Trimethyl phosphate

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Males: 42 days including 14 days before mating. Females: from 14 days before mating to day 3 of lactation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Trimethyl phosphate

EC Number:

208-144-8

EC Name:

Trimethyl phosphate

Cas Number:

512-56-1

Molecular formula:

C3H9O4P

IUPAC Name:

trimethyl phosphate

Test material form:

liquid

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Duration of treatment / exposure:

Males: 42 days
Females: from 14 days prior to mating to Day 3 of lactation

Frequency of treatment:

7 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

40 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

250 mg/kg bw/day (nominal)

No. of animals per sex per dose:

13 animals/group

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Mortality:

mortality observed, treatment-related

Description (incidence):

Twelve males and one female given 250 mg/kg died during the 4th to 6th week of the dosing period.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight gain of the males and females of the 250 mg/kg dose groups were significantly reduced.
Twelve and 2 pregnant females given 40 and 100 mg/kg, respectively, demonstrated significant decrease in body weight gain during mid and late pregnancy.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption of the males of the 250 mg/kg dose group was significantly reduced.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

In the males of the 100 mg/kg dose group, significantly decreased erythrocyte counts, hemoglobin concentration, hematocrit and A/G ratio, and increased platelet count, percentage of segmented neutrophils, cholinesterase activity, total cholesterol and calcium levels were noted. Similar alteration in hematological and clinical chemistry parameters was observed in one surviving male of the 250 mg/kg dose group.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At terminal necropsy, compound-related alterations in organ weights included significant increases in the kidney weight of males of the 40 and 100 mg/kg dose groups and in the thymus weight of males of the 100 mg/kg dose group and of females of the 40 mg/kg dose group, and a significant decreases in the epididymal weight of males of 100 mg/kg dose group.

Neuropathological findings:

effects observed, treatment-related

Description (incidence and severity):

Progressive development of a paralytic gait and decreased motor activity in twelve males and one female.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

On histopathological examination, major lesions noted in males and females given 100 mg/kg or more included nephropathy characterized by tubular and papillary alteration such as increased eosinophilic droplets in tubular epithelium, increased regeneration of tubules and papillary necrosis, atrophy of the thymus, liver and testis, increased atretic follicles in the ovary (250 mg/kg female only), and degeneration of nerve fiber in the spinal cord or the peripheral nerves (e.g., sciatic nerve). The incidence and severity of these lesions increased with dose and were greater in males than females.

Effect levels

1

Key result

Dose descriptor:

NOEL

Effect level:

< 40 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

2

Key result

Dose descriptor:

LOEL

Effect level:

40 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

The NOELs for repeat dose toxicity are considered to be less than 40 mg/kg/day for both sexes.