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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Rationale: GLP Guideline study

Data source

Reference
Reference Type:
other: Unpublished data
Title:
Unnamed
Year:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Principles of method if other than guideline:
Method: Other
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 18 and 21 grams
- Fasting period before study: The animals were fasted overnight prior to dosing.
- Housing: group-housed in plastic caging maintained in a controlled environment
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22oC
- Air changes (per hr): 30 air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: corn oil;
Duration of treatment / exposure:
24 hours
Frequency of treatment:
Two single doses administered over 24 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1250, 2500, and 5000 mg/kg (total dose)
Basis:

No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
The concurrent positive control group was given an intraperitoneal injection of mitomycin C at a concentration of 0.4 mg/mL.

Examinations

Tissues and cell types examined:
A direct bone marrow smear from each femur was placed onto a slide and prepared for microscopic analysis to determine the incidence of micronucleated cells per 1000 polychromatic erythrocytes per animal and the ratio of normochromatic to polychromatic erythrocytes (PCE/NCE ratio).
Evaluation criteria:
A material was considered to show evidence of mutagenic activity if it produced a statistically significant increase (p>0.05) using Wilcoxin’s ‘sum or ranks test’) in micronucleated cells compared to the concurrent negative control group values. If the erythrocyte ratios at the top dose were not significantly different from the concurrent negative control values, then the ratios of the two lower doses were not scored.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Additional information on results:
There was no statistically significantly difference between any of the test article treatments and the negative control.

RESULTS OF RANGE-FINDING STUDY
- Dose range: A preliminary range-finding toxicity study was performed prior to the conduct of the definitive assay to determine the maximum tolerated dose (MTD) of the test article. The MTD was designed to produce one or two deaths over the treatment period. From the results of the preliminary test, doses of 0, 1250, 2500, and 5000 mg/kg were used in the main study.

RESULTS OF DEFINITIVE STUDY
- After administration of TPP at 1250 and 2500, no signs of toxicity were observed in either sex. At a dose of 5000 mg/kg, five animals (3 male/2 female) died within 48 hours. Signs of toxicity at this dose included tremors observed 30 minutes after dosing in both males and females. The tremors decreased in severity over the next hour and were not evident after 2 hours. Gross necropsy revealed no remarkable findings. No toxic reactions were observed in the corn oil negative control group or the 4450 mg/kg group in either sex. After administration of mitomycin C, no toxic reactions or mortality were observed in either sex.

Any other information on results incl. tables

 Test Group  PCE/NCE Ratio mean (range)  # micronucle01ed cells/1000 PCE's animal mean (range)
Negative Control  0.1 (0–1)  1.86 (1.15–4.96)
1250 mg/kg TDP  0.2 (0 -1)  
2500 mg/kg TDP  0.2 (0 -1)  
5000 mg/kg TDP  0.2 (0 -1)  1.38 (1.09–1.86)
Mitomycin  27.7 (7 -67)  7.52 (3.24-16.37)
Historical Control * * 0.79 (0.1 -1.8)  0 -5

Historical Control

After administration of TPP at all dosages in both sexes, the group mean number of micronucleated cells per 1000 polychromatic erythrocytes per animal was comparable to the concurrent control value and within the laboratory standard range for negative controls obtained in 18 previous experiments. The PCE/NCE ratio for the test article at 5000 mg/kg in both sexes was comparable to that of the negative corn oil control group.

The mean number of micronucleated cells per 1000 polychromatic erythrocytes per animal for the concurrent positive control group (mitomycin C) was significantly higher than the negative control group. Also, the PCE/NCE for mitomycin C was significantly higher than the negative control group.

Based on the conditions of this study, it was concluded that the test article, TPP, was considered to be negative in both sexes for mutagenic potential and bone marrow toxicity when administered orally.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Based on the conditions of this study, it was concluded that the test article, TPP, was considered to be negative in both sexes for mutagenic potential and bone marrow toxicity when administered orally.
Executive summary:

Based on the conditions of this study, it was concluded that the test article, TPP, was considered to be negative in both sexes for mutagenic potential and bone marrow toxicity when administered orally.