Dimethyl propylphosphonate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

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: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test)

Principles of method if other than guideline:

Dimethyl propylphosphonate was evaluated for the induction of dominant lethal mutations in male C6B3F1-mice. Males were treated with 500, 1000, and 2000 mg/kg/day dimethyl propylphosphonate by gavage five days per week for 13 weeks. After 4, 8 and 12 weeks of treatment each male mouse was mated from Monday to Friday of the following week to two untreated CD-1 female mice. In addition to dimethyl propylphosphonate 2000 mg/kg/day dimethyl methylphosphonate were tested under the same conditions as class-specific positive control.

GLP compliance:

yes

Type of assay:

rodent dominant lethal assay

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl propylphosphonate

EC Number:

242-555-3

EC Name:

Dimethyl propylphosphonate

Cas Number:

18755-43-6

Molecular formula:

C5H13O3P

IUPAC Name:

dimethyl propylphosphonate

Test material form:

other: clear liquid

Details on test material:

-Purity: 99.05%

Test animals

Species:

mouse

Strain:

other: Male mice, strain B6C3F1/BOM, Female mice, strain CRL:CD1 (ICR)

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Duration of treatment / exposure:

All the females in the test remained untreated.
The males in the dimethyl propylphosphonate groups were treated with 500 mg/kg/day, 1000 mg/kg/day, and 2000 mg/kg/day by gavage
5 days a week for 13 weeks.
The males in the dimethyl methylphosphonate group (control group) were treated with 2000 mg/kg/day in the same way.

Frequency of treatment:

once daily

Post exposure period:

Starting with Monday of week 5, 9 and 13, each male was mated until Friday with two untreated virginal females.
Approximately sixteen days after the relevant mating period, the evaluation took place to assess for pre- and post-implantation losses. After sacrifice of the females, Caesarean section was performed.

Doses / concentrations

Remarks:

Doses / Concentrations:
Females: untreated; males: 500 mg/kg/day, 1000 mg/kg/day, and 2000 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

In each group 20 males were treated.

Control animals:

other: dimethyl methylphosphonate group (control group)

Examinations

Tissues and cell types examined:

After sacrifice of the females, Caesarean section was performed. Uteri were spread out and the relevant parameters were examined. For this purpose, the total number of implantations, the number of living and dead implants as well as the number of corpora lutea was established. The number
of dead implantations was established by counting the deciduomata ("empty" implantation sites), and dead implants.

Results and discussion

Test results

Sex:

female

Genotoxicity:

positive

Toxicity:

yes

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Any other information on results incl. tables

The males treated orally with dimethyl propylphosphonate using doses of 1000 mg/kg/day and 2000 mg/kg/day showed symptoms

of toxicity for up to at least eight hours after each administration. Body weight gain was strongly reduced in the group treated with 2000 mg/kg/day dimethyl propylphosphonate. One and twelve of twenty males died due to the toxicity of 1000 and 2000 mg/kg/day dimethyl propylphosphonate.

The fertility of the mice in the dimethyl propylphosphonate group treated with 2000 mg/kg/day was strongly reduced. This was accounted for to general toxic effects and not to specific effects on the germ cells. Due to toxicity males were physically not able to mate. No effects were seen for the dimethyl propylphosphonate groups treated with 500 mg/kg/day and 1000 mg/kg/day.

Treatment-related differences were seen between the dimethyl propylphosphonate-dosed groups and the control group with

respect to those parameters of importance for an assessment of a mutagenic effect (dead implants, viable implants, total implants, pre-implantation loss). All parameters were clearly increased for every mating interval.

The positive control dimethyl methylphosphonate using a dose of 2000 mg/kg/day was well tolerated and did not cause any

symptoms of toxicity nor mortality. Treatment-related differences were seen between the dimethyl methylphosphonate-dosed group and the control group with respect to those parameters of importance for an assessment of a mutagenic effect (dead implants, viable implants, total implants). By these effects dimethyl methylphosphonate, the class-specific positive control, demonstrated the sensitivity

of the test system for the detection of mutagenic effects.

Thus the dominant lethal test on the male mouse provided clear indications of dimethyl propylphosphonate having a mutagenic effect using subchronic oral treatment with doses of 500 mg/kg/day 1000 mg/kg/day, and 2000 mg/kg/day body weight.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: positive

Executive summary:

Dimethyl propylphosphonate was evaluated for the induction of dominant lethal mutations in male C6B3F1-mice. Males were treated with 500, 1000, and 2000 mg/kg/day dimethyl propylphosphonate by gavage five days per week for 13 weeks. After 4, 8 and 12 weeks of treatment each male mouse was mated from Monday to Friday of the following week to two untreated CD-1 female mice. In addition to dimethyl propylphosphonate 2000 mg/kg/day dimethyl methylphosphonate were tested under the same conditions as class-specific positive control.

The males treated orally with dimethyl propylphosphonate using doses of 1000 mg/kg/day and 2000 mg/kg/day showed symptoms

of toxicity for up to at least eight hours after each administration. Body weight gain was strongly reduced in the group treated with 2000 mg/kg/day dimethyl propylphosphonate. One and twelve of twenty males died due to the toxicity of 1000 and 2000 mg/kg/day dimethyl propylphosphonate.

The fertility of the mice in the dimethyl propylphosphonate group treated with 2000 mg/kg/day was strongly reduced. This was accounted for to general toxic effects and not to specific effects on the germ cells. Due to toxicity males were physically not able to mate. No effects were seen for the dimethyl propylphosphonate groups treated with 500 mg/kg/day and 1000 mg/kg/day.

Treatment-related differences were seen between the dimethyl propylphosphonate-dosed groups and the control group with

respect to those parameters of importance for an assessment of a mutagenic effect (dead implants, viable implants, total implants, pre-implantation loss). All parameters were clearly increased for every mating interval.

The positive control dimethyl methylphosphonate using a dose of 2000 mg/kg/day was well tolerated and did not cause any

symptoms of toxicity nor mortality. Treatment-related differences were seen between the dimethyl methylphosphonate-dosed group and the control group with respect to those parameters of importance for an assessment of a mutagenic effect (dead implants, viable implants, total implants). By these effects dimethyl methylphosphonate, the class-specific positive control, demonstrated the sensitivity

of the test system for the detection of mutagenic effects.

Thus the dominant lethal test of dimethyl propylphosphonate on the male mouse was positive with doses of 500 mg/kg/day, 1000 mg/kg/day, and 2000 mg/kg/day.

Due to these results in the dominant lethal test, the surviving animals were separated in different groups and were used for the following additional investigations:

• Micronucleus test in bone marrow cells (Report 24010A)
• Cytogenetics in bone marrow cells (Report 24010D)
• Cytogenetics in spermatogonia (Report 24010B)
• Alkaline elution with testes (Report 24010C)
• Histopathology of gonads (Report 24010E)

The results of these examinations are reported in the other study records of section 7.6.2 (genetic toxicity in vivo)