Name: COMPLETE / SUBSTANCE : 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide / 35948-25-5
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Printing date: 2022-12-16T15:07:57.161+09:00

iTable of Contents
0/0 ............................................................................................................................. 1
National Institute of Health Science ..................................................................... 2
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide ............................................................. 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 ......................................................... 13
Genetic toxicity in vitro.001 ................................................ 13
Genetic toxicity in vitro.002 ................................................ 19
73 Toxicity to reproduction ........................................................ 23
Toxicity to reproduction.001 ............................................... 23
DOMAIN .................................................................................................... 33
Substance ......................................................................................... 33
Substance ................................................................................ 33
References ................................................................................................................ 34
Reference Substances ...................................................................................... 34
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide .................................................... 34
Test Materials .................................................................................................. 35
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide .................................................... 35
Literatures ....................................................................................................... 36
Combined repeated dose toxicity study with the reproductive/
developmental toxicity screening test of 6H-dibenz[c,e][1,2]oxaphosphorin
6-oxide by oral administration in rats .......................................................... 36
In Vitro Chromosomal Aberration Test of 6H-dibenz[c,e][1,2]oxaphosphorin
6-oxide on Cultured Chinese Hamster Cells. ................................................ 37
Reverse Mutation Test of 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide on
Bacteria. ................................................................................................... 38
Legal Entities ................................................................................................... 39
National Institute of Health Sciences, Japan .............................................. 39ii

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6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide / 35948-25-5
Public name
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
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LEGAL_ENTITY: National Institute of Health
Science
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General information
Legal entity nameNational Institute of Health Science2

6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
CORE
General information
Assessment approach (assessment entities)
FIXED_RECORD: Assessment approach

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Remarks:3

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

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Administrative data
Endpoint
short-term repeated dose toxicity: oral
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
other: The study was conducted in accordance with Test Guidelines and under GLP
Cross-reference
Reason / purpose for cross-reference
reference to same study 7.8.1 Toxicity to reproduction: Toxicity to reproduction. 001
Related information
OECD / Toxicity to reproduction / Toxicity to reproduction.001 / 6H-dibenz[c,e][1,2]oxaphosphorin 6oxide / 35948-25-5

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 published4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
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
Specific details on test material used for the study- Name of test material (as cited in study report): 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide- Analytical purity: 99.4%- Storage condition of test material: Cold and dark place (3 - 6°C)
- Stability under test conditions: The stability of test material was identified by analysis of the remainder.

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: 384 g (359-409 g), Female: 236 g (212-265 g)- Housing: Animals were individually housed in bracket-type metallic wire-mesh cages (254W × 350D
× 170H mm), from gestation day 17 to lactation day 4, Dams were bred individually or with individual
littermates in plastic cages (340W x 400D x 185H mm) and bedding.
- Diet: Solid feed (NMF: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: 17 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 23±3 (actual temperature: 22-26°C)- Humidity (%): 50±20% (actual humidity: 38-61%)5

- Air changes (per hr): 10-15- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 7:00~19:00)

Administration / exposure
Route of administration
oral: gavage
Vehiclecorn 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
Details on analytical verification of doses or concentrations
Test suspensions at each concentration to be used for males in week 1 and six week of admi
nistration were analyzed by absorption spectrophotometry method at BoZo Research Center Inc.
Results showed that the concentration of test article in each concentration was 102.0 to 105.7% of
the nominal concentration and both values were within the acceptable range (concentration: percent
age of nominal concentration, 100±10%)Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating(P)Females: 41-46 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.
100

mg/kg bw/day (actual dose received)

Dose / conc.
300

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 group: 12 females/dose (0, 100, 300, and 1000 mg/kg bw/day), 7, 12, 12, and 7 males/dose (0,100, 300, and 1000 mg/kg bw/day)6

Satellite group: 5 females/dose (0 and 1000 mg/kg bw/day)Recovery group: 5 males/dose and 5 females (satellite group)/dose (0 and 1000 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 of1000 mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 100 mg/
kg bw/day was selected as an expected no toxic dose. The middle dose levels of 300 mg/kg bw/day
were selected.
[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0, 100, 300 or 1000 mg/kg bw/day).
In the 300 mg/kg bw/day or more, decrease in total protein was observed. In the 1000 mg/kg bw/day,decrease in red blood cell count, hemoglobin and hematocrit value were observed.
- Rationale for animal assignment (if not random): Body weight-balanced randomization

Examinations
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes- Time schedule: 3 times/day (before administration, immediately after administration and 2 hours
after administration) during the administration period. Once a day during the recovery period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Male main and female satellite groups: once before the start of administration, once every weekly
during the administration.
Female main group: once before the start of administration, days 1, 7, 14 and 20 of gestation, and day
4 of lactation.
Male and female recovery groups: once before the start of administration, once every weekly during the administration and recovery periods.
BODY WEIGHT: Yes- Time schedule for examinations:
Males in the main and females satellite groups were weighed on days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32,
36, 39 and 42 of administration and on the day of necropsy, and males and females in the recovery
groups were weighed on days 1, 4, 8, 11 and 14 of recovery and on the day of necropsy in addition to
the measurement days for males in the main groups.
Females in the main groups were weighed on days 1, 4, 8, 11 and 15 of administration (uncopulated
animals were weighed on days 18 and 22 of administration as well), days 0, 4, 7, 11, 14, 17 and 20 of
gestation, days 0 and 4 of lactation and the day of necropsy.
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 females satellite groups on days 1, 4, 8, 11, 15, 32, 36, 39 and 42 of admini
stration; males and females in the recovery groups on days 1, 4, 8, 11 and 14 of recovery in addition to
the measurement days for males in the main groups; and females in the main groups on days 1, 4, 8,
11 and 15 of administration, days 1, 4, 7, 11, 14, 17 and 20 of gestation and days 2 and 4 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 sexes7

- Anaesthetic used for blood collection: ether- Animals fasted: Yes- How many animals:
All animals/sex/group (Control and 1000 mg/kg/day),5 animals/sex/group (100 and 300 mg/kg/day)- Parameters examined: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume,
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte percentage, platelet count, white blood cell count, differential white blood cell count, absolute number of each
white blood cell, prothrombin time, activated partial thromboplastin time, fibrinogen.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery p
eriod in both sexes- Animals fasted: Yes- How many animals:
All animals/sex/group (Control and 1000 mg/kg/day),5 animals/sex/group (100 and 300 mg/kg/day)- Parameters checked: ALP, total cholesterol, triglyceride, phospholipids, total bilirubin, glucose, bloodurea nitrogen, creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, al
bumin, A/G ratio, AST (GOT), ALT (GPT), LDH, γ-GTP
URINALYSIS: Yes- Time schedule for collection of urine: final week of administration (days 36 to 37 of administration)and in the final week of recovery (days 8 to 9 of recovery)- Metabolism cages used for collection of urine: Yes
A urine collector to collect four-hour urine samples under fasting but ad libitum drinking conditions, fo
llowed by collection of 20-hour urine samples under ad libitum feeding and drinking conditions.
- How many animals: 5 animals/group- Parameters checked: pH, protein, ketones, glucose, occult blood, bilirubin, urobilinogen, color,
sediment, urine volume (4-hour volume), osmotic pressure, urine volume (20-hour volume), water intake (24-hour volume)
BLOOD HORMONE: Yes- Time schedule for collection of serum: Same as clinical chemistry- Animals fasted: Yes- How many animals:
All animals/sex/group (Control and 1000 mg/kg/day),5 animals/sex/group (100 and 300 mg/kg/day)- Parameters checked: Triiodothyronine (T3), Thyroxin (T4), and thyroid stimulating hormone (TSH)
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations:
Males in the main groups: final week of administration (day 40 of administration)
Females in the main groups: lactation day 4 (day 42 to day 44 of administration) after necropsy of F1
pups
Males and females in the recovery groups: final week of administration (day 40 of administration) andin the final week of recovery (day 12 of recovery).
- Dose groups that were examined: All dose groups (5 animals/sex/group)- Battery of functions tested:
1) Manipulative Test. Auditory response, approach response, touch response, tail pinch response, pu
pillary reflex, aerial righting reflex, landing foot splay
2) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb
was measured by CPU gauge MODEL-RX-5 (AIKOH Engineering Co., Ltd.).
3) Measurement of Motor Activity. Following measurement of grip strength, motor activity wasmeasured by a motor activity sensor for experimental animals NS-AS01 (Neuro Science, Inc). The me
asurement was conducted for 1 hour, and measured values at 10-minute intervals and from 0 to 60
minutes were collected.
Sacrifice and pathology
GROSS PATHOLOGY: Yes
8

ORGAN WEIBHT: Yes [brain, pituitary, thyroids (including parathyroids), adrenal gland, thymus, spleen,
heart, liver, kidney, testis, epididymis, ovary, uterus]
HISTOPATHOLOGY: Yes, [cerebrum, cerebellum (including pons) , pituitary, spinal cord (thoracic), sc
iatic nerve, eye ball, thyroid, parathyroid, adrenal glands, thymus, spleen, submandibular lymph nod
es, mesenteric lymph nodes, heart, trachea, lung (including bronchial), stomach, duodenum, jejunum,
ileum, cecum, colon, rectum, liver, kidney, bladder, testis, epididymis, ovary, uterus, vagina, prostate,seminal vesicles, sternum and femur (including bone marrows),and macroscopic lesions]
Statistics
The data were analyzed for homogeneity of variance by the Bartlett test. If variances were
homogeneous, data was analyzed by the Dunnett test, whereas heterogeneous data was analyzed by
the Dunnett type mean rank test (p<0.05, two-sided).
In the recovery test, these values of two groups were analyzed by F test. If variances were homogeneo
us, data was analyzed by the Student t-test, whereas heterogeneous data was analyzed by the AspinWelch t-test (p<0.05, two-sided).

Results and discussion
Results of examinations
Clinical signs
no effects observed
Mortality
no mortality observed
Body weight and weight changes
effects observed, treatment-related
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
Description (incidence and severity)
Including blood hormones (T3, T4, TSH)
Urinalysis findings
no effects observed
Behaviour (functional findings)
no effects observed
Immunological findings
not examined
9Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Gross pathological findings
effects observed, treatment-related
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
effects observed, treatment-related
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 in any groups at the dosing andrecovery periods.
DETAILED CLINICAL OBSERVATIONS: There were no changes related to the test substance in anygroups at the dosing and recovery periods.
BODY WEIGHT:
A decrease in body weight gain was observed from the second week of administration in males
receiving 1000 mg/kg bw/day.
Slight decrease in body weight gain was observed during pregnancy in mating females receiving 1000
mg/kg bw/day.
FOOD CONSUMPTION:
There were no changes related to the test substance in any groups at the dosing and recovery pe
riods.
URINALYSIS:There were no changes related to the test substance in any groups at the dosing and recovery periods.
NEUROBEHAVOURAL EXAMINATION: There were no changes related to the test substance in anygroups at the dosing and recovery periods.
HAEMATOLOGY:
There were no changes related to the test substance in any groups at the end of dosing and recovery
periods.
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.
ORGAN WEIGHTS:[At the end of dosing period]:
Decreases in absolute and relative weights of thymus were observed in non-mating females receiving
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:[At the end of dosing period]:
Forestomach: Focus raised region and focus dark red region were observed in mating females receiving 100 mg/kg bw/day and above, and in males receiving 300 mg/kg bw/day and above. Thi
10ckening of limiting ridge was observed in mating and non-mating females receiving 1000 mg/kg bw/
day.
[At the end of recovery period]: There were no changes related to the test substance in any groups.
HISTOPATHOLOGY: NON-NEOPLASTIC:[At the end of dosing period]:
Forestomach: Erosion/ulcer and edema of mucosal/submucosal were observed in mating females
receiving 100 mg/kg bw/day and above and in males receiving 300 mg/kg bw/day and above. Hyperp
lasia of squamous cells were observed in males and mating females receiving 100 mg/kg bw/day andabove. Degeneration/necrosis of squamous cells were observed in males receiving 100 mg/kg bw/
day and above and in mating females receiving 300 mg/kg bw/day and above. These findings werealso observed in non-mating females receiving 1000 mg/kg bw/day.
Cecum: Single cell necrosis and diffuse hyperplasia of mucosa were observed in males and mating
females receiving 300 mg/kg bw/day. These findings were also observed in non-mating females receiving 1000 mg/kg bw/day.
[At the end of recovery period]:
Cecum: Single cell necrosis and diffuse hyperplasia of mucosa were persisted in males receiving
1000 mg/kg bw/day, but to a lesser degree.

Effect levels
Key result
true
Dose descriptor
LOAEL
Effect level100

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
histopathology: non-neoplastic
Forestomach legions were observed in males and females receiving 100 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/PDF35948-25-5d.pdf

Applicant's summary and conclusion
Conclusions
Based on the effects of 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide on the stomach, the LOAEL for
repeated oral dosing was determined to be 100 mg/kg bw/day.
11

Executive summary
A combined repeated-dose toxicity study with the reproduction/developmental toxicity screening test
was done according to OECD TG 422. Male and female rats (12 animals/sex/dose) were administeredwith 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide via oral gavage at doses of 0 [vehicle: corn oil], 100, 300,
and 1,000 mg/kg bw/day. Males (12/dose) were then treated with 6H-dibenz[c,e][1,2]oxaphosphorin
6-oxide for 42 days, which include a 14-day premating period and a subsequent mating period, whilefemales (12/dose) were treated for 41–46 days, which include a 14-day premating, mating and gestation
periods until lactation day 4. Among the 12 males administered with 0 and 1,000 mg/kg bw/day, 5were assigned as recovery group. Additional 10 females treated with 0 and 1,000 mg/kg bw/day wereassigned as a satellite group and treated with 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide for 42 days,
with no mating, and examined after a 14-day recovery period.
No deaths were recorded, and no changes in clinical signs, manipulative test, grip strength, motor
activity, body weight, food consumption, urinalysis, hematology, blood chemistry as a result of treatment
in any of the dose groups for both males and females at the end of the treatment and recovery periods.
There was a decrease in body weight gain in males receiving 1,000 mg/kg bw/day after 2 weeks ofadministration, and a statistically significant decreased body weight gain was observed in the matinggroup females receiving 1,000 mg/kg bw/day in the gestation period. The absolute and relative weightsof the thymus were significantly decreased in the satellite group females receiving 1,000 mg/kg bw/day
at the end of the administration period. In the gross pathological examination of males receiving ≥300
mg/kg bw/day, a raised and dark red forestomach was seen. Additionally, there was thickening of thelimiting ridge of the forestomach in females receiving 100 mg/kg bw/day at the end of the administration
period. Histopathological findings show an erosion/ulcer and edema in the mucosa/submucosa of theforestomach in females receiving 100 mg/kg bw/day and both males and females receiving ≥300 mg/
kg bw/day, and degeneration/necrosis of squamous cells of the forestomach was indicated in males
receiving 100 mg/kg bw/day and both males and females receiving ≥300 mg/kg bw/day. There was alsoa hyperplasia of squamous cells of the forestomach in both males and females at ≥100 mg/kg bw/day.
These histopathological findings in the forestomach mean that there is a mucosal irritation by the test
substance. Single-cell necrosis and diffuse hyperplasia of cecum mucosa were seen in both males andfemales at ≥300 mg/kg bw/day. Since the changes observed in the organ weight and histopathologicalexamination were lessened or disappeared at the end of the recovery period, they are thought to bereversible. With these effects of the forestomach at 100 mg/kg bw/day in males and females, the NOAEL
for repeated-dose toxicity of 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide was 100 mg/kg bw/day in rats.

12

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

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Dossier UUID:
Author:Date: 2022-12-14T15:04:48.110+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 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide on Bacteria. / 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)
in vitro gene mutation study in bacteria
13

Deviationsno
GLP compliance
yesType of assay
bacterial reverse mutation assay
in vitro gene mutation study in bacteria

Test material
Test material information
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
Specific details on test material used for the study
Purity 99.4%

MethodSpecies / strain
Species / strain / cell typeS. typhimurium TA 1535, TA 1537, TA 98 and TA 100
bacteria
Species / strain / cell type
E. coli WP2 uvr A pKM 101
bacteria
Metabolic activation
with and without
Metabolic activation system
S9 mix; SD male rat liver, induced by phenobarbital and 5,6-benzoflavone
Test concentrations with justification for top dose
-S9 mix:
156, 313, 625, 1250, 2500, 5000 μg/plate (TA100, TA1535, TA98 strains)
39.1, 78.1, 156, 313, 625, 1250 μg/plate (TA1537 strain)
156, 313, 625, 1250, 2500, 5000 μg/plate (WP2uvrA/pKM101 strain)+S9 mix:
313, 625, 1250, 2500, 5000 μg/plate (TA100, TA98 strains)
156, 313, 625, 1250, 2500, 5000 μg/plate (TA1535, TA1537 strains)
313, 625, 1250, 2500, 5000 μg/plate (WP2uvrA/pKM101 strain)
Maximum concentration was established based on the result of the preliminary test at concentration
up to 5000 ug/plate. In this test, the growth inhibition was observed at 1250 μg/plate and above for S.
typhimurium TA1537 without S9 mix, at 5000 μg/plate for S. typhimurium TA100, TA1535, TA 98, andE. coli WP2 uvrA without S9 mix, and S. typhimurium TA 1535 and TA1537 with S9 mix.
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
Controls
Untreated negative controlsno14

Negative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceother: -S9 mix: 2-(2-Furyl)-3-(5-nitro-2-furyl) acrylamide, sodium azide and 2-Methoxy-6-chloro-9-[3-(2chloroethyl)-aminopropylamino]acridine 2HCl; +S9 mix: 2-aminoanthracene, benzo(a)pyrene
Details on test system and experimental conditions
METHOD OF APPLICATION: Preincubation
DURATION- Preincubation period: 20 min at 37°C
- Exposure duration:48 or 49 hrs
NUMBER OF PLATES: 3
NUMBER OF REPLICATIONS: 2
DETERMINATION OF CYTOTOXICITY- Method: other: growth inhibition
Evaluation criteria
A chemical was judged to be mutagenic when the mean number of revertant colonies per plateincreased more than twice that of the negative control and when the dose-related and reproducible increase was observed.
StatisticsnoResults and discussion
Test results
Key result
trueSpecies / strain
S. typhimurium TA 1535
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 5000 μg/plate; +S9 mix: 5000 μg/plate
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid

15

Key result
trueSpecies / strain
S. typhimurium TA 1537
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 1250 μg/plate; +S9 mix: 2500 μg/plate or more
Vehicle controls validity
valid
Untreated negative controls validity
not examined
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
cytotoxicity -S9 mix: 5000 μg/plate
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 100
bacteria
Metabolic activation
with and without
16

Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 2500 μg/plate or more (test 2: 5000 μg/plate)
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validity
valid
Key result
trueSpecies / strain
E. coli WP2 uvr A pKM 101
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 5000 μg/plate
Vehicle controls validity
valid
Untreated negative controls validity
not examined
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.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF35948-25-5e.pdf
Please also see the attached files (Tables in English)

Overall remarks, attachments
Attachments
Attached (sanitised) documents for publication
35948-25-5_Ames.xlsx / 34.77 KB (application/vnd.openxmlformatsofficedocument.spreadsheetml.sheet)

Applicant's summary and conclusion
17

Conclusions
Interpretation of results (migrated information): negative
In a bacterial reverse mutation assay using Salmonella typhimurium TA100, TA1535, TA98, and TA
1537, and Escherichia coli WP2uvrA/pKM101 (OECD TG 471), 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxi
de was negative with or without metabolic activation.
.

18

ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.002

UUID: 4a40f69a-43f6-4948-8da2-6d606b8c0219
Dossier UUID:
Author:Date: 2019-12-19T11:53:31.000+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
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 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide on Cultured
Chinese / 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
no19

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
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
Specific details on test material used for the study
Purity 99.4%

MethodSpecies / strain
Species / strain / cell typeother: Chinese hamster lung(CHL/IU) cells
Metabolic activation
with and without
Metabolic activation system
S9 mix; SD male rat liver, induced by phenobarbital and 5,6-benzoflavone
Test concentrations with justification for top dose
Cell growth inhibition study-S9 mix (short-term treatment): 17.2, 34.4, 68.8, 138, 275, 550, 1100, 2200 ug/mL (IC50=1457.5 ug/
mL)+S9 mix (short-term treatment): 17.2, 34.4, 68.8, 138, 275, 550, 1100, 2200 ug/mL (IC50=1200.0 ug/m
L)
-S9 mix (continuous treatment, 24hr): 17.2, 34.4, 68.8, 138, 275, 550, 1100, 2200 ug/mL (IC50=902.0
ug/mL)-S9 mix (continuous treatment, 48hr): 17.2, 34.4, 68.8, 138, 275, 550, 1100, 2200 ug/m L (IC50=811.9
ug/mL)
Main study-S9 (short-term treatment): 275, 550, 1100, 2200 ug/mL+S9 (short-term treatment): 275, 550, 1100, 2200 ug/mL-S9 (continuous treatment, 24hr): 275, 550, 1100, 2200 ug/mL-S9 (continuous treatment, 48hr): 275, 550, 1100, 2200 ug/mL

Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
20

Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceother: [-S9]: mitomycin C; [+S9]: cyclophosphamide
Details on test system and experimental conditions
METHOD OF APPLICATION: Exposure duration: [short-term treatment]:6 hrs + 18 hr, [continuous
treatment]: 24, 48 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(±): 5% or more and less than 10%, Positive(+): 10% or more
StatisticsnoResults and discussion
Test results
Key result
trueSpecies / strainother: Chinese hamster lung (CHL/IU) cells
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity
Vehicle controls validity
valid
Untreated negative controls validity
not examined
21

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/PDF35948-25-5f.pdf

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

22

Toxicity to reproduction
ENDPOINT_STUDY_RECORD: Toxicity to reproduction.001

UUID: f41cabd7-dc43-4c7d-baff-ade412356203
Dossier UUID:
Author:Date: 2020-10-01T12:14:04.000+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
other: OECD Test Guideline study under GLP condition
Cross-reference
Reason / purpose for cross-reference
reference to same study 7.5.1 Repeated dose toxicity: oral: Repeated dose toxicity: oral. 001
Related information
OECD / Repeated dose toxicity: oral / Repeated dose toxicity: oral.001 / 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide / 35948-25-5

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
23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
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
Specific details on test material used for the study- Name of test material (as cited in study report): 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide- Analytical purity: 99.4%- Storage condition of test material: Cold and dark place (3 - 6°C)
- Stability under test conditions: The stability of test material was identified by analysis of the remainder.

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: 384 g (359-409 g), Female: 236 g (212-265 g)- Housing: Animals were individually housed in bracket-type metallic wire-mesh cages (254W × 350D
× 170H mm), from gestation day 17 to lactation day 4, Dams were bred individually or with individual
littermates in plastic cages (340W x 400D x 185H mm) and bedding.
- Diet: Solid feed (NMF: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: 19 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 23±3 (actual temperature: 22-26°C)- Humidity (%): 50±20% (actual humidity: 38-61%)- Air changes (per hr): 10-15- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 7:00~19:00)

24

Administration / exposure
Route of administration
oral: gavage
Vehiclecorn oil
Details on exposure- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Details on mating procedure- M/F ratio per cage:1/1- Length of cohabitation: up to 5 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
Test suspensions at each concentration to be used for males in week 1 and six week of admi
nistration were analyzed by absorption spectrophotometry method at BoZo Research Center Inc.
Results showed that the concentration of test article in each concentration was 102.0 to 105.7% of
the nominal concentration and both values were within the acceptable range (concentration: percent
age of nominal concentration, 100±10%)Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating(P)Females: 41-46 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.
100

mg/kg bw/day (actual dose received)

Dose / conc.
300

mg/kg bw/day (actual dose received)

Dose / conc.
1000

mg/kg bw/day (actual dose received)

25

No. of animals per sex per dose
Main group:12 females/dose (0, 100, 300, and 1000 mg/kg bw/day), 7, 12, 12, and 7 males/dose (0,100, 300, and 1000 mg/kg bw/day)Satellite group: 5 females/dose (0 and 1000 mg/kg bw/day)Recovery group: 5 males/dose and 5 females (satellite group)/dose (0 and 1000 mg/kg bw/day)Control animals
yes, concurrent no treatment
Details on study design- Dose selection rationale: Based on the results of a 14-day preliminary study, the highest dose of1000 mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 100 mg/
kg bw/day was selected as an expected no toxic dose. The middle dose levels of 300 mg/kg bw/day
were selected.
[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0, 100, 300 or 1000 mg/kg bw/day).
In the 300 mg/kg bw/day or more, decrease in total protein was observed. In the 1000 mg/kg bw/day,decrease in red blood cell count, hemoglobin and hematocrit value were observed.
- Rationale for animal assignment (if not random): Body weight-balanced randomization

Examinations
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes- Time schedule: 3 times/day (before administration, immediately after administration and 2 hours
after administration) during the administration period. Once a day during the recovery period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Male main and female satellite groups: once before the start of administration, once every weekly
during the administration.
Female main group: once before the start of administration, days 1, 7, 14 and 20 of gestation, and day
4 of lactation.
Male and female recovery groups: once before the start of administration, once every weekly during the administration and recovery periods.
BODY WEIGHT: Yes- Time schedule for examinations:
Males in the main and females satellite groups were weighed on days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32,
36, 39 and 42 of administration and on the day of necropsy, and males and females in the recovery
groups were weighed on days 1, 4, 8, 11 and 14 of recovery and on the day of necropsy in addition to
the measurement days for males in the main groups.
Females in the main groups were weighed on days 1, 4, 8, 11 and 15 of administration (uncopulated
animals were weighed on days 18 and 22 of administration as well), days 0, 4, 7, 11, 14, 17 and 20 of
gestation, days 0 and 4 of lactation and the day of necropsy.
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 females satellite groups on days 1, 4, 8, 11, 15, 32, 36, 39 and 42 of admini
stration; males and females in the recovery groups on days 1, 4, 8, 11 and 14 of recovery in addition to
the measurement days for males in the main groups; and females in the main groups on days 1, 4, 8,
11 and 15 of administration, days 1, 4, 7, 11, 14, 17 and 20 of gestation and days 2 and 4 of lactation.
OPHTHALMOSCOPIC EXAMINATION: No
26

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- Animals fasted: Yes- How many animals:
All animals/sex/group (Control and 1000 mg/kg/day),5 animals/sex/group (100 and 300 mg/kg/day)- Parameters examined: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume,
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte percentage, platelet count, white blood cell count, differential white blood cell count, absolute number of each
white blood cell, prothrombin time, activated partial thromboplastin time, fibrinogen.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery p
eriod in both sexes- Animals fasted: Yes- How many animals:
All animals/sex/group (Control and 1000 mg/kg/day),5 animals/sex/group (100 and 300 mg/kg/day)- Parameters checked: ALP, total cholesterol, triglyceride, phospholipids, total bilirubin, glucose, bloodurea nitrogen, creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, al
bumin, A/G ratio, AST (GOT), ALT (GPT), LDH, γ-GTP
URINALYSIS: Yes- Time schedule for collection of urine: final week of administration (days 36 to 37 of administration)and in the final week of recovery (days 8 to 9 of recovery)- Metabolism cages used for collection of urine: Yes
A urine collector to collect four-hour urine samples under fasting but ad libitum drinking conditions, fo
llowed by collection of 20-hour urine samples under ad libitum feeding and drinking conditions.
- How many animals: 5 animals/group- Parameters checked: pH, protein, ketones, glucose, occult blood, bilirubin, urobilinogen, color,
sediment, urine volume (4-hour volume), osmotic pressure, urine volume (20-hour volume), water intake (24-hour volume)
BLOOD HORMONE: Yes- Time schedule for collection of serum: Same as clinical chemistry- Animals fasted: Yes- How many animals:
All animals/sex/group (Control and 1000 mg/kg/day),5 animals/sex/group (100 and 300 mg/kg/day)- Parameters checked: Triiodothyronine (T3), Thyroxin (T4), and thyroid stimulating hormone (TSH)
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations:
Males in the main groups: final week of administration (day 40 of administration)
Females in the main groups: lactation day 4 (day 42 to day 44 of administration) after necropsy of F1
pups
Males and females in the recovery groups: final week of administration (day 40 of administration) andin the final week of recovery (day 12 of recovery).
- Dose groups that were examined: All dose groups (5 animals/sex/group)- Battery of functions tested:
1) Manipulative Test. Auditory response, approach response, touch response, tail pinch response, pu
pillary reflex, aerial righting reflex, landing foot splay
2) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb
was measured by CPU gauge MODEL-RX-5 (AIKOH Engineering Co., Ltd.).
3) Measurement of Motor Activity. Following measurement of grip strength, motor activity wasmeasured by a motor activity sensor for experimental animals NS-AS01 (Neuro Science, Inc). The me27

asurement was conducted for 1 hour, and measured values at 10-minute intervals and from 0 to 60
minutes were collected.
Oestrous cyclicity (parental animals)
Vaginal smears were collected from all females in the main groups and microscopically examined
every day from the day after the start of administration until the day copulation was confirmed.
During the pre-mating administration period, vaginal smear pictures were classified as proestrus,
estrus, metestrus or diestrus and examined for the frequency of estrus and interval between estruses(estrous cycle). During the mating period, vaginal smears were examined for the presence of sperm.
Sperm parameters (parental animals)
Parameters examined in all P male parental generations: testis weight, epididymis weight, histopatho
logical 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 ether anesthesia.
SACRIFICE: Male main and female satellite animals: On next day after the last administration (Day43), Maternal animals: on Day 4 of lactation, and male and females recovery animals: on Day 14 of recovery.
GROSS PATHOLOGY: Yes
ORGAN WEIBHT: Yes [brain, pituitary, thyroids (including parathyroids), adrenal gland, thymus, spleen,
heart, liver, kidney, testis, epididymis, ovary, uterus]
HISTOPATHOLOGY: Yes, [cerebrum, cerebellum (including pons) , pituitary, spinal cord (thoracic), scia
tic nerve, eye ball, thyroid, parathyroid, adrenal glands, thymus, spleen, submandibular lymph nodes, mesenteric lymph nodes, heart, trachea, lung (including bronchial), stomach, duodenum, jejunum,
ileum, cecum, colon, rectum, liver, kidney, bladder, testis, epididymis, ovary, uterus, vagina, prostate,seminal vesicles, sternum and femur (including bone marrows),and macroscopic lesions]
Postmortem examinations (offspring)
SACRIFICE- The F1 offsprings were euthanized on PND4 by exsanguination under ether anesthesia.
GROSS NECROPSY: Yes- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, andabdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS- Not examined.
Statistics
The data were analyzed for homogeneity of variance by the Bartlett test. If variances were
homogeneous, data was analyzed by the Dunnett test, whereas heterogeneous data was analyzed by
the Dunnett type mean rank test (p<0.05, two-sided).
In the recovery test, these values of two groups were analyzed by F test. If variances were homogeneo
us, data was analyzed by the Student t-test, whereas heterogeneous data was analyzed by the AspinWelch t-test (p<0.05, two-sided).
Reproductive indices
Each parameter was determined by the following equations:
Copulation index (%) = (No. of copulated animals / No. of mated animals) × 100
Fertility index (%) = (No. of pregnant females / No. of copulated females) × 100
Insemination index (%) = (No. of impregnated males / No. of copulated males) × 100
Gestation length (days) = No. of days from pregnancy 0 to delivery 0
Delivery index (%) = (No. of females which delivered liveborns / No. of pregnant females) × 100
28

Implantation index (%) = (No. of implantation sites / No. of corpora lutea) × 100
Stillborn index (%) = (No. of stillborn / No of liveborns and stillborns) × 100
Live birth index (%) = (No. of liveborn / No. of implantation sites) × 100
External abnormalities (%) = (No. of pups with external abnormalities / No. of liveborns) × 100
Sex ratio = No. of liveborns males / No. of liveborns
Offspring viability indices
Viability index on postnatal day 4 (%) = (No. of live pups on day 4 / No. of liveborns on day 0) × 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
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1
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
Description (incidence and severity)
Including blood hormones (T3, T4, TSH)
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-related29

Description (incidence and severity)
See 7.5.1
Gross pathological findings
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1
Histopathological findings: neoplastic
not examined

Reproductive function / performance (P0)
Reproductive function: oestrous cycle
no effects observed
Reproductive function: sperm measures
not examined
Reproductive performanceno effects observed

Details on results (P0)1) Estrous Cycle
There were no animals showing abnormal estrous cycles, and there were no significant differences in
the average length of the estrous cycle between the control group and any treatment groups.
2) Results of Mating
There were no significant differences in the incidence of females with irregular estrus cycle, mating
period with the number of estrus and day of conceiving, copulation index, and fertility index between
the control group and any treatment groups.
3) Delivery Data and Delivery
There were no significant differences in the gestation length, number of corpora lutea, number of imp
lantation sites, implantation index, and delivery index between the control group and any treatmentgroups.
Body weight and weight changes
See 7.5.1
Organ weight findings
See 7.5.1
Gross pathological findings
See 7.5.1
Histopathological findings
See 7.5.1

Effect levels (P0)30Key result
true
Dose descriptor
NOAEL
Effect level1000

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 level1000

mg/kg bw/day (actual dose received)

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

Overall reproductive toxicity
31

Key result
true
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/PDF35948-25-5d.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), there were no effects on reproductive and developmental parameters up to
1000 mg/kg bw/day. The NOAEL for the rat reproductive/developmental toxicity of 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide was regarded as 1000 mg/kg bw/day, the highest dose tested.
Executive summary
A combined repeated-dose toxicity study with the reproduction/developmental toxicity screening test
was done according to OECD TG 422. Male and female rats (12 animals/sex/dose) were administeredwith 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide via oral gavage at doses of 0 [vehicle: corn oil], 100, 300,
and 1,000 mg/kg bw/day. Males (12/dose) were then treated with 6H-dibenz[c,e][1,2]oxaphosphorin
6-oxide for 42 days, which include a 14-day premating period and a subsequent mating period, whilefemales (12/dose) were treated for 41–46 days, which include a 14-day premating, mating and gestation
periods until lactation day 4. Among the 12 males administered with 0 and 1,000 mg/kg bw/day, 5were assigned as recovery group. Additional 10 females treated with 0 and 1,000 mg/kg bw/day wereassigned as a satellite group and treated with 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide for 42 days,
with no mating, and examined after a 14-day recovery period.
No effects on reproductive toxicity (fertility and reproductive organs) and developmental toxicity up to
the highest dose were recorded.Since the effects were not even observed at 1,000 mg/kg bw/day,the
NOAEL for the reproduction and development toxicity was 1,000 mg/kg bw/dayin rats.

32

DOMAIN
Substance
SUBSTANCE: 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
UUID: adb0411e-4315-4747-be09-3ca5483be250
Dossier UUID:
Author:Date: 2022-12-16T15:07:46.267+09:00
Remarks:
Substance name
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
Public name
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
Legal entity
National Institute of Health Sciences, Japan
Contact persons

Identification of substance
Reference substance
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide / 35948-25-5
EC number

EC name

CAS number

CAS name

35948-25-5
IUPAC nameRole in the supply chain
Manufacturer
false
Importer
false
Only representativefalse
Downstream user
false

33

References
Reference Substances
REFERENCE_SUBSTANCE: 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
UUID: 08514a60-3c3a-450d-a41f-2ead8f0631a6
Dossier UUID:
Author:Date: 2019-12-19T11:26:29.000+09:00
Remarks:
Reference substance name
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide

Inventory
CAS number
35948-25-5

Synonyms
Synonyms
Identifier
EC name
Identity
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
Identifier
EC number
Identity
252-813-7

34

Test Materials
TEST_MATERIAL_INFORMATION: 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide
UUID: b3f2f291-72fd-45df-b3b7-59d132f039da
Dossier UUID:
Author:Date: 2019-12-19T11:36:43.000+09:00
Remarks:
Name
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide35Literatures
LITERATURE: Combined repeated dose toxicity study
with the reproductive/developmental toxicity screening
test of 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide by oral
administration in rats
UUID: 87fb1591-7111-41f5-a1a3-064c2272fdcc
Dossier UUID:
Author:Date: 2020-03-24T10:22:29.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Combined repeated dose toxicity study with the reproductive/developmental toxicity screening test of
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide 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/PDF35948-25-5d.pdf
Testing facility
BoZo Research Center
Report number
R-105036

LITERATURE: In Vitro Chromosomal Aberration Test of
6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide on Cultured
Chinese Hamster Cells.
UUID: 9ce1f33e-43a6-47e7-9568-b4a6bd2072da
Dossier UUID:
Author:Date: 2020-03-17T15:53:44.000+09:00
Remarks:

General information
Reference Typestudy report
Title
In Vitro Chromosomal Aberration Test of 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide on Cultured
Chinese Hamster Cells.
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF3
5948-25-5f.pdf
Testing facility
Bozo Research Center Inc.
Report number
M-140637

LITERATURE: Reverse Mutation Test of 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide on Bacteria.
UUID: 174bb4bd-0c13-4e59-9957-9ecac2937682
Dossier UUID:
Author:Date: 2020-03-17T16:05:23.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Reverse Mutation Test of 6H-dibenz[c,e][1,2]oxaphosphorin 6-oxide on Bacteria.
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF35
948-25-5e.pdf
Testing facility
Bozo Research Center Inc.
Report number
T-046538

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

General information
Legal entity nameNational Institute of Health Sciences, Japan

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