Triisodecyl phosphite

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Remarks:

Type of genotoxicity: gene mutation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

other: unpublished report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

Deviations:

not specified

Principles of method if other than guideline:

No further information available.

GLP compliance:

yes

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

Triisodecyl phosphite

EC Number:

246-998-3

EC Name:

Triisodecyl phosphite

Cas Number:

25448-25-3

Molecular formula:

C30H63O3P

IUPAC Name:

tris(2-methylnonyl) phosphite

Details on test material:

- Name of test material (as cited in study report): Triisodecyl phosphite - Commercial, purity: > 97% (Phosphorus content = 6.17 %)- Lot/batch No.: TDPx-003-04070A - Supplier: Borg Warner Company, Parkersburg, WV

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Weight at study initiation: 18 and 21 grams - Assigned to test groups randomly: [no/yes, under following basis: ]- Fasting period before study: fasted overnight prior to dosing. - Housing: plastic caging - Diet: ad libitum- Water: ad libitumENVIRONMENTAL CONDITIONS- Temperature: 22oC- Air changes: 30 air changes/hour- Photoperiod: 12-hour light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

24 hours

Frequency of treatment:

Two single doses

Post exposure period:

6 hours

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

4 450 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

9 100 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

18 200 mg/kg bw/day

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

Details of tissue and slide preparation:

Following the last dose, the animals were observed for six hours, sacrificed, and both femurs were removed from each animal. 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 in micronucleated cells compared to the concurrent negative control group values. Due to heterogeneity of vairance [Bartlett’s test; p<0.01], non-parametric methods based on Kruskal-Wallis mean ranks were used to analyse the micronucleated cell counts. If the erythrocyte ratios at the top dose were significantly different from the concurrent negative control values, then the ratios of the two lower doses were scored.

Results and discussion

Test results

Sex:

male/female

Genotoxicity:

negative

Toxicity:

yes

Remarks:

See comments in additional information on toxicity

Negative controls validity:

valid

Positive controls validity:

valid

Additional information on results:

After administration of TDP at 9100 and 18200 mg/kg, signs of toxicity (piloerection and lethargy) were observed 30 minutes after dosing in all animals. The symptoms decreased over the next several hours and were not observed 6 hours after administration. No toxic reactions were observed in the corn oil negative control group or the 4450 mg/kg TDP group. After administration of mitomycin C, no toxic reactions or mortality were observed.

Any other information on results incl. tables

PCE/NCE Ratio    # micronucleated cells/1000 PCE's animal Test Group   Mean (Range)  Mean (range)  Negative Control 1.9 (0.4) 1.75 (1.15 - 3.93)  4450 mg/kg TDP 1.2 (0.3) 2.21 (1.05 - 4.22)  9100  mg/kg TDP 1.0 (0.2) 1.61 (0.76 - 2.44)  18200  mg/kg TDP 2.7 (0.5) 2.34 (1.62 - 3.55)*  Mitomycin 89.1 (13 -182) 8.61 (2.25 - 1.67)  Historical Control** 0.79 (0.1 - 1.8) 0 - 5 * For all three TDP groups in both sexes, the micronucleus counts were not statistically different from the concurrent control values. For the PCE/NCE ratio, the 18200 mg/kg TDP group was statistically different from the concurrent control value (p<0.01). The positive control group, mitomycin C, produced statistically significant increases in both the number of micronucleated cells per 1000 PCEs/animal and the PCE/NCE ratio. ** The historical control values from this laboratory were based on the previous 18 experiments. In this experiment, the negative control mean value of 1.9 (range = 0-4) for the number of micronucleated cells per 1000 PCEs per animals was higher than the historical control value. Based on the conditions of this study, it was concluded that the test article, TDP, failed to show any evidence of mutagenic potential when administered orally to either sex. Evidence of toxicity to bone marrow was evident only at the highest total dosage of 18200 mg/kg body weight in both males and females.

Applicant's summary and conclusion

Conclusions:

Based on the conditions of this study, it was concluded that the test article, TDP, failed to show any evidence of mutagenic potential when administered orally to either sex. Evidence of toxicity to bone marrow was evident only at the highest total dosage of 18200 mg/kg body weight in both males and females.

Executive summary:

 Based on the conditions of this study, it was concluded that the test article, TDP, failed to show any evidence of mutagenic potential when administered orally to either sex. Evidence of toxicity to bone marrow was evident only at the highest total dosage of 18200 mg/kg body weight in both males and females.