Name: COMPLETE / SUBSTANCE : Tetraphenyltin(IV) / tetraphenylstannane / 595-90-4 Fri,
16 Dec 2022, 16:56:43+0900 /Legal entity owner: National Institute of Health Sciences
Printing date: 2022-12-16T16:56:43.511+09:00

iTable of Contents
0/0 ............................................................................................................................. 1
National Institute of Health Science ..................................................................... 2
Tetraphenyltin(IV) ................................................................................................ 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 ................................................ 1773 Toxicity to reproduction ........................................................ 21
Toxicity to reproduction.001 ............................................... 21
DOMAIN .................................................................................................... 30
Substance ......................................................................................... 30
Substance ................................................................................ 30
References ................................................................................................................ 31
Reference Substances ...................................................................................... 31
tetraphenyltin ............................................................................................ 31
Literatures ....................................................................................................... 33
A combined repeated dose/reproductive developmental toxicity study oftetraphenyltin by oral administration in rats. ................................................ 33
In Vitro Chromosomal Aberration Test of Tetraphenyltin(IV) on Cultured
Chinese Hamster Cells .............................................................................. 34
Reverse Mutation Test of Tetraphenyltin(IV) ............................................... 35
Legal Entities ................................................................................................... 36
National Institute of Health Sciences .......................................................... 36ii

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Tetraphenyltin(IV) / tetraphenylstannane / 595-90-4
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National Institute of Health Science
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1

LEGAL_ENTITY: National Institute of Health
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General information
Legal entity nameNational Institute of Health Science2

Tetraphenyltin(IV)
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
repeated dose toxicity: oral, otherType of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study
Related information
OECD / Toxicity to reproduction / Toxicity to reproduction.001 / Tetraphenyltin(IV) /tetraphenylstannane / 595-90-4

Data source
Reference
A combined repeated dose/reproductive developmental toxicity study of tetraphenyltin by oral adminis /Ministry of Health, Labor and Welfare, Japan / study report4Data accessdata published

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
Specific details on test material used for the study- Name of test material (as cited in study report): Tetraphenyltin- Analytical purity: 97.9%- Storage condition of test material: at a cold (temperature 2-6°C) and dark place, with airtight stopper.
- 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., Atsugi Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation: male 388 g (357-421 g), female 243 g (213-278 g)- Housing: Animals were individually housed in bracket-type metallic wire-mesh cages (265W × 426D ×200H mm), Dams were bred individually or with individual littermates in polycarbonate cages with flat
floors (265W x 426D x 200H mm) and standard bedding.
- Diet: Solid feed (MR stock: Nosan Corporation) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
5

- Temperature (°C): 22±3 (actual temperature: 20.7-24.9°C)- Humidity (%): 55±10% (actual humidity: 45-63%)- Air changes (per hr): >10- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 7:00~19:00)

Administration / exposure
Route of administration
oral: gavage
Vehicleolive oil
Details on oral exposure- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Analytical verification of doses or concentrations
yes
Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating(P)Females: 42-54 days including 14 days pre-mating, mating and gestation periods and the days until
day 4 of lactation
Female (no mating, satellite group): 42 days
Frequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
4

mg/kg bw/day (actual dose received)

Dose / conc.
20

mg/kg bw/day (actual dose received)

Dose / conc.
100

mg/kg bw/day (actual dose received)

Dose / conc.
500

mg/kg bw/day (actual dose received)

No. of animals per sex per dose
Main group:12 animals/sex/dose
6Satellite (Recovery) group: 5 males/dose and 5 females/dose (0 and 500 mg/kg bw/day)Control 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 500
mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 4 mg/kg bw/
day was selected as an expected no toxic dose. The middle dose levels of 20 and 100 mg/kg bw/day
were selected.
- Rationale for animal assignment (if not random): Body weight-balanced randomization[14-day preliminary study]
Study 1:
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0 (olive oil), 50, 100, 200, 500 or 100
0 mg/kg bw/day). At 50 mg/kg bw/day or more, treatment rerated effects were observed. High valueof ALT were observed in males 1000 mg/kg bw/day.
Study 2:
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0 (olive oil), 1.5, 3, 6, 12.5, 25 or 50
mg/kg bw/day). Increase in relative liver weights were observed in males at 3 mg/kg bw/day, females
at 6 mg/kg bw/day and 25 mg/kg bw/day or more.

Examinations
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes- Time schedule: 3 times/day (am: before and after administration; pm) during the administration
period. 2 times/day (am and pm) during the recovery period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: Once before the start of administration, and once every week by the end of the study
period.
BODY WEIGHT: Yes- Time schedule for examinations:
Males were weighed on Day 1, 7, 14, 21, 28, 35, and 42 of administration, and weighed on Day 7 and
14 of recovery.
Female satellite groups were weighted same frequencies to male recovery groups.
Females in the main groups were weighed on Day 1, 7 and 14 of administration and copulated
females were weighed on Day 0, 7, 14 and 20 of gestation, and days 0 and 4 of lactation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes
Measurement of food consumption was conducted on all animals at the following frequencies:
Males in the main and recovery groups; on Day 1, 7, 14, 21, 28, 35, and 41 of administration, and on
Day 7 and 13 of recovery.
Female satellite groups were weighted same frequencies to male recovery groups.
Females in the main group; on Day 1, 7 and 14 of administration and copulated females were weighedon Day 0, 7, 14 and 20 of gestation, and days 0 and 3 of lactation.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery
period in both sexes- Anaesthetic used for blood collection: ether
7

- Animals fasted: Yes- How many animals: 5 animals/sex/group- Parameters examined included RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet, ret
iculocyte, PT, APTT, WBC and differential WBC.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery
period in both sexes- Animals fasted: Yes- How many animals: 5 animals/sex/group- Parameters examined included total protein, albumin, A/G ratio, total bilirubin, glucose, total cho
lesterol, triglyceride, phospholipid, AST, ALT, LDH, ChE, ALP, gamma-GTP, BUN, creatinine, Na, K, Cl,
Ca and IP.
URINALYSIS OF MALES: Yes- Time schedule for collection of urine (male only): On Day 37 of administration, and on Day 9 of recovery.
- Metabolism cages used for collection of urine: Yes- How many animals: 5 animals/group- Parameters examined included color, cloudy, urine volume, specific gravity, pH, protein, glucose, ketone body, bilirubin, occult blood and urobilinogen.
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations: On week 6 of the administration period, and on week 2 of therecovery period- Dose groups that were examined: All dose groups (5 animals/sex/group)- Battery of functions tested: sensory activity (hearing reaction, eye sight reaction, sense of touch
reaction, pain reaction, pupil reflex, righting reflex), grip strength, motor activity
Sacrifice and pathology
GROSS PATHOLOGY: Yes
ORGAN WEIBHT: Yes [brain, thymus, heart, liver, kidney, adrenal gland, spleen, seminal vesicle, testis,
epididymis, pituitary, thyroid]
HISTOPATHOLOGY: Yes, [brain, pituitary, spinal cord, thyroid, parathyroid, heart, thymus, trachea, lung,
liver, kidney, adrenal, spleen, stomach, small intestine, large intestine, sciatic nerve, bone, bone marrow, lymph nodes (mesenteric and cervical lymph nodes), urinary bladder, testis, seminal vesicle, prostate, epididymis, mammary gland, ovary and uterus.]

Statistics
As for parametric data (grip strength, locomotor activity, body weight, body weight gain, food consu
mption, hematology and clinical chemistry data, organ weights, quantitative urinalysis data, numberof corpora lutea, number of implantation sites, number of pups born, number of pups alive, number ofstillborn), the values of means and standard deviations were calculated per group. When more than
three groups exist in the test group, Bartlett test for variance was done, and if the variance was ho
mogenous, ANOVA was applied. If the variance was not homogenous or data was non-parametric(differential WBC percentage, qualitative urinalysis data, stages of spermatogenesis, length of the
estrous cycle, implantation index, delivery index, live birth index, viability index,), Kruskal-Wallis rank s
um test was used. Consequently, if the result was significant, Dunnett multiple comparison or Dunnett typed method was used for detection of statistical significance against control group. When the nu
mber of the test group was two, F-test was used as for parametric data.
Then, student's t-test or Aspin-Welch's t-test was applied depending on the result of homogeneity ofvariance. While, as for non-parametric data, Man-Whitney's U-test was applied. Furthermore, as fo
r categorized data (incidence of abnormal findings in clinical observation, detailed observation, se8nsory functional examination, necropsy and histopathology, copulation index, fertility index, gestationindex), Fischer's exact test was used. In the histopathological examination findings, Mann-Whitney's
U test was used for graded data, and chi-squared test was used for sex ratio of pups. In any tests,
level of significance was set at 5%.

Results and discussion
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)
not examined
Ophthalmological findings
not examined
Haematological findings
no effects observed
Clinical biochemistry findings
no effects observed
Urinalysis findings
no effects observed
Behaviour (functional findings)
no effects observed
Organ weight findings including organ / body weight ratios
no effects observed
Gross pathological findings
no effects observed
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 effects related to the test substance.

9

DETAILED CLINICAL OBSERVATIONS, MANIPULATIVE TEST, GRIP STRENGTH TEST AND LOCO
MOTOR ACTIVITY MEASUREMENT: There were no changes related to the test substance.
BODY WEIGHT:
There were no changes related to the test substance in any groups at the dosing and recovery p
eriods.
FOOD CONSUMPTION: There were no changes related to the test substance in any groups at thedosing and recovery periods.
URINALYSIS: There were no changes related to the test substance in any groups at the dosing andrecovery periods.
HAEMATOLOGY:
There were no changes related to the test substance in any groups at the end of dosing and recovery
periods.
CLINICAL CHEMISTRY:
There were no changes related to the test substance in any groups at the end of dosing and recovery
periods.
URINALYSES OF MALES: There were no changes related to the test substance in any groups at thedosing and recovery periods.
ORGAN WEIGHTS:
There were no changes related to the test substance in any groups at the end of dosing and recovery
periods.
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
true
Dose descriptor
NOAEL
Effect level500

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
other: There were no effects related to the test substance.

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
10http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF595-90-4d.pdf

Applicant's summary and conclusion
Executive summary
The combination of a study of repeated-oral-dose toxicity and a reproduction/developmental toxicity
screening test was performed in accordance with OECD TG 422. Tetraphenyltin (IV) was administered
to male and female rats (12 animals/sex/dose) at 0 (vehicle: olive oil), 4, 20, 100, and 500 mg/kg bw/
day. The males were dosed for 42 days, including a 14-day pre-mating period and a subsequent mating
period. The females were dosed for 42–54 days, including 14-day pre-mating, mating, and gestation
periods and until lactation day 4. Of the 12 males in the control and 500 mg/kg bw/day groups, 5 weretreated as a recovery group. Additionally, five females per dose were administered the test substanceat 0 and 500 mg/kg bw/day for 42 days without mating; they were examined after a 14-day recovery
period (satellite group).
No adverse effects were observed in clinical characteristics, FOB, body weight, food consumption,
urinalysis, hematology, clinical biochemistry, organ weight, or pathology after the administration andrecovery periods for any of the treated groups. In a 14-day preliminary study of tetraphenyltin (IV) in rats,
relative liver weights were found to increase by 3 to 1,000 mg/kg bw/day in males and by 6 to 1,000
mg/kg bw/day in females. For this reason, the largest dose tested in this main study was expected tocause overt toxicity. No clear reason was adduced why no adverse effects on the liver were observed inthis study, but age at necropsy and duration of administration might each have affected the response.
These data indicate that the NOAEL of repeated-dose toxicity for tetraphenyltin (IV) should be estimatedto be 500 mg/kg bw/day (the highest dose tested).

11

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

UUID: 185693f0-194e-44c0-b530-3d7fd8644326
Dossier UUID:
Author:Date: 2019-09-03T16:11:29.000+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
true
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study
Reliability 1

Data source
Reference
Reverse Mutation Test of Tetraphenyltin(IV) / Ministry of Health, Labour and Welfare (MHLW), Japan /study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
12

in vitro gene mutation study in bacteria
GLP compliance
yes

Test material
Specific details on test material used for the study- Lot No.: EWJ4190- Purity: 99%- Solubility: insoluble in water, DMSO, acetone, N,N-dimethylformamide, 1,4-dioxane, and tetrahy
drofuran- Physical state: white powder- Storage condition of test material: room temperature (16-28 degree C)

MethodSpecies / strain
Species / strain / cell typeS. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2bacteria
Metabolic activation
with and without
Metabolic activation system
S9 mix: Rat liver, induced with phenobarbital and 5,6-benzoflavone
Test concentrations with justification for top dose
Dosage of each strain with or without S9+/-S9 mix: 0, 19.5, 39.1, 78.1, 156, 313 μg /plate
Maximum concentration was established based on the result of the preliminary test at concentration
up to 5000 ug/plate. In this test, growth inhibition was not observed, but precipitation was observed
at 313-5000 μg/plate for all strains with and without S9 mix.
Vehicle / solvent
Water (suspended)
Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substancesodium azide13

- S9 mix (TA 1535)
benzo(a)pyrene+S9 mix (TA100, TA98, TA1537)
other: see Remarks
Remarks
without S9 mix:2-(2-Furyl)-3-(5-nitro -2-furyl)acrylamide (TA100, TA98, WP2uvrA), without S9 mix:
2-Methoxy-6-chloro-9-[3-(2-chloroethyl) aminopropylamino]acridine-2HCl (TA1537) with S9 mix: 2aminoanthracene (TA 1535, WP2uvrA)
Details on test system and experimental conditions
METHOD OF APPLICATION: Preincubation
DURATION- Preincubation period: 20 min at 37°C
- Exposure duration:48 hrs
NUMBER OF PLATES: 3
NUMBER OF REPLICATIONS: 2
DETERMINATION OF CYTOTOXICITY- Method: other: growth inhibition
Evaluation criteria
A chemical was judged to be mutagenic when the mean number of revertant colonies per plateincreased more than twice that of the negative control and when the dose-related or reproducible increase was observed.
Statistics
not used

Results and discussion
Test results
Key result
trueSpecies / strain
S. typhimurium TA 1535
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
14

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
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 Precipitation
was observed at 313 μg /plate.
Vehicle controls validity
valid
Positive controls validity
valid

15

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, but tested up to precipitating concentrations
Vehicle controls validity
valid
Positive controls validityvalid

Any other information on results incl. tables
Figures and Tables (in Japanese) are available in the following full report of the study. http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF595 -90 -4e.pdf
Tables (in English) are attachted to this document. Please download the export file to see the Tables.

Applicant's summary and conclusion
Conclusions
With metabolic activation: Negative
Without metabolic activation: Negative
Executive summary
In a bacterial reverse mutation assay using S. typhimuriumTA100, TA1535, TA98, and TA1537, and E.
coli WP2uvrA/pKM101 (OECD TG 471), negative results were obtained for tetraphenyltin(IV) with orwithout metabolic activation.

16

ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.002

UUID: c4b9729b-d2a6-4818-baa4-c844c57812c2
Dossier UUID:
Author:Date: 2022-12-16T16:52:12.805+09:00
Remarks:

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

Data source
Reference
In Vitro Chromosomal Aberration Test of Tetraphenyltin(IV) on Cultured Chinese Hamster Cells /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
GLP complianceyes
17Test material
Specific details on test material used for the study- Lot No.: EWJ4190- Purity: 99%- Solubility: insoluble in water, suspend in DMSO
- Physical state: white powder- Storage condition of test material: room temperature (15-24 degree C)

MethodSpecies / strain
Species / strain / cell typeother:
Details on mammalian cell type (if applicable)
Chinese hamster lung(CHL/IU) cell
Metabolic activation
with and without
Metabolic activation system
S9 mix: Rat liver, induced with phenobarbital and 5,6- benzoflavone
Test concentrations with justification for top dose
Short-term treatment(+S9 mix): 0, 134.4, 268.8, 537.5, 1075, 2150 μg/mL
Confirmation test: 1200, 1400, 1600, 1800, 2000 μg/mL
Short-term treatment(-S9 mix): 0, 16.8, 33.59, 67.19, 134.4 μg/mL
Confirmation test:80, 90, 100, 110, 120 μg/mL
Cell-growth inhibition test was conducted up to the limited concentration of 4300 μg/mL (10 mM)
Cell growth inhibition (>50%) was observed for short-term treatment at 1075 μg/mL (+S9 mix) and
134.4 μg/mL (-S9mix), and continuous treatment at 67.19 μg/mL (24h) and 33.59 μg/mL (48h).
Vehicle / solvent
DMSO
Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substancecyclophosphamide(with S9 mix)
mitomycin C
18

(without S9 mix)
Details on test system and experimental conditions
METHOD OF APPLICATION: Exposure duration: [short-term treatment]:6 h + 18 h, [continuous t
reatment]: 24h and 48h
NUMBER OF CELLS EVALUATED: 200 cells /concentration (100 cells/plate x 2)
Plates/test: 2
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(-): lessthan 5%, Equivocal(±): 5% or more and less than 10%, Positive(+): 10% or more
Statistics
not used

Results and discussion
Test results
Key result
trueSpecies / strainother: Chinese hamster lung(CHL/IU) cells
Metabolic activation
with and without
Genotoxicity
positive
Cytotoxicity / choice of top concentrations
cytotoxicity at 2000 μg/mL and higher with S9 mix, at 134.4 μg/mL without S9 mix
Vehicle controls validity
valid
Positive controls validity
valid
Additional information on results
In the confirmation tests, Tetraphenyltin(IV) induced structural aberrations with and without S9 mix.
Incidence of structural aberrations were 2.0%, 3.5%, 17.5%, and 52.5 % at 1200, 1400, 1600, and 1800μg/mL with S9 mix, and 0.5%, 1.0%, 0.5%, 6.5%, and 11.0% at 80, 90, 100, 110, and 120 μg/mL without
S9mix. Polyploidy was not observed in any test conditions. Positive and vehicle control groups werevalid.

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF595-90-4f.pdf

Applicant's summary and conclusion
19

Conclusions
Tetraphenyltin(IV) induced structural aberrations with and without S9 mix
Executive summary
In an in vitro chromosomal aberration test using CHL/IU cells (OECD TG 473), positive results wereobtained with or without metabolic activation.

20

Toxicity to reproduction
ENDPOINT_STUDY_RECORD: Toxicity to reproduction.001

UUID: e2e5b6da-25b9-460d-a293-2213b468e32f
Dossier UUID:
Author:Date: 2022-12-16T16:53:52.724+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
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study
Related information
OECD / Repeated dose toxicity: oral / Repeated dose toxicity: oral.001 / Tetraphenyltin(IV) /tetraphenylstannane / 595-90-4

Data source
Reference
A combined repeated dose/reproductive developmental toxicity study of tetraphenyltin by oral adminis /Ministry of Health, Labor and Welfare, Japan / study report
Data accessdata published

Materials and methods
21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
Specific details on test material used for the study- Name of test material (as cited in study report): Tetraphenyltin- Analytical purity: 97.9%- Storage condition of test material: at a cold (temperature 2-6°C) and dark place, with airtight stopper.
- 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., Atsugi Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation: male 388 g (357-421 g), female 243 g (213-278 g)- Housing: Animals were individually housed in bracket-type metallic wire-mesh cages (265W × 426D
× 200H mm) , Dams were bred individually or with individual littermates in polycarbonate cages withflat floors (265W x 426D x 200H mm) and standard bedding.
- Diet: Solid feed (MR stock: Nosan Corporation) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 22±3 (actual temperature: 20.7-24.9°C)- Humidity (%): 55±10% (actual humidity: 45-63%)- Air changes (per hr): >10- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 7:00~19:00)

22

Administration / exposure
Route of administration
oral: gavage
Vehicleolive oil
Details on exposure- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Analytical verification of doses or concentrations
yes
Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating(P)Females: 42-54 days including 14 days premating, mating and gestation periods and the days until
day 4 of lactation
Female (no mating, satellite group): 42 days
Frequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
4

mg/kg bw/day (actual dose received)

Dose / conc.
20

mg/kg bw/day (actual dose received)

Dose / conc.
100

mg/kg bw/day (actual dose received)

Dose / conc.
500

mg/kg bw/day (actual dose received)

No. of animals per sex per dose
Main group:12 animals/sex/dose23Satellite (Recovery) group: 5 males/dose and 5 females/dose (0 and 500 mg/kg bw/day)Control 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 500
mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 4 mg/kg bw/
day was selected as an expected no toxic dose. The middle dose levels of 20 and 100 mg/kg bw/day
were selected.
- Rationale for animal assignment (if not random): Body weight-balanced randomization[14-day preliminary study]
Study 1:
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0 (olive oil), 50, 100, 200, 500 or 100
0 mg/kg bw/day). At 50 mg/kg bw/day or more, treatment rerated effects were observed. High valueof ALT were observed in males 1000 mg/kg bw/day.
Study 2:
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0 (olive oil), 1.5, 3, 6, 12.5, 25 or 50
mg/kg bw/day). Increase in relative liver weights were observed in males at 3 mg/kg bw/day, females
at 6 mg/kg bw/day and 25 mg/kg bw/day or more.

Examinations
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes- Time schedule: 3 times/day (am: before and after administration; pm) during the administration
period. 2 rimes/day (am and pm) during the recovery period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: Once before the start of administration, and once every week by the end of the study
period.
BODY WEIGHT: Yes- Time schedule for examinations:
Males were weighed on Day 1, 7, 14, 21, 28, 35, and 42 of administration, and weighed on Day 7 and
14 of recovery.
Female satellite groups were weighted same frequencies to male recovery groups.
Females in the main groups were weighed on Day 1, 7 and 14 of administration and copulated
females were weighed on Day 0, 7, 14 and 20 of gestation, and days 0 and 4 of lactation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption: Yes
Measurement of food consumption was conducted on all animals at the following frequencies:
Males in the main and recovery groups; on Day 1, 7, 14, 21, 28, 35, and 41 of administration, and on
Day 7 and 13 of recovery.
Female satellite groups were weighted same frequencies to male recovery groups.
Females in the main group; on Day 1, 7 and 14 of administration and copulated females were weighedon Day 0, 7, 14 and 20 of gestation, and days 0 and 3 of lactation.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery
period in both sexes- Anaesthetic used for blood collection: ether
24

- Animals fasted: Yes- How many animals: 5 animals/sex/group- Parameters examined included RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet, ret
iculocyte, PT, APTT, WBC and differential WBC.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery
period in both sexes- Animals fasted: Yes- How many animals: 5 animals/sex/group- Parameters examined included total protein, albumin, A/G ratio, total bilirubin, glucose, total cho
lesterol, triglyceride, phospholipid, AST, ALT, LDH, ChE, ALP, gamma-GTP, BUN, creatinine, Na, K, Cl,
Ca and IP.
URINALYSIS OF MALES: Yes- Time schedule for collection of urine (male only): On Day 37 of administration, and on Day 9 of recovery.
- Metabolism cages used for collection of urine: Yes- How many animals: 5 animals/group- Parameters examined included color, cloudy, urine volume, specific gravity, pH, protein, glucose, ketone body, bilirubin, occult blood and urobilinogen.
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations: On week 6 of the administration period, and on week 2 of therecovery period- Dose groups that were examined: All dose groups (5 animals/sex/group)- Battery of functions tested: sensory activity (hearing reaction, eye sight reaction, sense of touch
reaction, pain reaction, pupil reflex, righting reflex), grip strength, motor activity
Oestrous cyclicity (parental animals)
Vaginal smears were collected from all females in the main groups and microscopically examined
every day from the day after the start of administration until the day copulation was confirmed.
Sperm parameters (parental animals)
Parameters examined in all P male parental generations: testis weight, epididymis weight, histopatho
logical examinations for testes, epididymides, seminal vesicle including coagulating gland 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, weight gain, physicalor behavioral abnormalities.
Postmortem examinations (parental animals)
METHOD OF SACRIFICED: All animals were sacrificed by exsanguination under ether anesthesia.
SACRIFICE: Male animals: On Day 42, Maternal animals: on Day 5 of lactation, and Male recovery andfemale satellite animals: on next Day 14 of recovery.
GROSS PATHOLOGY: Yes
ORGAN WEIBHT: Yes [brain, thymus, heart, liver, kidney, adrenal gland, spleen, seminal vesicle, testis,
epididymis, pituitary, thyroid]
HISTOPATHOLOGY: Yes, [brain, pituitary, spinal cord, thyroid, parathyroid, heart, thymus, trachea,
lung, liver, kidney, adrenal, spleen, stomach, small intestine, large intestine, sciatic nerve, bone, bonemarrow, lymph nodes (mesenteric and cervical lymph nodes), urinary bladder, testis, seminal vesicle,
prostate, epididymis, mammary gland, ovary and uterus.]
25

Postmortem examinations (offspring)
SACRIFICE- The F1 offspring were sacrificed at 4 days of age.
GROSS NECROPSY- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, andabdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS- Not examined.
Statistics
As for parametric data (grip strength, locomotor activity, body weight, body weight gain, food consu
mption, hematology and clinical chemistry data, organ weights, quantitative urinalysis data, numberof corpora lutea, number of implantation sites, number of pups born, number of pups alive, number ofstillborn), the values of means and standard deviations were calculated per group. When more than
three groups exist in the test group, Bartlett test for variance was done, and if the variance was ho
mogenous, ANOVA was applied. If the variance was not homogenous or data was non-parametric(differential WBC percentage, qualitative urinalysis data, stages of spermatogenesis, length of the
estrous cycle, implantation index, delivery index, live birth index, viability index,), Kruskal-Wallis rank s
um test was used. Consequently, if the result was significant, Dunnett multiple comparison or Dunnett typed method was used for detection of statistical significance against control group. When the nu
mber of the test group was two, F-test was used as for parametric data.
Then, student's t-test or Aspin-Welch's t-test was applied depending on the result of homogeneity ofvariance. While, as for non-parametric data, Man-Whitney's U-test was applied. Furthermore, as fo
r categorized data (incidence of abnormal findings in clinical observation, detailed observation, sensory functional examination, necropsy and histopathology, copulation index, fertility index, gestationindex), Fischer's exact test was used. In the histopathological examination findings, Mann-Whitney's
U test was used for graded data, and chi-squared test was used for sex ratio of pups. In any tests,
level of significance was set at 5%.
Reproductive indices
Estrous cycle: Mean days from metestrus I (III) to next III.
Copulation index (%) = (No. of pairs with successful copulation/No. of pairs mated) × 100
Fertility index (%) = (No. of pregnant females/No. of pairs with successful copulation) × 100
Gestation index (%) = (No. of females with live pups/No. of pregnant females) × 100
Implantation index (%) = (No. of implantation sites/No. of corpora lutea) × 100
Delivery index (%) = (No. of pups born/No. of implantation sites) × 100
Live birth index (%) = (No. of live pups on day 0/No. of pups born) × 100
Sex ratio =Total number of male pups/Total number of female pups
Offspring viability indices
Viability index (%) = (No. of live pups on day 4/No. of live pups on day 0) × 100

Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
Clinical signs
no effects observed26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
Haematological findings
no effects observed
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
no effects observed
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

Effect levels (P0)27Key result
true
Dose descriptor
NOAEL
Effect level500

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
other: No effects on reproduction

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

Effect levels (F1)
Key result
true
Dose descriptor
NOAEL
Generation
F1
Effect level500

mg/kg bw/day (actual dose received)

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

Any other information on results incl. tables
28

Figures and Tables (in English) are available in the following full report of the study.
http://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF595-90-4d.pdf

Applicant's summary and conclusion
Executive summary
In the above-described OECD TG 422 study, no effects were observed for reproduction or development.
The NOAEL for rat reproduction/developmental toxicity of tetraphenyltin was estimated to be 500 mg/
kg bw/day (the highest dose tested).

29

DOMAIN
Substance
SUBSTANCE: Tetraphenyltin(IV)UUID: 2bcc0ba6-3b8c-49ce-98d1-aec95545fade
Dossier UUID:
Author:Date: 2022-12-16T16:56:31.588+09:00
Remarks:
Substance name
Tetraphenyltin(IV)Legal entity
National Institute of Health Sciences / Kawasaki / Japan

Identification of substance
Reference substancetetraphenyltin / tetraphenylstannane / 595-90-4 / 209-872-9
EC number

EC name209-872-9

EC Inventory

CAS number

CAS name

595-90-4
IUPAC nametetraphenylstannane

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

30

References
Reference Substances
REFERENCE_SUBSTANCE: tetraphenyltin
UUID: ECB5-45d3e092-7d22-496f-9a88-14707a9fbb48
Dossier UUID:
Author:Date: 2007-05-10T18:00:00.000+09:00
Remarks:
Reference substance nametetraphenyltin
IUPAC nametetraphenylstannane

Inventory
Inventory number
Inventory nametetraphenyltin
Inventory
EC Inventory
Inventory number
209-872-9
CAS number
595-90-4
Molecular formula
C24H20Sn
Description
CAS number
595-90-4

Synonyms
Synonyms
Identity
Stannane, tetraphenylIdentity
Stannane, tetraphenyl-

31

Identity
Stannane, tetraphenyl-

Molecular and structural information
Molecular formula
C24H20Sn
Molecular weight427.1256
SMILES notation
c1ccc(cc1)[Sn](c2ccccc2)(c3ccccc3)c4ccccc4
InChl
InChI=1/4C6H5.Sn/c4*1-2-4-6-5-3-1;/h4*1-5H;/rC24H20Sn/c1-5-13-21(14-6-1)25(22-15-7-2-8-1622,23-17-9-3-10-18-23)24-19-11-4-12-20-24/h1-20H
Structural formula

Related substancesGroup / category information
DSL Category: Organometallics
USEPA Category: Organotins

32

Literatures
LITERATURE: A combined repeated dose/reproductive
developmental toxicity study of tetraphenyltin by oral
administration in rats.
UUID: 1af8d23f-8a61-4114-8149-fa5d07a694a6
Dossier UUID:
Author:Date: 2019-03-22T10:28:19.000+09:00
Remarks:

General information
Reference Typestudy report
Title
A combined repeated dose/reproductive developmental toxicity study of tetraphenyltin by oral
administration in rats.
Author
Ministry of Health, Labor and Welfare, Japan
Bibliographic source
Japan Existing Chemical Data Base (JCDB)
Testing facility
Research institute for animal science in biochemistry and toxicology (RIAS)
Report number
07-11033

LITERATURE: In Vitro Chromosomal Aberration Test of
Tetraphenyltin(IV) on Cultured Chinese Hamster Cells
UUID: 878c6213-6342-4ca1-99a3-7563daf9e0ca
Dossier UUID:
Author:Date: 2019-02-15T15:12:31.000+09:00
Remarks:

General information
Reference Typestudy report
Title
In Vitro Chromosomal Aberration Test of Tetraphenyltin(IV) on Cultured Chinese Hamster Cells
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Bibliographic source
http://dra4.nihs.go.jp/mhlw_data/jsp/SearchPageENG.jsp
Testing facility
BoZo Research Center

34

LITERATURE: Reverse Mutation Test of
Tetraphenyltin(IV)UUID: 61c00801-5ba2-4de0-a22c-287d1168673f
Dossier UUID:
Author:Date: 2019-02-15T14:51:16.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Reverse Mutation Test of Tetraphenyltin(IV)Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Bibliographic source
http://dra4.nihs.go.jp/mhlw_data/jsp/SearchPageENG.jsp
Testing facility
BoZo Research Center

35

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

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

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

Identifiers
Other IT system identifiers
IT system
LEO
ID
10767
IT systemIUCLID436

ID
16558402024DIV750

37