Name: COMPLETE / SUBSTANCE : Polyoxyethylenesorbitan fatty acid(C12-18)ester /9005-70-3 Tue, 5 Sep 2023, 13:41:03+0900 /Legal entity owner: National Institute of Health Sciences / Kawasaki / Japan
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iTable of Contents
0/0 ............................................................................................................................. 1
National Institute of Health Sciences .................................................................... 2
Polyoxyethylenesorbitan fatty acid(C12-18)ester ................................................... 4
OECD .......................................................................................................... 4
D Health Effects .................................................................................. 4
67 Repeated dose toxicity: oral .................................................... 4
RepeatedDoseToxicityOral.001 ............................................. 470 Genetic toxicity in vitro ......................................................... 14
Genetic toxicity in vitro.001 ................................................ 14
Genetic toxicity in vitro.002 ................................................ 20
73 Toxicity to reproduction ........................................................ 24
ToxicityReproduction.001 ................................................... 24
DOMAIN .................................................................................................... 35
Polyoxyethylenesorbitan fatty acid(C12-18)ester ................................. 35
References ................................................................................................................ 36
Reference Substances ...................................................................................... 36
Polyoxyethylenesorbitan fatty acid(C12-18)ester ......................................... 36
Test Materials .................................................................................................. 38
Polyoxyethylenesorbitan fatty acid(C12-18)ester ......................................... 38
Literatures ....................................................................................................... 39
Combined repeated dose toxicity study with the reproductive/
developmental toxicity screening test of polyoxyethylene sorbitan trioleateby oral administration in rats ..................................................................... 39
In Vitro Chromosomal Aberration Test of Polyoxyethylene sorbitan
trioleate on Cultured Chinese Hamster Cells. .............................................. 40
Reverse Mutation Test of Polyoxyethylene sorbitan trioleate on Bacteria. ...... 41ii

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Dossier subject
Dossier subject
Polyoxyethylenesorbitan fatty acid(C12-18)ester / 9005-70-3
Public nameSubmitting legal entity
National Institute of Health Sciences / Kawasaki / Japan
Dossier creation date/time
Tue, 5 Sep 2023, 13:41:03+0900
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LEGAL_ENTITY: National Institute of Health
Sciences
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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 systemIUCLID42

ID
16558402024DIV750

3

Polyoxyethylenesorbitan fattyacid(C12-18)ester
OECD
Health Effects
Repeated dose toxicity: oral
ENDPOINT_STUDY_RECORD: RepeatedDoseToxicityOral.001

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Administrative data
Endpoint
short-term repeated dose toxicity: oral
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study OECD Test Guideline study under GLP condition
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study
Related information
OECD / Toxicity to reproduction / ToxicityReproduction.001 / Polyoxyethylenesorbitan fattyacid(C12-18)ester / 9005-70-3

Data source
4Reference
Combined repeated dose toxicity study with the reproductive/developmental toxicity screening test of /Ministry of Health, Labour and Welfare (MHLW), Japan / study report
Data accessdata published https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF9005-70-3d.pdf

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

Test material
Test material information
Polyoxyethylenesorbitan fatty acid(C12-18)ester
Specific details on test material used for the study- Name of test material (as cited in study report): Polyoxyethylene sorbitan trioleate- CAS No.: 9005-70-3- Analytical purity: －- Storage condition of test material: Room temperature, shading, airtightness- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

Test animals
Speciesratcommon rodent species
Strainother: Crl: CD (SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Japan, Inc., Hino Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation:5

Males (main study groups): 357-412 g, females (main study groups): 226-265 g, females (mating stu
dy groups): 211-255 g- Housing: Animals were individually housed in stainless steel suspension cage (240W × 380D × 200Hmm), from gestation day 18 to lactation day 4, Dams were bred individually or with individual litte
rmates in plastic cages (310W x 360D x 175H mm) and bedding.
- Diet: Solid feed (CRF-1: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: Males (main study groups): 19 days, females (main study groups): 20 days,
females (mating study groups): 19 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 20-26°C (actual temperature: 22.3-24.3°C)- Humidity (%): 40.0-70.0% (actual humidity: 40.6-65.9%)- Air changes (per hr): 12- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 6:00-18:00)

Administration / exposure
Route of administration
oral: gavage
Vehiclewater water for injection
Details on oral exposure- Amount of vehicle (if gavage): 10 mL/kg- Dosing volume: 10 mL/kg
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
The concentrations of each test solution using administration on day 1 were analyzed with a spectrop
hotometer. Results showed that the concentrations of each test solution were 98.7 to 103.7% of thenominal concentration and both values were within the acceptable range (concentration: percentage
of nominal concentration, 100±10%)Duration of treatment / exposure
Males: 28 days including 14 days pre-mating
Females (main study groups): 28 days
Females (mating study groups): 42-54 days including 14 days pre-mating, mating and gestation periods and the days until day 4 of lactation
Frequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
62.5

mg/kg bw/day (actual dose received)

6

Dose / conc.
250

mg/kg bw/day (actual dose received)

Dose / conc.
1000

mg/kg bw/day (actual dose received)

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

Examinations
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes- Time schedule:
Males and females (main study groups): 2 times/day (before administration, 61-189 minutes afteradministration) during the administration period. Once a day during the recovery period.
Females (mating study groups): 2 times/day (before administration, 60-211 minutes after administration) during the administration period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Males and females (main study groups): on day of grouping, on days 7, 14, 21 and 27 of administration period.
Females (mating study groups): on day of grouping, on days 7 and 14 of administration period, ondays 1, 8 and 15 of gestation period, on day 4 of lactation period.
BODY WEIGHT: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (On days 1, 4, 8, 11, 15, 18, 22, 25, 28 and 29 of administration period, on days 1, 4, 8, 11,
14 and 15 of recovery period).
Females (mating study groups): Twice a week (On days 1, 4, 8, 11, 15 and 18 of administration period,on days 0, 7, 14 and 20 of gestation period, on days 0, 4 and 5 of lactation period).

7

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (Males: On days 2, 5, 9 and 12 of administration period, on days 2, 5, 9 and 12 of recovery period; Females: On days 2, 5, 9, 12, 16, 19, 23 and 26 of administration period, on days 2, 5, 9
and 12 of recovery period).
Females (mating study groups): Twice a week (On days 2, 5, 9 and 12 of administration period, on days 2, 9, 16 and 20 of gestation period, on days 2 of lactation period).
WATER INTAKE: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (Males: On days 2, 5, 9 and 12 of administration period, on days 2, 5, 9 and 12 ofrecovery period; Females: On days 2, 5, 9, 12, 16, 19, 23 and 26 of administration period, on days 2, 5,
9 and 12 of recovery period).
Females (mating study groups): Twice a week (On days 2, 5, 9 and 12 of administration period, ondays 2, 9, 16 and 20 of gestation period, on days 2 of lactation period).
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood:
Males and females (main study groups): At the end of administration period, or at the end of recovery
period in both sexes- Anaesthetic used for blood collection: Pentobarbital sodium- Animals fasted: Yes- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters examined: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte p
ercentage, platelet count, white blood cell count, differential white blood cell count, prothrombin time,
activated partial thromboplastin time, fibrinogen.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood:
Males and females (main study groups): At the end of administration period, or at the end of recovery
period in both sexes- Animals fasted: Yes- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters checked: ALP, total cholesterol, triglyceride, total bilirubin, glucose, urea nitrogen, creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, albumin, A/G ratio,
AST, ALT, γ-GT
URINALYSIS: Yes- Time schedule for collection of urine:
Males and females (main study groups): Before the end of the administration period (day 23 of administration period) and before the end of recovery (days 12 of recovery period).
- Metabolism cages used for collection of urine: Yes
A urine collector to collect fresh urine samples under fasting but ad libitum drinking conditions, follo
wed by collection of 24-hour urine samples under ad libitum feeding and drinking conditions.
- How many animals:
8

At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters checked:
Fresh urine: Color, pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen, sediment24-urine: Specific gravity, urine volume (24-hour volume)
BLOOD HORMONE: Yes- Time schedule for collection of serum:
Males and females (main study groups): At the end of administration period in both sexes- Animals fasted: Yes- How many animals:
6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0, 62.5, 250, 1000 mg/kg bw/day)- Parameters checked: Triiodothyronine (T3), Thyroxin (T4), and thyroid stimulating hormone (TSH)
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations:
Males and females (main study groups): Final week of administration (Manipulative test and meas
urement of grip strength: Day 27 of administration, measurement of motor activity: Day 26 of adminis
tration)- Dose groups that were examined: Autopsy animals after the end of the administration period- Battery of functions tested:
1) Manipulative Test. Pupillary reflex, approaching behavior, response to touch, auditory reflex, painreflex2) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb
were measured by CPU gauge (San Diego Instruments Inc.).
3) Measurement of Spontaneous Motor Activity. Spontaneous motor activity (Ambulatory and verticalcounts) was measured by Activity Monitor (MED Associates Inc.).
The measurements were collected at 10-minute intervals from 1 hour to 2 hours after administration.
Sacrifice and pathology
GROSS PATHOLOGY: Yes
ORGAN WEIGHT: Yes [main study groups: brain, pituitary, salivary glands, thyroids, adrenal gland, thymus, spleen, heart, liver, kidney, testes, epididymides, ventral prostate, seminal vesicles, ovaries,
uterus; females in mating group: ovary, uterus ]HISTOPATHOLOGY: Yes, [main study groups: heart, lung, trachea, liver, pancreas, sublingual gland,
submandibular gland, esophagus, stomach, duodenum, jejunum, ileum (including Peyer’s patch),cecum, colon, rectum, thymus, spleen, mandibular lymph nodes, mesenteric lymph nodes, kidney,urinary bladder, testis, epididymis, ventral prostate, seminal vesicles (including coagulating gland),ovaries, uterus, vagina, pituitary, adrenal glands, thyroid (including parathyroid), cerebrum, cere
bellum, pons, spinal cord, sciatic nerve, eye ball, Harderian gland, sternum and femur (including bonemarrows), muscle (rectus femoris), mammary gland; females in mating group: ovaries, uterus, vagina]
Statistics
For quantitative data, homogeneity of variance was tested using Bartlett method first. If the variance
was homogenous, statistical difference between each treatment group and the control group was
analyzed using Dunnett method. If not homogenous, statistical difference between each treatmentgroup and the control group was tested using Steel method. For comparison of quantitative data be
tween two groups in the recovery test, homogeneity of variance was analyzed by F-test. Then, if homo
genous, student's t-test was applied. If not homogenous, Aspin-Welch's t-test was used.
Regarding clinical observation (except for frequency of urination, defecation, rearing and grooming)and sensory reactivity, Steel test was applied.

Results and discussion
9

Results of examinations
Clinical signs
no effects observed
Mortality
no mortality observed
Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)no effects observed
Ophthalmological findings
not examined
Haematological findings
effects observed, treatment-related
Clinical biochemistry findings
no effects observed
Urinalysis findings
no effects observed
Behaviour (functional findings)
no effects observed
Immunological findings
not examined
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Gross pathological findings
no effects observed
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
no effects observed
Histopathological findings: neoplastic
not examined
Details on results
CLINICAL SIGNS AND MORTALITY:
Mortality: There was no death.
Clinical signs: There were no changes related to the test substance in any groups at the dosing andrecovery periods.
10

DETAILED CLINICAL OBSERVATIONS:
There were no changes related to the test substance in any groups at the dosing and recovery perio
ds.
BODY WEIGHT:
There were no changes related to the test substance in any groups at the dosing and recovery
periods.
FOOD CONSUMPTION:
There were no changes related to the test substance in any groups at the dosing and recovery
periods.
WATER CONSUMPTION:
There were no changes related to the test substance in any groups at the dosing and recovery periods.
URINALYSIS:There were no changes related to the test substance in any groups at the dosing and recovery p
eriods.
HAEMATOLOGY:[At the end of dosing period]: Decreases in hematocrit and hemoglobin were observed in females at1000 mg/kg bw/day.
[At the end of recovery period]: There were no changes related to the test substance in any groups.
CLINICAL CHEMISTRY (Including blood hormones (T3, T4, TSH)):
There were no changes related to the test substance in any groups at the end of dosing and recovery
periods.
NEUROBEHAVOURAL EXAMINATION:
1) MANIPULATIVE TEST:
There were no changes related to the test substance in any groups at the dosing and recovery pe
riods.
2) GRIP STRENGTH TEST:
There were no changes related to the test substance in any groups at the dosing and recovery periods.
3) LOCOMOTOR ACTIVITY MEASUREMENT:
There were no changes related to the test substance in any groups at the dosing and recovery
periods.
ORGAN WEIGHTS:[At the end of dosing period]: Increases in absolute and relative liver weights, an increase in absoluteadrenal weight and an increase tendency in relative adrenal weight were observed in females at 1000
mg/kg bw/day.
[At the end of recovery period]: There were no changes related to the test substance in any groups.
GROSS PATHOLOGY:
There were no changes related to the test substance in any groups at the end of dosing and recovery
periods.
HISTOPATHOLOGY: NON-NEOPLASTIC:
There were no changes related to the test substance in any groups at the end of dosing and recovery
periods.

Effect levels
Key result
false
11

Dose descriptor
NOAEL
Effect level1000

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
male
Basis for effect level
other:
No toxic effects were observed in males up to the highest dose of 1000 mg/kg bw/day.
Key result
false
Dose descriptor
NOAEL
Effect level250

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
femaleBasis for effect level
haematology
Decreases in hematocrit and hemoglobin were observed in females at 1000 mg/kg bw/day.
organ weights and organ / body weight ratios
Increases in absolute and relative liver weights, an increase in absolute adrenal weight and an increase tendency in relative adrenal weight were observed in females at 1000 mg/kg bw/day.

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/PDF9005-70-3d.pdf

Applicant's summary and conclusion
Conclusions
The NOAEL for repeated dose toxicity in this study was determined to be 1000 and 250 mg/kg bw/day
for males and females, respectively.
Executive summary
In the combined repeated dose and reproductive/developmental screening test (OECD TG422), SD rats
were treated orally with polyoxyethylenesorbitan fatty acid(C12-18)ester at the doses of 0, 62.5, 250 and
121000 mg/kg bw/day. Males (12 animals/dose: 6 animals were treated as a recovery group) were dosed
for 28 days including a 14 day pre-mating period. Females (12 animals/dose) were dosed for 42-46 days
including 14 day premating, mating, and gestation periods and days until day 4 of lactation. In addition,
as the main study group of females, 5 or 10 females/group was dosed for 28 days without mating (5females were treated at 0 and 1000 mg/kg bw/day as recovery groups).
The following findings were observed in the examination at the end of the administration period. In
the haematology, decreases in hematocrit and hemoglobin were observed in females at 1000 mg/kg
bw/day. In the organ weight, increases in absolute and relative liver weights, an increase in absoluteadrenal weight, and an increase tendency in relative adrenal weight were observed in females at 1000
mg/kg bw/day. On the other hand, no toxic effects were observed in males up to the highest doseof 1000 mg/kg bw/day. Based on the above results, the NOAEL for the repeated dose toxicity ofpolyoxyethylenesorbitan fatty acid(C12-18)ester was determined to be 1000 and 250 mg/kg bw/day formales and female rats, respectively.

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

UUID: 81610097-3af9-4ecb-96ae-08c565e96657
Dossier UUID:
Author:Date: 2022-03-25T15:25:17.000+09:00
Remarks:

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

Data source
Reference
Reverse Mutation Test of Polyoxyethylene sorbitan trioleate on Bacteria. / Ministry of Health, Labourand Welfare (MHLW), Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
14

in vitro gene mutation study in bacteria
Deviations
not specified
Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, otherDeviations
not specified
GLP compliance
yesType of assay
bacterial reverse mutation assay
in vitro gene mutation study in bacteria

Test material
Test material information
Polyoxyethylenesorbitan fatty acid(C12-18)ester
Specific details on test material used for the study- Name of test material (as cited in study report): Polyoxyethylene sorbitan trioleate- CAS No.: 9005-70-3- Analytical purity: －- Storage condition of test material: Room temperature, shading, airtightness- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

MethodSpecies / strain
Species / strain / cell typeS. typhimurium TA 1535, TA 1537, TA 98 and TA 100
bacteria
Species / strain / cell type
E. coli WP2 uvr A
bacteria
Metabolic activation
with and without
Metabolic activation system
S9 mix; SD male rat liver, induced by phenobarbital and 5,6-benzoflavone
Justification for deviation from the high dose level-S9 mix:
15

312.5, 625, 1250,2500, 5000 μg/plate (TA100, TA1535, WP2uvrA, TA98, TA1537 strains)+S9 mix:
312.5, 625, 1250,2500, 5000 μg/plate (TA100, TA1535, WP2uvrA, TA98, TA1537 strains)
Maximum concentration was established based on the result of the preliminary test at concentration
up to 5000 ug/plate. In this test, this chemical did not induce gene mutations in S. typhimurium andE. coli strains, and cytotoxicity was not observed in all strains at up to 5000 μg/plate with and without
S9 mix.
Vehicle / solvent- Vehicle(s)/solvent(s) used: Water for injection
Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceother: -S9 mix: 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2), sodium azide (NaN3), 9-aminoacridinehydrochloride (9AA);+S9 mix: 2-aminoanthracene (2AA)
Details on test system and experimental conditions
METHOD OF APPLICATION: Preincubation
DURATION- Preincubation period: 20 min at 37°C
- Exposure duration:48 hrs
NUMBER OF PLATES: 3
NUMBER OF REPLICATIONS: 1
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 / strain
S. typhimurium TA 1535
16

bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity
valid
Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 1537
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity
valid
Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 98
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity
valid
Positive controls validity
valid

17

Key result
trueSpecies / strain
S. typhimurium TA 100
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity
valid
Positive controls validity
valid
Key result
trueSpecies / strain
E. coli WP2 uvr A
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity
valid
Positive controls validityvalid

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF9005-70-3e.pdf

Applicant's summary and conclusion
Conclusions
Interpretation of results (migrated information): negative18

In a bacterial reverse mutation assay using Salmonella typhimurium TA100, TA1535, TA98, and TA
1537, and Escherichia coli WP2uvrA (OECD TG 471), polyoxyethylenesorbitan fatty acid(C12-18)ester
was negative with or without metabolic activation.

19

ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.002

UUID: b337dbf0-d1e2-41c0-adfa-a532f1751a4e
Dossier UUID:
Author:Date: 2022-03-25T15:25:46.000+09:00
Remarks:

Administrative data
Endpoint
in vitro 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 Polyoxyethylene sorbitan trioleate on Cultured Chinese
Hamst / Ministry of Health, Labour and Welfare (MHLW), Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)in vitro cytogenicity / chromosome aberration study in mammalian cells
Deviations
no20

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
Polyoxyethylenesorbitan fatty acid(C12-18)ester
Specific details on test material used for the study- Name of test material (as cited in study report): Polyoxyethylene sorbitan trioleate- CAS No.: 9005-70-3- Analytical purity: －- Storage condition of test material: Room temperature, shading, airtightness- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

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
Justification for deviation from the high dose level
Cell growth inhibition study-S9 mix (short-term treatment): 33.6, 67.2, 134.4, 268.8, 537.5, 1075, 2150, 4300 ug/mL+S9 mix (short-term treatment): 33.6, 67.2, 134.4, 268.8, 537.5, 1075, 2150, 4300 ug/mL-S9 mix (continuous treatment, 24hr): 33.6, 67.2, 134.4, 268.8, 537.5, 1075, 2150, 4300 ug/mL
Main study-S9 (short-term treatment): 62.5, 125, 250, 500 ug/mL+S9 (short-term treatment): 62.5, 125, 250, 500 ug/mL-S9 (continuous treatment, 24hr): 31.3, 62.5, 125, 250 ug/mL
Vehicle / solvent- Vehicle(s)/solvent(s) used: Water for injection
21

Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceother: [-S9]: mitomycin C; [+S9]: N-dimethylnitrosamine
Details on test system and experimental conditions
METHOD OF APPLICATION:
Exposure duration:- [short-term treatment]: 6 hrs + 18 hrs- [continuous treatment]: 24 hrs
SPINDLE INHIBITOR: Colcemid
STAIN: Giemsa stain (2 v/v%) for 15 min.
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 100 + 100 cells /concentration
DETERMINATION OF CYTOTOXICITY- Method: relative total growth
Evaluation criteria
For the evaluation of the frequencies of structural aberrations and of polyploidy induced, the following
criteria were employed. Appearance incidence of cell with chromosomal aberrations: Negative (-):
less than 5%, Equivocal(±): more than 5% and less than 10%, Positive(+): 10% and above
StatisticsnoResults and discussion
Test results
Key result
trueSpecies / strainother: Chinese hamster lung (CHL/IU) cells
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity
Vehicle controls validity
valid
22

Positive controls validity
valid
Additional information on results
RANGE-FINDING/SCREENING STUDIES (if applicable):
50% cell growth inhibition (IC50): 340 ug/mL (short-term treatment, +S9 mix), 370 ug/mL (short-term treatment, -S9 mix), 190 ug/mL (continuous treatment)

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/PDF9005-70-3f.pdf

Applicant's summary and conclusion
Conclusions
Interpretation of results (migrated information): negative with or without metabolic activation
In an in vitro chromosomal aberration test using CHL/IU cells (OECD TG 473), polyoxyethylenes
orbitan fatty acid(C12-18)ester was negative with or without metabolic activation.

23

Toxicity to reproduction
ENDPOINT_STUDY_RECORD: ToxicityReproduction.001

UUID: 8cf29cfa-a458-46fc-84f1-4e868dd8a6ef
Dossier UUID:
Author:Date: 2022-03-25T15:36:47.000+09:00
Remarks:

Administrative data
Endpoint
reproductive toxicity, other A combined repeated dose/reproductive developmental toxicity study
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study OECD Test Guideline study under GLP condition
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study
Related information
OECD / Repeated dose toxicity: oral / RepeatedDoseToxicityOral.001 / Polyoxyethylenesorbitan fattyacid(C12-18)ester / 9005-70-3

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

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

Test material
Test material information
Polyoxyethylenesorbitan fatty acid(C12-18)ester
Specific details on test material used for the study- Name of test material (as cited in study report): Polyoxyethylene sorbitan trioleate- CAS No.: 9005-70-3- Analytical purity: －- Storage condition of test material: Room temperature, shading, airtightness- Stability under test conditions: The stability of test material was identified by analysis of theremainder.

Test animals
Speciesrat
Strainother: Crl: CD (SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Japan, Inc., Hino Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation: Males in main group male: 357-412 g, females in main group: 226-265 g,
females in mating group: 211-255 g- Housing: Animals were individually housed in stainless steel suspension cage (240W × 380D × 200Hmm), from gestation day 18 to lactation day 4, Dams were bred individually or with individual littermat
es in plastic cages (310W x 360D x 175H mm) and bedding.
- Diet: Solid feed (CRF-1: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: Males in main group: 19 days, females in main group: 20 days, females in matinggroup: 19 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 20-26°C (actual temperature: 22.3-24.3°C)- Humidity (%): 40.0-70.0% (actual humidity: 40.6-65.9%)- Air changes (per hr): 12
25

- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 6:00-18:00)

Administration / exposure
Route of administration
oral: gavage
Vehiclewater water for injection
Details on exposure- Amount of vehicle (if gavage): 10 mL/kg- Dosing volume: 10 mL/kg
Details on mating procedure- M/F ratio per cage:1/1- Length of cohabitation: up to 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
The concentrations of each test solution using administration on day 1 were analyzed with a spectrop
hotometer. Results showed that the concentrations of each test solution were 98.7 to 103.7% of thenominal concentration and both values were within the acceptable range (concentration: percentage
of nominal concentration, 100±10%)Duration of treatment / exposure
Males: 28 days including 14 days pre-mating
Females (main study groups): 28 days
Females (mating study groups): 42-54 days including 14 days pre-mating, mating and gestation periods and the days until day 4 of lactation
Frequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
62.5

mg/kg bw/day (actual dose received)

Dose / conc.
250

mg/kg bw/day (actual dose received)

Dose / conc.
1000

mg/kg bw/day (actual dose received)

26

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

Examinations
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes- Time schedule:
Males and females (main study groups): 2 times/day (before administration, 61-189 minutes afteradministration) during the administration period. Once a day during the recovery period.
Females (mating study groups): 2 times/day (before administration, 60-211 minutes after administration) during the administration period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Males and females (main study groups): on day of grouping, on days 7, 14, 21 and 27 of administration period.
Females (mating study groups): on day of grouping, on days 7 and 14 of administration period, ondays 1, 8 and 15 of gestation period, on day 4 of lactation period.
BODY WEIGHT: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (On days 1, 4, 8, 11, 15, 18, 22, 25, 28 and 29 of administration period, on days 1, 4, 8, 11,
14 and 15 of recovery period).
Females (mating study groups): Twice a week (On days 1, 4, 8, 11, 15 and 18 of administration period,on days 0, 7, 14 and 20 of gestation period, on days 0, 4 and 5 of lactation period).
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (Males: On days 2, 5, 9 and 12 of administration period, on days 2, 5, 9 and 12 of recovery period; Females: On days 2, 5, 9, 12, 16, 19, 23 and 26 of administration period, on days 2, 5, 9
and 12 of recovery period).

27

Females (mating study groups): Twice a week (On days 2, 5, 9 and 12 of administration period, on days 2, 9, 16 and 20 of gestation period, on days 2 of lactation period).
WATER INTAKE: Yes- Time schedule for examinations:
Males and females (main study groups):
Twice a week (Males: On days 2, 5, 9 and 12 of administration period, on days 2, 5, 9 and 12 ofrecovery period; Females: On days 2, 5, 9, 12, 16, 19, 23 and 26 of administration period, on days 2, 5,
9 and 12 of recovery period).
Females (mating study groups): Twice a week (On days 2, 5, 9 and 12 of administration period, ondays 2, 9, 16 and 20 of gestation period, on days 2 of lactation period).
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood:
Males and females (main study groups): At the end of administration period, or at the end of recovery
period in both sexes- Anaesthetic used for blood collection: Pentobarbital sodium- Animals fasted: Yes- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters examined: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte p
ercentage, platelet count, white blood cell count, differential white blood cell count, prothrombin time,
activated partial thromboplastin time, fibrinogen.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood:
Males and females (main study groups): At the end of administration period, or at the end of recovery
period in both sexes- Animals fasted: Yes- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters checked: ALP, total cholesterol, triglyceride, total bilirubin, glucose, urea nitrogen, creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, albumin, A/G ratio,
AST, ALT, γ-GT
URINALYSIS: Yes- Time schedule for collection of urine:
Males and females (main study groups): Before the end of the administration period (day 23 of administration period) and before the end of recovery (days 12 of recovery period).
- Metabolism cages used for collection of urine: Yes
A urine collector to collect fresh urine samples under fasting but ad libitum drinking conditions, follo
wed by collection of 24-hour urine samples under ad libitum feeding and drinking conditions.
- How many animals:
At the end of administration period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose(0, 62.5, 250, 1000 mg/kg bw/day)
At the end of recovery period: 6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0and 1000 mg/kg bw/day)- Parameters checked:
Fresh urine: Color, pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen, sediment24-urine: Specific gravity, urine volume (24-hour volume)28

BLOOD HORMONE: Yes- Time schedule for collection of serum:
Males and females (main study groups): At the end of administration period in both sexes- Animals fasted: Yes- How many animals:
6 males/dose (0, 62.5, 250, 1000 mg/kg bw/day), 5 females/dose (0, 62.5, 250, 1000 mg/kg bw/day)- Parameters checked: Triiodothyronine (T3), Thyroxin (T4), and thyroid stimulating hormone (TSH)
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations:
Males and females (main study groups): Final week of administration (Manipulative test and meas
urement of grip strength: Day 27 of administration, measurement of motor activity: Day 26 of adminis
tration)- Dose groups that were examined: Autopsy animals after the end of the administration period- Battery of functions tested:
1) Manipulative Test. Pupillary reflex, approaching behavior, response to touch, auditory reflex, painreflex2) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb
were measured by CPU gauge (San Diego Instruments Inc.).
3) Measurement of Spontaneous Motor Activity. Spontaneous motor activity (Ambulatory and verticalcounts) was measured by Activity Monitor (MED Associates Inc.).
The measurements were collected at 10-minute intervals from 1 hour to 2 hours after administration.
Oestrous cyclicity (parental animals)
Vaginal smears were collected from all females in the mating study groups and microscopicallyexamined every day from the day after the start of administration until the day copulation was c
onfirmed.
Sperm parameters (parental animals)
Parameters examined in all P male parental generations: testis, epididymis and seminal vesicle weight, histopathological examinations for testes, epididymides, seminal vesicle and ventral prostate.
Litter observations
PARAMETERS EXAMINED: The following parameters were examined in F1 offspring: Number and sexof pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, and weight gain.
GROSS EXAMINATION OF DEAD PUPS: Yes, for external and internal abnormalities.
Postmortem examinations (parental animals)
METHOD OF SACRIFICED: All animals were sacrificed by exsanguination under pentobarbital sodium
anesthesia.
SACRIFICE: Males and females (main study groups): On next day after the last administration,
Maternal animals: on Day 5 of lactation, and males and females recovery group: on Day 14 of recovery.
GROSS PATHOLOGY: Yes
ORGAN WEIGHT: Yes [main study groups: brain, pituitary, salivary glands, thyroids, adrenal gland,
thymus, spleen, heart, liver, kidney, testes, epididymides, ventral prostate, seminal vesicles, ovaries,
uterus; females in mating group: ovary, uterus]
HISTOPATHOLOGY: Yes, [main study groups: heart, lung, trachea, liver, pancreas, sublingual gland, submandibular gland, esophagus, stomach, duodenum, jejunum, ileum (including Peyer’s patch),cecum, colon, rectum, thymus, spleen, mandibular lymph nodes, mesenteric lymph nodes, kidney,urinary bladder, testis, epididymis, ventral prostate, seminal vesicles (including coagulating gland),ovaries, uterus, vagina, pituitary, adrenal glands, thyroid (including parathyroid), cerebrum, cerebellum,
pons, spinal cord, sciatic nerve, eye ball, Harderian gland, sternum and femur (including bone marrows), muscle (rectus femoris), mammary gland; females in mating group: ovaries, uterus, vagina ]29

Postmortem examinations (offspring)
SACRIFICE- The F1 offsprings were euthanized on PND4 by exsanguination under 20%Isoflurane anesthesia.
GROSS NECROPSY: Yes- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, andabdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS- Not examined.
Statistics
For quantitative data, homogeneity of variance was tested using Bartlett method first. If the variance
was homogenous, statistical difference between each treatment group and the control group was
analyzed using Dunnett method. If not homogenous, statistical difference between each treatmentgroup and the control group was tested using Steel method. For comparison of quantitative data be
tween two groups in the recovery test, homogeneity of variance was analyzed by F-test. Then, if homo
genous, student's t-test was applied. If not homogenous, Aspin-Welch's t-test was used.
Regarding clinical observation (except for frequency of urination, defecation, rearing and grooming)and sensory reactivity, Steel test was applied. Regarding implantation index, delivery index, birth index,
live birth index, viability index, sex ratio and external abnormalities, Steel test was applied. Regarding
copulation, fertility index, and gestation index, Fisher's test was applied.
Reproductive indices
Each parameter was determined by the following equations:
Copulation index (%) = (No. of pairs with successful copulation / No. of pairs) × 100
Fertility index (%) = (No. of pregnant females / No. of pairs with successful copulation) × 100
Gestation index (%) = (No. of dams having live pups / No. of pregnant dams) × 100
Length of gestation (days)
Implantation index (%) = (No. of implantation scars / No. of corpora lutea) × 100
Delivery index (%) = (No. of pups born / No. of implantation scars) × 100
Birth index (%) = (No. of live pups born / No. of implantation scars) × 100
Live birth index (%) = (No. of live pups born / No. of pups born) × 100
Sex ratio on Day 4 of lactation = No. of male pups / No. of female pups
External abnormalities (%) = (No. of pups with external abnormalities / No. of live pups) × 100
Offspring viability indices
Viability index (%) = (No. of live pups on Day 4 of lactation/ No. of live pups born) × 100

Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
Clinical signs
no effects observed
Mortality
no mortality observed
Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
30

Food efficiency
not examined
Water consumption and compound intake (if drinking water study)no effects observed
Ophthalmological findings
not examined
Haematological findings
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity.001
Clinical biochemistry findings
no effects observed
Urinalysis findings
no effects observed
Behaviour (functional findings)
no effects observed
Immunological findings
not examined
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity.001
Gross pathological findings
no effects observed
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
no effects observed
Histopathological findings: neoplastic
not examined

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

Details on results (P0)General toxicity: See 7.5.1 Repeated dose toxicity.001
Reproductive function / performance: There were no effects on reproductive parameters up to 1000
mg/kg bw/day.
31

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

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
male
Basis for effect level
other:
No toxic effects were observed in males up to the highest dose of 1000 mg/kg bw/day.
Key result
false
Dose descriptor
NOAEL
Effect level250

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
femaleBasis for effect level
haematology
Decreases in hematocrit and hemoglobin were observed in females at 1000 mg/kg bw/day.
organ weights and organ / body weight ratios
Increase in absolute and relative liver weights, increase in absolute adrenal weight and increase tendency in relative adrenal weight were observed in females at 1000 mg/kg bw/day.
Key result
false
Dose descriptor
NOAEL
Effect level1000

mg/kg bw/day (actual dose received)

Based ontest mat.
32

Sex
male/female
Basis for effect level
reproductive performance
No reproductive effects were observed in both males and females up to 1000 mg/kg bw/day.

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

Details on results (F1)
F1 offspring in the 1000 mg/kg bw/day group showed a tendency to lower body weight or lower bodyweight on lactation day 0.

Effect levels (F1)
Key result
false
Dose descriptor
NOAEL
Generation
F1
Effect level250

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
body weight and weight gain
F1 offspring in the 1000 mg/kg bw/day group showed a tendency to lower body weight or lower
body weight on lactation day 0.

Overall reproductive toxicity
33

Key result
false
Reproductive effects observednoAny other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF9005-70-3d.pdf

Applicant's summary and conclusion
Conclusions
In the combined repeated oral dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) described above, low body weights of pups on lactation day 0 were observed
at maternally toxic doses. The NOAEL for reproductive toxicity of polyoxyethylenesorbitan fatty acid(C12-18)ester was regarded to be 1000 mg/kg bw/day because no reproductive toxic effects wereobserved.
The NOAEL for developmental toxicity of polyoxyethylenesorbitan fatty acid(C12-18)ester was regar
ded to be 250 mg/kg bw/day because of a trend towards lower or lower body weights in F1 pups at
1000 mg/kg bw/day.

34

DOMAIN
SUBSTANCE: Polyoxyethylenesorbitan fatty acid(C12-18)ester
UUID: c8355b50-875d-42c8-a5d3-3094f20b1fde
Dossier UUID:
Author:Date: 2022-03-25T15:25:46.000+09:00
Remarks:
Substance name
Polyoxyethylenesorbitan fatty acid(C12-18)ester
Legal entity
National Institute of Health Sciences / Kawasaki / Japan

Identification of substance
Reference substance
Polyoxyethylenesorbitan fatty acid(C12-18)ester / 9005-70-3 / 618-422-4
EC number

EC name618-422-4

EC Inventory

CAS number

CAS name

9005-70-3
IUPAC nameRole in the supply chain
Manufacturer
false
Importer
false
Only representativefalse
Downstream user
false

35

References
Reference Substances
REFERENCE_SUBSTANCE: Polyoxyethylenesorbitan fattyacid(C12-18)ester
UUID: 9152eb94-d1f7-4d0a-ac90-0470dcfc2f34
Dossier UUID:
Author:Date: 2022-03-25T14:42:39.000+09:00
Remarks:
Reference substance name
Polyoxyethylenesorbitan fatty acid(C12-18)ester

Inventory
Inventory number
Inventory nameInventory
EC Inventory
Inventory number
618-422-4
CAS number
Molecular formula
Description
CAS number
9005-70-3

Synonyms
Synonyms
Identifier
other:
Identitypolyoxyethylene sorbitan trioleate
Identifier
other:
Identity
Tween 85

Molecular and structural information
36

Molecular formula
C60H108O8(C2H4O)20
Molecular weight
1838.537

Test Materials
TEST_MATERIAL_INFORMATION:
Polyoxyethylenesorbitan fatty acid(C12-18)ester
UUID: dc6c1a49-b20f-4b3b-b187-a4d631c1e214
Dossier UUID:
Author:Date: 2022-03-25T14:49:31.000+09:00
Remarks:
Name
Polyoxyethylenesorbitan fatty acid(C12-18)ester

Composition
Other characteristics
Test material form
liquid: viscous
Details on test material
CAS No.: 9005-70-3

38

Literatures
LITERATURE: Combined repeated dose toxicity study withthe reproductive/developmental toxicity screening test ofpolyoxyethylene sorbitan trioleate by oral administrationin rats
UUID: 74c15b50-0eb8-4ad3-bc6f-5bf480e3c3a6
Dossier UUID:
Author:Date: 2021-10-18T14:53:15.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Combined repeated dose toxicity study with the reproductive/developmental toxicity screening test ofpolyoxyethylene sorbitan trioleate by oral administration in rats
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Bibliographic source
available in the web of Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/
mhlw_data/home/pdf/PDF9005-70-3d.pdf
Testing facility
Nihon Bioresearch Inc.
Report number
10023039

LITERATURE: In Vitro Chromosomal Aberration Test of
Polyoxyethylene sorbitan trioleate on Cultured Chinese
Hamster Cells.
UUID: 62452636-5f6e-49ef-bd68-199fbb3700af
Dossier UUID:
Author:Date: 2022-03-03T17:07:07.000+09:00
Remarks:

General information
Reference Typestudy report
Title
In Vitro Chromosomal Aberration Test of Polyoxyethylene sorbitan trioleate on Cultured Chinese
Hamster Cells.
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Year
2011
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF90
05-70-3f.pdf
Testing facility
Nihon Bioresearch Inc.
Report date2011-03-29
Report number
97063040

LITERATURE: Reverse Mutation Test of Polyoxyethylene
sorbitan trioleate on Bacteria.
UUID: 4d39dcfb-06cf-42d1-85cb-db5ff4a3cfe0
Dossier UUID:
Author:Date: 2022-03-01T15:15:07.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Reverse Mutation Test of Polyoxyethylene sorbitan trioleate on Bacteria.
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Year
2011
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF90
05-70-3e.pdf
Testing facility
Nihon Bioresearch Inc.
Report date2011-03-29
Report number
90093041