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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented and scientifically acceptable

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991

Materials and methods

Principles of method if other than guideline:
Male and female sprague-Dawley rats were treated by gavage with 300, 600, or 1200 mg Tributyl phosphate/kg body weight which was given as single administration. The high dose level was set at the maximum tolerated dose. Bone marrow cells, arrested in metaphase and collected 12, 24 and 36 hours after treatment, were examined microscopically for structural chromosome aberrations.
GLP compliance:
yes
Type of assay:
mammalian bone marrow chromosome aberration test

Test material

Constituent 1
Chemical structure
Reference substance name:
Tributyl phosphate
EC Number:
204-800-2
EC Name:
Tributyl phosphate
Cas Number:
126-73-8
Molecular formula:
C12H27O4P
IUPAC Name:
tributyl phosphate
Details on test material:
purity: 99.5 +-0.4%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague Dawley Inc., Frederick, MD
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 197 to 241 g (males), 166 to 209 g (females)
- Housing: single housed
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 74+-6 °F
- Humidity (%): 50 +-20%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 1991

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil; 10 mL/kg bw
Details on exposure:
For dose selection, tributyl phosphate was adminstered to male and female rats at 4 treatment levels and a vehicle control: 463, 833, 1500, and 2700 mg/kg bw. Mortality occurred within 2 days after dosing: 2/5 males and 4/5 females receiving 1500 mg/kg bw and 4/5 males and 5/5 males receiving 2700 mg/kg bw. A single dose of 1200 mg/kg bw was estimated to be the maximum tolerated dose.

all rats in the experimental and control groups were weighed immediately prior to dose administration and the dose volume was based in individual body weights. Colchicine, used to arrest dividing cells at metaphase, was administed i.p. at 2.5 mg/kg bw to all rats 2-4 hours prior to sacrifice.
Duration of treatment / exposure:
single administration
Frequency of treatment:
single administration
Post exposure period:
12, 24 or 36 hours
Doses / concentrationsopen allclose all
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
600 mg/kg bw/day (actual dose received)
Dose / conc.:
1 200 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
Cyclophosphamide at 20 mg/kg bw

Examinations

Tissues and cell types examined:
bone marrow cells
Evaluation criteria:
Mitotic index and total number and types of aberrations found in each animal are presented. Gaps are counted but not included in the results.
Statistics:
Fischer's exact test

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Remarks:
1200 mg/kg was the maximum tolerated dose
Vehicle controls validity:
valid
Negative controls validity:
not specified
Positive controls validity:
valid

Any other information on results incl. tables

A reduction in the rate of body weight gain was observed in males and females at 1200 mg/kg bw and in males only at 600 mg/kg bw. One male and 4 females receiving 1200 mg/kg bw died during the study period and were replaced at the time of bone marrow collection with animals from a replacement group which had also been dosed with 1200 mg/kg bw. One male and 1 female died from this replacement group.


The % damaged cells in the total poöulation of cells scored and the number of aberrations per cell for each treatment group are presented for male and female rats in tables 3 and 4 attached. The percentage of damaged cells was not statistically increased in the test article treated animals, regardless of sex, dose or sacrifice time (p>0.05). Cyclophosphamide induced a significant increase in cells containing one or more aberrations (p<0.01). 

Applicant's summary and conclusion

Executive summary:

Male and female sprague-Dawley rats were treated by gavage with 300, 600, or 1200 mg Tributyl phosphate/kg body weight which was given as single administration. The high dose level was set at the maximum tolerated dose established in the toxicity study. Mortality occurred in the high dose group. Bone marrow cells, arrested in metaphase and collected 12, 24 and 36 hours after treatment, were examined microscopically for structural chromosome aberrations.


No statistically significant increases in % aberrant cells were observed in the test item groups. Under the conditions of the assay described in this report, tributyl phosphate, was negative in the acute cytogenetics assay using male and female sprague-Dawley rats.