2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Study conducted using reliable Japanese guidelines

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: In accordance with the "28-day Repeated Dose Toxicity study in Mammalian Species" prescribed in "Notification on Partial Revision of Testing Methods Relating to the New Chemical Substances" published in Notification No. 700 of the planning and Coordinati

Principles of method if other than guideline:

See attached methods

GLP compliance:

yes

Remarks:

The study is conducted in confirmity with "Concerning Testing Facilities Stipulated in article 4 of the Order Prescribing the Item of the test related to the New Chemical Substances" published in Notification No. 233 of the planning and Coordination Burea

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine

EC Number:

426-040-2

EC Name:

2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine

Cas Number:

25713-60-4

Molecular formula:

C 21 H 6 Br 9 N 3 O 3

IUPAC Name:

tris(2,4,6-tribromophenoxy)-1,3,5-triazine

Constituent 2

Reference substance name:

4260402

IUPAC Name:

4260402

Details on test material:

Description: SR-245
Lot No: 691Z18
Supplier: DAI-ICHI KOGYO SEIYAKU CO. LTD
Purity: 100 wt%
Appearence: White powder
Storage conditions: Stored in cold and dark place
Stability: The stability test was conducted in our laboratories, and confirmed that the test substance was stable during dosing period.

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age: 5 weeks old at initiation
weight: Males: 133.4-159.3g Females: 118.6- 135.8g

Housing:
Temp: 23±2°C
RH: 55±10°C
10-15 air changes/hr
Artificial light for 12 hours (between 7:00 and 19:00)
Animals had free access to an MF pelleted diet and chlorinated water. The diet and housing materials were autoclaved at 121°C for 30 minutes prior to use.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: purified water and 0.5% carboxymethylcellulose

Details on oral exposure:

Carboxymethylcellulose Sodium was mixed with with purified water to make 0.5% CMC solution. The test substance weighed accurately and mixed with 0.5% CMC solution to make 10, 2.5, 0.5 and 0.1 w/v% solutions once a week.
treatment by oral gavage was carried out daily using a Nelaton catheter and a syringe in the morning for 28 days, and the subsequent 14 days were used as a recovery period.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The stability of the test substance in the preparations were confirmed by HITA research laboratories.

Duration of treatment / exposure:

Test duration: 28 days+ 14 recovery period

Frequency of treatment:

Once daily for 28 consecutive days

No. of animals per sex per dose:

Male: 6 animals at 0 mg/kg bw/day
Male: 6 animals at 10 mg/kg bw/day
Male: 6 animals at 50 mg/kg bw/day
Male: 6 animals at 250 mg/kg bw/day
Male: 6 animals at 1000 mg/kg bw/day
Female: 6 animals at 0 mg/kg bw/day
Female: 6 animals at 10 mg/kg bw/day
Female: 6 animals at 50 mg/kg bw/day
Female: 6 animals at 250 mg/kg bw/day
Female: 6 animals at 1000 mg/kg bw/day

Details on study design:

The test material was adminstered to 3 groups, each of six male and six female rats, by gavage, for twenty eight consecutive days. A control of six male and six female rats was dosed with vehicle alone.
Two recovery groups, each of six male and six females, were treated with the high dose (1000mg/kg/day) or the vehicle for twenty eight consecutive days and then maintained without treatment for further forteen days.

Positive control:

A control of six male and six female rats was dosed with vehicle alone.

Examinations

Observations and examinations performed and frequency:

Clinical signs, body weight development, food and water consumption were monitored during the study. Haematology, blood Chemistry and urinalysis were evaluated for all non-recovery group animals at the end of the treatment period and for recovery group animals at the end of the
treatment-free period.

Sacrifice and pathology:

All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissus from non-recovery high dose and control animals.

Other examinations:

n/a

Statistics:

See attached file on Statistical analysis

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:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:
No deaths and no abnormalities in body weights, food
consumption and urinalysis were noted.

Laboratory findings:
No treatment-related changes were observed apart from a
non-dose related, statistically significant decrease in
reticulocyte count in females at dose levels 10 mg/kg and
above. No difference was reported in the recovery groups.

Effects in organs:
No treatment-related gross or microscopic findings were
observed.

Effect levels

Dose descriptor:

NOEL

Effect level:

> 1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Haematology:

At the end of the Dosing period:

Male: No abnormalities were noted.

Female: Decreased reticulocytes count in the 10mg/kg/day and higher groups, decreased mean corpuscular hemoglobin in the 50 and 250mg/kg/day groups were noted.

Recovery Period:

Males: No abnormalities were noted.

Females: Increased mean corpuscular volume and mean corpuscular hemoglobin were noted in the 1000mg/kg/day group.

 

The abnormal reticulocytes were considered to have no toxicological significance since it was light decrease and no other related changes were noted.

Blood (clinical) Chemistry:

At the end of the Dosing period:

No abnormalities were noted in both sexes.

Recovery Period:

Males: Decreasedg- GTP was noted in the 1000mg/kg/day group.

Females:Decreased A/G ratio was noted in the 1000mg/kg/day group.

Organ weights:

At the end of the Dosing period:

Male: No abnormalities were noted.

Female: Decreased relative adernal glands weight was noted in the 50mg/kg group.

Recovery Period:

Males: Increased relative liver weight and decreased relative kidney weight were noted in the 1000mg/kg group.

Females: No abnormalities were noted.

Applicant's summary and conclusion

Conclusions:

Clinical signs body weights, food consumption, hematology, blood biochemistry, uranalysis, organ weight, gross pathological reusults and histopathological findings showed no effect of the test substance.
The statistically significant differences noted in hematology, blood chemistry, organ weight, clinical signs, gross pathology and histopathology were not considered treatment related since there was no dose response relationship.
The NOEL was therefore, considered to be > 1000mg/kg/day

Executive summary:

SR-245: 28 DAY REPEATED DOSE ORAL (GAVAGE) TOXICITY STUDY IN RATS

1		TEST SUBSTANCE
1.1Identity		FR-245
1.2CAS number		25713-60-4
2		GUIDELINES AND QUALITY ASSURANCE
2.1 Testing Facility		Hita Research Laboratories, Japan
2.2Guideline followed		In accordance with the "28-day Repeated Dose Toxicity study in Mammalian Species" prescribed in "Notification on Partial Revision of Testing Methods Relating to the New Chemical Substances" published in Notification No. 700 of the planning and Coordination Bureau, EA, No. 1039 of the Pharmaceutical Affairs Bureau, MHW and No. 1014 (1986) of the Basic Industries Bureau, MITI (December 5, 1986).
2.3GLP (Y/N)		The study is conducted in confirmity with "Concerning Testing Facilities Stipulated in article 4 of the Order Prescribing the Item of the test related to the New Chemical Substances" published in Notification No. 233 of the planning and Coordination Bureau, EA, Notification No. 823 (1998) of the basic Industries Bureau, MITI (November 18, 1998).
2.4Year		1990
3		METHODS
3.1 Test Animals
3.1.1Species		Rat
3.1.2 Strain		Crj:CD(SD)
3.1.3 Sex		Males and females
3.1.4 Age/ weight at study initiation		Animals were 5 weeks old at initiation Males: 133.4-159.3g Females: 118.6- 135.8g
3.1.5 Number of animals per test group and control		6 males and 6 females
3.2 Administration/ Exposure
3.2.1 Route of administration		Oral gavage
3.2.2 Duration of test		28 consecutive days + 14 days recovery period
3.2.3 Frequency of exposure		Once daily for28 consecutive days
3.2.4 Concentration levels		10, 50, 250, 1000mg/kg/day,based on a preliminary 14-day range-findinding study
3.2.5 Vehicle		Carboxymethylcellulose sodium (CMC) 0.5% in water
3.2.5 Stability & Homogeneity		The formulation of the test substance in Carboxymethylcellulose sodium was prepared once a week. The stability of the test substance in the preparations were determined .
3.3 Test Design
		The test material was adminstered to 3 groups, each of six male and six female rats, by gavage, for twenty eight consecutive days. A control of six male and six female rats was dosed with vehicle alone.   Two recovery groups, each of six male and six females, were treated with the high dose (1000mg/kg/day) or the vehicle for twenty eight consecutive days and then maintained without treatment for further forteen days.
		Clinical signs, body weight development, food and water consumption were monitored during the study. Haematology, blood Chemistry and urinalysis were evaluated for all non-recovery group animals at the end of the treatment period and for recovery group animals at the end of the treatment-free period. All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissus from non-recovery high dose and control animals.
4		RESULTS
4.1 Mortality		There were no deaths during the study
4.2 Clinical observations		No Clinical abnormalities were attributed to the treatment with FR-245.
4.3 Body weight		At the end of the Dosing period: No abnormalities in body weights were noted in both sexes. Recovery Period: No abnormalities in body weights were noted in both sexes.
4.4 Food consumption		At the end of the Dosing period: No significant changes in food consumption were noted in both sexes during Recovery Period: Males: An increase in food consumption was noted in the 1000mg/kg/day male group at day 11.  Females: No significant changes were noted.
4.5 Haematology		At the end of the Dosing period: Male: No abnormalities were noted. Female: Decreased reticulocytes count in the 10mg/kg/day and higher groups, decreased mean corpuscular hemoglobin in the 50 and 250mg/kg/day groups were noted. Recovery Period: Males: No abnormalities were noted. Females: Increased mean corpuscular volume and mean corpuscular hemoglobin were noted in the 1000mg/kg/day group.   The abnormal reticulocytes were considered to have no toxicological significance since it was light decrease and no other related changes were noted.
4.6 Blood Chemistry		At the end of the Dosing period: No abnormalities were noted in both sexes. Recovery Period: Males: Decreasedg- GTP was noted in the 1000mg/kg/day group. Females:Decreased A/G ratio was noted in the 1000mg/kg/day group.
4.7 Urinalysis		At the end of the Dosing period: No abnormalities were noted in both sexes. Recovery Period: No abnormalities were noted in both sexes.
4.8 Pathology
4.8.1 Organ weights		At the end of the Dosing period: Male: No abnormalities were noted. Female: Decreased relative adernal glands weight was noted in the 50mg/kg group. Recovery Period: Males: Increased relative liver weight and decreased relative kidney weight were noted in the 1000mg/kg group. Females: No abnormalities were noted.
4.8.2 Necropsy		At the end of the Dosing period: No effects were attributed to the treatment with the test substance. Recovery Period: No effects were attributed to the treatment with the test substance.
4.8.3 Histopathology		At the end of the Dosing period No effects were attributed to the treatment with the test substance. Recovery Period: No effects were attributed to the treatment with the test substance.
5		DISCUSSION AND CONCLUSIONS
		Clinical signs body weights, food consumption, hematology, blood biochemistry, uranalysis, organ weight, gross pathological reusults and histopathological findings showed no effect of the test substance. The statistically significant differences noted in hematology, blood chemistry, organ weight, clinical signs, gross pathology and histopathology were not considered treatment related since there was no dose response relationship. The NOEL was therefore, considered to be > 1000mg/kg/day
6		DATA QUALITY
Reliabilties (Klilimisch code)		1