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Repeated dose toxicity: other routes

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Administrative data

Endpoint:
short-term repeated dose toxicity: other route
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
15 June 1989 - 20 September 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study was conducted under GLP conditions, but not according to an OECD guideline. However, the study design is proper and comparable to that of other scientific subacute studies (only alternative route of exposure). The results are reported extensively.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
CR733S was administered by IP injection at a dose level of 0, 0.000175, 0.00175, 0.5, 50 or 500 mg/kg bw/day for at least 28 days. 50 mg/kg bw/day Triphenyl phosphate (TPPA) was used as comparative control. Animals were observed twice daily for signs of toxicity or mortality. Body weight and food consumption were assessed. Urine and blood samples were collected for evaluation of hematology, clinical chemistry and cholinesterase activity prior to necropsy and postmortem examinations.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)
EC Number:
701-337-2
Cas Number:
not available
Molecular formula:
C30H24O8P2
IUPAC Name:
Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)
Details on test material:
- Name of test material (as cited in study report): CR733S
- Physical state: Liquid
- Lot/batch No.: Confidential information
- Storage condition of test material: At room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
corn oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.000175, 0.00175, 0.5, 50 or 500 mg/kg bw/day
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
other: comparative control: 50 mg/kg bw/day triphenyl phosphate (TPPA)

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
0.5 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Decreased plasma cholinesterase in females; inhibition of esterase activity in males and females

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

- No mortality

- No adverse clinical signs (indicating that blood-brain barrier cannot be penetrated to cause CNS response)

- No effect on body weight, food consumption, whole blood or erythrocyte cholinesterase, hematology or serum chemistry parameters or urinanalysis

- Significant decrease in plasma cholinesterase for both sexes of 500 mg/kg bw/day group and females of 50 mg/kg bw/day and TPPA control group

- Significant increase in relative liver weight for both sexes in the 500 mg/kg bw/day group and TPPA control group

- Non-specific esterase stains of liver imprints showed clear presence of esterase inhibition in 50 and 500 mg/kg bw/day groups and TPPA control group

- Histopathology: Local irritation of mesentery and adjacent adipose tissue or on the serosal surface of some visceral organs in 500 mg/kg bw/day group: slight to moderate fat necrosis and granulomatous inflammatory response (with increased number of lymphoid cells and macrophages as compared to controls; also presence of numerous multinucleated phagocytic giant cells)

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, the dose level of 500 mg/kg bw/day caused significant adverse effects (decrease in plasma cholinesterase, increase of relative liver weight, inhibition of esterase activity and histopathological effects). At 50 mg/kg bw/day inhibition of esterase activity was observed (both male and female), as well as decreased plasma cholinesterase levels in females. The comparative control group (TPPA) showed a decrease in plasma cholinesterase, increase of liver weight and inhibition of esterase activity. Based on the observed resultsNOAEL of 0.5 mg/kg bw/day.
Executive summary:

CR733S was administered by IP injection at a dose level of 0, 0.000175, 0.00175, 0.5, 50 or 500 mg/kg bw/day for at least 28 days. 50 mg/kg bw/day Triphenyl phosphate (TPPA) was used as comparative control. Animals observed twice daily for signs of toxicity or mortality. Body weight and food consumption were assessed. Urine and blood samples were collected for evaluation of hematology, clinical chemistry and cholinesterase activity prior to necropsy and postmortem examinations.

No mortality and adverse clinical signs were observed in any group. No effect on body weight, food consumption, whole blood or erythrocyte cholinesterase, hematology or serum chemistry parameters or urinanalysis. A significant decrease in plasma cholinesterase for both sexes of 500 mg/kg bw/day group and females of 50 mg/kg bw/day and TPPA control group was noted. Additionally, a significant increase in relative liver weight for both sexes in the 500 mg/kg bw/day group and TPPA control group was observed. Inhibition of esterase was clearly present in non-specific esterase stains of liver imprints in the 50 and 500 mg/kg bw/day groups and TPPA control group. Local irritation of mesentery and adjacent adipose tissue or on the serosal surface of some visceral organs in 500 mg/kg bw/day group: slight to moderate fat necrosis and granulomatous inflammatory response. This was accompanied with increased number of lymphoid cells and macrophages as compared to controls and also the presence of numerous multinucleated phagocytic giant cells.

Under the conditions of this study, the dose level of 500 mg/kg bw/day caused significant adverse effects (decrease in plasma cholinesterase, increase of relative liver weight and histopathological effects). At 50 mg/kg bw/day decrease in plasma cholinesterase in females was observed, and clear inhibition of esterase activity in both males and females. A NOAEL of 0.5 mg/kg bw/day could be established based on these results.