Phosphorous acid, tri-C12-14-alkyl esters

Genetic toxicity: in vivo

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

Study period:

1981

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

U.S. HIGH PRODUCTION VOLUME (HPV) CHEMICAL CHALLENGE PROGRAM ROBUST SUMMARY Phosphorous acid, triisodecyl ester (CAS# 25448-25-3)

Author:

General Electric Company on behalf of the Phosphite Producers HPV Consortium and Phosphite Manufacturers Consortium

Year:

2001

Bibliographic source:

US Environmental Protection Agency, HPV Information System

Reference 2

Reference Type:

study 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

GLP compliance:

yes

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

Triisodecyl phosphite (CAS# 25448-25-3)

IUPAC Name:

Triisodecyl phosphite (CAS# 25448-25-3)

Test material form:

other: liquid

Details on test material:

Triisodecyl phosphite (CAS# 25448-25-3, Lot #TDPx-003-04070A from
Borg Warner Company, Parkersburg, WV)
Commercial, purity: >= 97% (Phosphorus content = 6.17 %)

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

All animals weighted between 18 and 21 grams and were group-housed in plastic caging maintained in a controlled environment (temperature 22 deg C, 30 air changes/hour, 12-hour light/dark cycle, and access to food and water ad libitum). The animals were fasted overnight prior to dosing.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

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, 4450, 9100, and 18200 mg/kg were used in the main study. The test article was administered (diluted in corn oil) via oral gavage to groups of mice (5/sex), at a volume of 0.1 mL per 10 grams of body weight.

Duration of treatment / exposure:

Two single doses administered over 24 hours

Frequency of treatment:

Two single doses administered over 24 hours

Post exposure period:

the animals were observed for six hours

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 4450, 9100, and 18200 mg/kg bw
Basis:
no data

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:

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 variance [Bartlett's test; p<0.01], non-parametric methods based on Kruskal-Wallis mean ranks were used to analyze 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

Vehicle controls validity:

valid

Positive controls validity:

valid

Additional information on results:

There was no statistically significant difference between any of the test article treatments and the negative control.
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

The mean number of micronucleated cells per 1000 polychromatic erythrocytes per animal and the PCE/NCE ratios for all test groups and both controls are presented below:

Nb Micronucleated Cells PCE/NCE per 1000 PCEs/animal Ratio

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 C	89.1 (13-182)	8.61 (2.25-16.67)
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:

Interpretation of results :
negative

Executive summary:

Triisodecyl phosphite was studied in a in vivo micronucleus assay to test its chromosomic aberration potential.

CD mouse (5/sex) were given TDC in corn oil via oral gavage at the doses of 0, 4450, 9100, and 18200 mg/kg.

There was no statistically significant difference between any of the test article treatments and the negative control in the count of micronucleated cells per 1000 polychromatic erythrocytes.

Based on the conditions of this study considered as reliable (Klimlisch rate 1), 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.