyms
Identity
Phenol, 2,6-bis(1,1-dimethylethyl)-4-(1-methylpropyl)Identity
Phenol, 2,6-bis(1,1-dimethylethyl)-4-(1-methylpropyl)-30

Identity
Phenol, 2,6-bis(1,1-dimethylethyl)-4-(1-methylpropyl)-

Molecular and structural information
Molecular formula
C18H30O
Molecular weight262.4302
SMILES notation
CCC(C)c1cc(c(O)c(c1)C(C)(C)C)C(C)(C)C
InChl
InChI=1/C18H30O/c1-9-12(2)13-10-14(17(3,4)5)16(19)15(11-13)18(6,7)8/h10-12,19H,9H2,1-8H3Structural formula

Related substancesGroup / category information
DSL Category: Organics
USEPA Category: Neutral Organics;Phenols

31Test Materials
TEST_MATERIAL_INFORMATION: 4-sec-butyl-2,6-di-tertbutylphenol
UUID: 57eadf5d-9389-4ab3-ae7c-8517aed5eecc
Dossier UUID:
Author:Date: 2019-12-17T14:59:36.000+09:00
Remarks:Name
4-sec-butyl-2,6-di-tert-butylphenol

32

Literatures
LITERATURE: In Vitro Chromosomal Aberration Test of
4-sec-butyl-2,6-di-tert-butylphenol on Cultured Chinese
Hamster Cells.
UUID: 22775324-3017-4f58-8b64-05b57fe2b4ac
Dossier UUID:
Author:Date: 2019-12-18T15:24:12.000+09:00
Remarks:

General information
Reference Typestudy report
Title
In Vitro Chromosomal Aberration Test of 4-sec-butyl-2,6-di-tert-butylphenol on Cultured Chinese Hams
ter Cells.
Author
MHLW, Japan
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF17
540-75-9f.pdf
Testing facility
Safety Research Institute for Chemical Compounds Co., Ltd.
Report number
SR08225

33

LITERATURE: Reproduction/Developmental Toxicity
Screening Test on 4-sec-butyl-2,6-di-tert-butylphenol
UUID: 243fe436-3b37-405c-815a-22caee3481e2
Dossier UUID:
Author:Date: 2020-02-18T11:14:20.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Reproduction/Developmental Toxicity Screening Test on 4-sec-butyl-2,6-di-tert-butylphenol
Author
MHLW, Japan
Year
2011
Bibliographic source
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF17540-75-9c.pdf
Testing facility
BoZo Recearch Center

34

LITERATURE: Reverse Mutation Test of 4-sec-butyl-2,6di-tert-butylphenol on Bacteria.
UUID: ae56849c-be2d-49f5-95a4-20dbe725402a
Dossier UUID:
Author:Date: 2019-12-17T14:46:26.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Reverse Mutation Test of 4-sec-butyl-2,6-di-tert-butylphenol on Bacteria.
Author
MHLW, Japan
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF17
540-75-9e.pdf
Testing facility
Safety Research Institute for Chemical Compounds Co., Ltd.
Report number
SR08224

35

LITERATURE: Twenty-eight-day Repeated Dose Oral
Toxicity Test of 4-sec-Butyl-2,6-di-tert-butylphenol in
Rats
UUID: 225d52ac-2e56-4309-b957-5acf7680b7cd
Dossier UUID:
Author:Date: 2020-03-23T15:54:17.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Twenty-eight-day Repeated Dose Oral Toxicity Test of 4-sec-Butyl-2,6-di-tert-butylphenol in Rats
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF17
540-75-9b.pdf
Testing facility
Safety Research Institute for Chemical Compounds Co., Ltd.
Report number
SR08226

36

Legal Entities
LEGAL_ENTITY: National Institute of Health Sciences,Japan
UUID: 0952b3b9-2d0c-4bc8-925e-b069be7789b7
Dossier UUID:
Author:Date: 2020-02-19T14:42:16.000+09:00
Remarks:

General information
Legal entity nameNational Institute of Health Sciences, Japan37