Dimethyl propylphosphonate

Endpoint summary

Description of key information

Two subacute (28 days) repeated dose toxicity studies are available.  In the first study dimethyl propylphosphonate was administered in doses of 0, 40, 200 and 1000 mg/kg bw . In a supplementary subacute study dimethyl propylphosphonate was administered in doses of 0, 5 and 20 mg/kg bw for a period of 4 weeks.
Based on alpha-2-microglobulin nephropathy findings a NOEL for dimethyl propylphosphonate cannot 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. For female rats a NOAEL at 20 mg/kg body weight/day is derived. 
Overall, 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 and female rats in comprehensive sub-acute toxicity studies.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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

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

Species:

rat

Strain:

Wistar

Sex:

male/female

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

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

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

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

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

Critical effects observed:

not specified

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.

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The materials/methods and results are described in detail und are sufficient for evaluation.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In a subacute study with doses of 0, 40, 200, and 1000 mg/kg body weight the kidney morphology was altered in all male treatment groups and liver enzyme activity (alkaline phosphatase) activity was decreased in all female treatment groups, but no severe toxicity occurred up to the high dose.

In the follow up study 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 in a study conducted according to OECD TG 407.

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 determined. 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 test substance-related effects.

According to the kidney findings a NOEL for dimethyl propylphosphonate cannot 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 observed 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 subacute 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.

A very limited pilot study originally performed as a dose range finder for a reproduction/developmental toxicity screening test is also available. In this study a premating period of 14 days was followed by a 2 weeks cohabitation period. Pregnant females were allowed to litter and nurse their pups at least up to PND 4. The experimental animals were inspected twice a day for morbidity and mortality. All signs of illness or clinical reactions to treatment were recorded online during a detailed clinical observation prior to each treatment. This investigation included the evaluation of the general state of health, behavior, condition of the fur, and the orifices as well as excretory products. Body weights of F0 parental animals and gross examination of the F0 animals were recorded. Necropsy revealed pelvic dilation of the kidneys in 4/5 females, which was microscopically confirmed in 3 out of 4 diagnosed females at 500 mg/kg. In one female this finding was combined with tubular dilation and degeneration, papillary necrosis, pelvic degeneration and transitional cell hyperplasia. Male kidneys showed an increase of cortical basophilic tubules together with tubular dilation starting at 20 mg/kg. Furthermore, cortical tubules revealed swelling and/or vacuolation at 20 mg/kg and above, tubular degeneration and debris was found in 20 and 100 mg/kg males. Hyaline droplets increased at 100 mg/kg and above. Pelvic dilation with urothelial degeneration occurred in one male at 20 mg/kg.

Overall, 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 and female rats in comprehensive subacute toxicity studies.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The most reliable study for the determination of a NOAEL was used as key study and for classification

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Dimethyl propylphosphonate was comprehensively investigated in rats in two subacute toxicity studies conducted according to OECD TG 407 and in a limited pilot reproduction/developmental toxicity study. In all studies alpha-2-microglobulin nephropathy was observed as the most sensitive observation. Since alpha-2-microglobulin nephropathy is seen only in rodents and not relevant for human risk assessment classification is not justified.