Diethyl phosphonate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study and GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Report date:

1993

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

6 rats/sex and dose instead of 5 rats/sex and dose

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diethyl phosphonate

EC Number:

212-091-6

EC Name:

Diethyl phosphonate

Cas Number:

762-04-9

Molecular formula:

C4H11O3P

IUPAC Name:

diethyl phosphonate

Test material form:

other: liquid

Details on test material:

content: 98.86 %

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 166 g; females: 132 g
- Housing: individually
- Diet ad libitum
- Water ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 50-60
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12 /12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

as described in the respective guideline

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

details not given

Duration of treatment / exposure:

29 days

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 30, 150, 750 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

6 males/dose and 6 females/dose

Control animals:

yes, concurrent vehicle

Details on study design:

dose selction rational:
the doses were selected following a pre-test in which male and female rats received bygavage 0 and 1000 mg/kg bw/day over a period of 3 weeks. At the end of the treatment period body weight development in the treatment groups were about 30% lower than in the respective control groups
main study is performed as described in the respective guideline

Positive control:

not required

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice per week

BODY WEIGHT: Yes
- Time schedule for examinations:
before the start of the study and then once per week

FOOD CONSUMPTION: yes

WATER CONSUMPTION : Yes

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
Differential blood picture. Erys, hemoglobin. hematocrit, leucos, MCH, MCHC, MCV , thrombos, clotting time.,

CLINICAL CHEMISTRY: Yes
Alkale phosphatase. Aspartate, GOT, , GPT, Albumin, bilirubin, cholestrol, total protein, urea, creatinine, glucose, anorganic phosphate, CA, K, Na, .Cloride

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
weights of brain, heart, testes, liver, spleen, kidneys and adrenals
HISTOPATHOLOGY: Yes
as required by the guideline

Statistics:

yes: mean value calculation including standard deviation, U-test according to mann and Whitney, Wilcoxon test,

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

gavage study

Food efficiency:

not specified

Description (incidence and severity):

gavage study

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

gavage study

Ophthalmological findings:

not examined

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
the test item was tolerated without mortality in males and females
the test item was tolerated without clinical signs up to and including 150 mg/kg bw
at 750 mg/kg bw
poor general condition, apathy. and increased salivation was observed in males and females

BODY WEIGHT AND WEIGHT GAIN
up to and including 150 mg/kg bw/day, males and females:
there were no significant differences in body weight and body weight gain compared to the respective controls
at 750 mg/kg bw/day, males and females:
from the second treatment week onwards body weight gain was significantly reduced. At the end of the treatment period
body weight of males was about 23 % and body weight of females was about 14 % reduced when compared to the concurrent controls

HAEMATOLOGY
up to and including 150 mg/kg bw/day, males and females.
there were no pathological findings
at 750 mg/kg bw/day, males and females,
compared to the concurrent controls
erythrocyte count was significantly increased and and MCV values and MCH-values were significantly decreased

CLINICAL CHEMISTRY
up to and including 750 mg/kg bw/day, males:
there were no pathological findings
up to and including 150 mg/kg bw/day, females:
there were no pathological findings
at 750 mg/kg bw/day, females:
compared to the concurrent controls
concentration of cholesterine , protein and albumine was significantly decreased

GROSS PATHOLOGY, ORGAN WEIGHTS
up to and including 750 mg/kg bw/day, males and females:
compared to the concurrent controls
there were no findings which could be attributed to treatment

HISTOPATHOLOGY: NON-NEOPLASTIC
females: up to and including 150 mgkg bw/day, ´
there were no no pathological findings
males: from 150 mg/kg bw/day onwards
perivascular granulocate infiltation in the lungs were observed
males and females: 750 mg/kg bw/day:
interstititial pneumonia, pulmonary fibrosis, presence of giant cells. distinctive hyperplasia of the bronchial mucous membrane.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: based on clinical signs, reduced body weight development, affected hematology and clinical chemistry values and histopathological changes in kidneys and lungs at 750 mg/kg bw/day

2

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: based on perivasculare granulocyte infiltration from 150 mg/kg bw/day onwards and clinical signs, reduced body weight development, affected hematological values and histopathological changes in lungs at 750 mg/kg bw

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

Diethylphosphite was examined for subacute toxicity according to the OECD TG 407 and GLP. 6 male and 6 female Wistrar rats/dose received by gavage 0, 30, 150 or 750 mg/kg bw/day diluted in polyethylene glycol 400 once daily for 29 days. Only at the highest test dose animals showed poor general condition, apathy, increased salivation and reduced body weight development (males 23 % and females 14 % lowered when compared to the controls). No rat died during the study. The only pathological findings in hematology or clinical chemistry occurred in females at the top dose including increase in erythrocite count, reduced MCV- and MCH-values, reduced cholesterol, protein and albumin. Histopathological examination revealed, in males, from 150 mg/kg bw/day onwards perivascular granulocate infiltation in the lungs and at 750 mg/kg bw/day, in males and females, interstititial pneumonia, pulmonary fibrosis, presence of giant cells. distinctive hyperplasia of the bronchial mucous membrane.

Thus, under condition of this test, the NOAEL (male rat) is 30 mg/kg bw/day and the NOAEL (female rat) is 150 mg/kg bw/day.