Dimethyl propylphosphonate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

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:

2005

Report date:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

Dimethyl propylphosphonate (DMPP) was administered daily via gavage in maize germ oil to 5 male and 5 female Wistar rats per dose group, in doses of 0, 5 and 20 mg/kg body weight for a period of 4 weeks. This study is a supplementary study to a 4-week rat study, in which a NOEL concerning effects on the kidney and liver could not be established.
The animals were regularly observed and weighed. Food intake was determined. Plasma levels of cholesterol, urea, and protein as well as plasma alkaline phosphatase activities were detennined. Brain, kidneys and liver were weighed. Gross lesions and specimen of the kidneys, liver and bone marrow of the sternum were investigated histopathologically.

GLP compliance:

yes

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: colourless liquid

Details on test material:

- Purity: 98.6%

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

maize oil

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, or 20 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

5 male and five female rats/dose

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

1

Dose descriptor:

LOEL

Effect level:

5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: alpha-2-microglobulin nephropathy; not regarded to be relevant for human risk assessment

2

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: NOAEL for effects not related to alpha-2-microglobulin; relevant for human risk assessment

3

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effect observed at any dose tested

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Mortality as well as behavior and appearance of the rats were not influenced by the treatment up to 20 mg/kg.

Body weights and food intake were unaffected up to 20 mg/kg.

There was no change in plasma cholesterol, urea and protein as well as APh activity up to 20 mg/kg.

Brain, kidney and liver weights were not remarkably changed.

Hepatocellular hypertrophy occurred more frequently in 20 mg/kg males.

The bone marrow of the sternum was not altered by the treatment up to 20 mg/kg.

Two of five 20 mg/kg females showed tubular vacuolation in the kidney.

Corresponding to renal surface changes noted macroscopically in males at 5 and 20 mg/kg morphological kidney lesions such as tubular degeneration with hyaline droplets, tubular dilation and increased basophilic tubules were detected in males of both substance exposed groups. This hyaline droplet nephropathy, which is known to be related to alpha-2-microglobulin and to occurs only in male rats, is discussed to be of no toxicological relevance for humans.

Gross investigations in the other organs gave no indication of dimethyl propylphosphonate related effects.

According to the kidney findings a NOEL for dimethyl propylphosphonate can not be established for male rats. However, as the alpha-2-microglobulin nephropathy of the male rat is generally not regarded to be relevant for man, a NOAEL for effects not related to alpha-2-microglobulin can be established at 20 mg/kg body weight/day for human relevance.

Applicant's summary and conclusion

Executive summary:

Dimethyl propylphosphonate (DMPP) was administered daily via gavage in maize germ oil to 5 male and 5 female Wistar rats per dose group, in doses of 0, 5 and 20 mg/kg body weight for a period of 4 weeks. This study is a supplementary study to a 4-week rat study, in which a NOEL concerning effects on the kidney and liver could not be established.

The animals were regularly observed and weighed. Food intake was determined. Plasma levels of cholesterol, urea, and protein as well as plasma alkaline phosphatase activities were detennined. Brain, kidneys and liver were weighed. Gross lesions and specimen of the kidneys, liver and bone marrow of the sternum were investigated histopathologically.

Mortality as well as behavior and appearance of the rats were not influenced by the treatment up to 20 mg/kg.

Body weights and food intake were unaffected up to 20 mg/kg.

There was no change in plasma cholesterol, urea and protein as well as APh activity up to 20 mg/kg.

Brain, kidney and liver weights were not remarkably changed.

Hepatocellular hypertrophy occurred more frequently in 20 mg/kg males.

The bone marrow of the sternum was not altered by the treatment up to 20 mg/kg.

Two of five 20 mg/kg females showed tubular vacuolation in the kidney.

Corresponding to renal surface changes noted macroscopically in males at 5 and 20 mg/kg morphological kidney lesions such as tubular degeneration with hyaline droplets, tubular dilation and increased basophilic tubules were detected in males of both substance exposed groups. This hyaline droplet nephropathy, which is known to be related to alpha-2-microglobulin and to occurs only in male rats, is discussed to be of no toxicological relevance for humans.

Gross investigations in the other organs gave no indication of dimethyl propylphosphonate related effects.

According to the kidney findings a NOEL for dimethyl propylphosphonate can not be established for male rats. However, as the alpha-2-microglobulin nephropathy of the male rat is generally not regarded to be relevant for man, a NOAEL for effects not related to alpha-2-microglobulin, and consequently relevant for human risk assessment, can be established at 20 mg/kg body weight/day in male rats, taking into account that the slight hepatocellular hypertrophy is oberved only in males and considered to be an adaptive effects and/or secondary to nephropathy.

For female rats a NOAEL at 20 mg/kg body weight/day is derived. The only observation in females in this study is tubular vacuolation in the kidney at 20 mg/kg/day. Since tubular vacuolation in the kidney was observed in the previously reported sub-acute study at higher doses (40, 200 and 1000 mg/kg/day) only in males but not in females (0/5, 0/5 and 0/5, respectively), the isolated observation at 20 mg/kg/day in females in this study is not regarded as an adverse effect.