[No public or meaningful name is available]

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

Principles of method if other than guideline:

Three groups of five male and five female CD rats received diphenyl cresyl phosphate at dosages of 62.5, 250 or 1000 mg/kg/day by oral gavage administration for 4 weeks. A similar constituted control group received the vehicle alone (maize oil).

Organ weights of thymus missing; Tissues not preserved for histopathology: Thyroid, Trachea, urinary bladder, peripheral nerve.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of 3-methylphenyl diphenyl phosphate, 4-methylphenyl diphenyl phosphate, bis(3-methylphenyl) phenyl phosphate, 3-methylphenyl 4-methylphenyl phenyl phosphate and triphenyl phosphate

Molecular formula:

3-methylphenyl diphenyl phosphate: C19H17O4P 4-methylphenyl diphenyl phosphate´: C19H17O4P triphenyl phosphate: C18H15O4P bis(3-methylphenyl) phenyl phosphate: C20H19O4P 3-methylphenyl 4-methylphenyl phenyl phosphate: C20H19O4P

IUPAC Name:

Reaction mass of 3-methylphenyl diphenyl phosphate, 4-methylphenyl diphenyl phosphate, bis(3-methylphenyl) phenyl phosphate, 3-methylphenyl 4-methylphenyl phenyl phosphate and triphenyl phosphate

Details on test material:

Diphenyl Cresyl Phosphate:
22.8% Triphenyl Phosphate
32.5% Diphenyl-p-cresyl phosphate
12.1% Diphenyl-m-cresyl phosphate
14.3% Phenyl-di-m-cresyl phosphate
9.9% Phenyl-m, p-cresyl phosphate
1.7% Phenyl-di-p-cresyl phosphate
3.0% Tri-m-cresylphosphate
2.8% Di-m-p-cresyl phosphate
0.7% Di-p-m-cresyl phosphate
0.1% Tri-p-cresyl phosphate
<0.05% Unknown products
0.03% Water

Test animals

Species:

rat

Strain:

other: CD

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:

1/day

Doses / concentrations

Remarks:

Doses / Concentrations:
62.5, 250 or 1000 mg/kg/day
Basis:
other: oral gavage administration

No. of animals per sex per dose:

5/sex/dose

Control animals:

yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Salivation associated with dosing was observed among animals receiving 1000mmg/kg/days and occassionally among animals receiving 250 mg/kg bw. Other signs include, at 1000 mg/kg/day, ungroomed coat and for females, general hairloss.

Mortality:

mortality observed, treatment-related

Description (incidence):

Four males and two females receiving 1000 mg/kg/day died during the last week of treatment. Necropsy findings included abnormal kidneys in one male and thickened wall or abnormal contents of the urinary bladder in two males. Histopathology indicated changes in the liver, kidneys and adrenals. These deaths were considered to be directly related to the administration of the test material.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Bodyweight gains were lower for males receiving 1000 mg/kg/day when compared with controls.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Lower food intake was recorded for high dosage males and females during the last week of treatment.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

The food conversion efficiencies of males receiving 1000 mg/kg/day was low throughout the study, whereas females at this dosage were similarly affected only during the last week of treatment.

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

effects observed, treatment-related

Description (incidence and severity):

When compared with control values, the water intake of animals receiving 1000 mg/kg/day was high and that for females receiving 250 mg/kg/day was slightly high.

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

After 24 days of treatment reduced mean cell volumes and mean cell haemoglobin were recorded for males and females receiving 1000 mg/kg/day with marginally low packed cell volume and haemoglobin concentrations also recorded for high dosage females. High total leucocyte and monocyte counts were recorded for males and females receiving 1000 mg/kg/day with high lymphocyte counts in all treated males and females receiving 1000 mg/kg/day.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Biochemical analysis of animals receiving 1000 mg/kg/day revealed high creatinine concentrations, low chloride concentrations and changes in plasma protein concentrations; high calcium and phosphorus concentrations and high aspartate alanine amino-transferase activities for high dosage males. Other findings included high phosphorus concentrations for females receiving 250 mg/kg/day and changes in plasma protein concentrations for males receiving 62.5 or 250 mg/kg/day.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

After 22 days of treatment, high urinary volumes and slightly low specific gravities for males and females receiving 1000 mg/kg/day; increased protein concentrations for treated males and females receiving 250 and 1000 mg/kg/day. In addition, the number of crystals detected for high dosage animals was low when compared with controls and epithelial cells or polymorphonuclear leucocytes were present in the urine of a number of animals receiving 250 or 1000 mg/kg/day.

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Organ weight analysis indicated high absolute and bodyweight-relative, liver, kidney and adrenal weights for males and females that received 1000 mg/kg/day and slightly high absolute and bodyweight-relative liver weights for males that received 250 mg/kg/day.

Gross pathological findings:

not specified

Neuropathological findings:

no effects observed

Description (incidence and severity):

There were no neurological changes in behavior.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopic changes comprised a high incidence of basophilic cortical tubules, hyaline casts and tubular dilatation in the kidneys of males that received 250 mg/kg/day and for males and females that received 1000 mg/kg/day with intracellular debris also recorded in the kidneys of high dosage animals; diffuse hypertrophy in the liver of animals that received 250 or 1000 mg/kg/day; increased incidence of cortical fatty vacuolation in the adrenals of high dosage animals.
As a conclusion it can be assumed that oral administration of Diphenyl Cresyl Phosphate to CD rats for four weeks at dosages of 250 mg/kg/day and above was associated with a number of toxic findings which included changes in renal function and, at 1000 mg/kg/day, change in the adrenals and mortality.
There were no treatment-related histopathological changes in the brain, sciatic nerve, spinal cord, testes, epididymides or ovaries.

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Description (incidence and severity):

There were no changes in the sperm numbers, motility or morphology of treated animals.

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 62.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Due to the absence of any major disturbances in the clinical pathology parameters at 62.5 mg/kg/day and as there were no treatment-related microscopic changes at this dosage, it was concluded that the NOAEL was 62.5 mg/kg/day.

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

250 mg/kg bw/day (nominal)

System:

hepatobiliary

Organ:

kidney

liver

other: adrenals

Treatment related:

yes

Dose response relationship:

yes

Any other information on results incl. tables

Four males and two females receiving 1000 mg/kg/day died during the last week of treatment. Necropsy findings included abnormal kidneys in one male and thickened wall or abnormal contents of the urinary bladder in two males. Histopathology indicated changes in the liver, kidneys and adrenals. These deaths were considered to be directly related to the administration of the test material.

From Day 4 of treatment, salivation associated with dosing was observed among animals receiving 1000 mg/kg/day and occasionally among animals receiving 250 mg/kg/day.

Other signs include, at 1000 mg/kg/day, ungroomed coat and for females, general hairloss.

There were no neurological changes in behavior.

Bodyweight gains were lower for males receiving 1000 mg/kg/day when compared with controls.

Lower food intake was recorded for high dosage males and females during the last week of treatment.

The food conversion efficiencies of males receiving 1000 mg/kg/day was low throughout the study, whereas females at this dosage were similarly affected only during the last week of treatment.

When compared with control values, the water intake of animals receiving 1000 mg/kg/day was high and that for females receiving 250 mg/kg/day was slightly high.

After 24 days of treatment reduced mean cell volumes and mean cell haemoglobin were recorded for males and females receiving 1000 mg/kg/day with marginally low packed cell volume and haemoglobin concentrations also recorded for high dosage females. High total leucocyte and monocyte counts were recorded for males and females receiving 1000 mg/kg/day with high lymphocyte counts in all treated males and females receiving 1000 mg/kg/day.

Biochemical analysis of animals receiving 1000 mg/kg/day revealed high creatinine concentrations, low chloride concentrations and changes in plasma protein concentrations; high calcium and phosphorus concentrations and high aspartate alanine amino-transferase activities for high dosage males. Other findings included high phosphorus concentrations for females receiving 250 mg/kg/day and changes in plasma protein concentrations for males receiving 62.5 or 250 mg/kg/day.

After 22 days of treatment, high urinary volumes and slightly low specific gravities for males and females receiving 1000 mg/kg/day; increased protein concentrations for treated males and females receiving 250 and 1000 mg/kg/day. In addition, the number of crystals detected for high dosage animals was low when compared with controls and epithelial cells or polymorphonuclear leucocytes were present in the urine of a number of animals receiving 250 or 1000 mg/kg/day.

There were no changes in the sperm numbers, motility or morphology of treated animals.

Organ weight analysis indicated high absolute and bodyweight-relative, liver, kidney and adrenal weights for males and females that received 1000 mg/kg/day and slightly high absolute and bodyweight-relative liver weights for males that received 250 mg/kg/day.

Microscopic changes comprised a high incidence of basophilic cortical tubules, hyaline casts and tubular dilatation in the kidneys of males that received 250 mg/kg/day and for males and females that received 1000 mg/kg/day with intracellular debris also recorded in the kidneys of high dosage animals; diffuse hypertrophy in the liver of animals that received 250 or 1000 mg/kg/day; increased incidence of cortical fatty vacuolation in the adrenals of high dosage animals.

Applicant's summary and conclusion

Conclusions:

As a conclusion it can be assumed that oral administration of diphenyl cresyl phosphate to CD rats for four weeks at dosages of 250 mg/kg/day and above was associated with a number of toxic findings which included changes in renal function and, at 1000 mg/kg/day, change in the adrenals and mortality. Diffuse hypertropy in the liver of animals that received 250 or 1000 mg/kg bw were observed.
There were no treatment-related histopathological changes in the brain, sciatic nerve, spinal cord, testes, epididymides or ovaries.
In the absence of any major disturbances in the clinical pathology parameters of animals that received 62.5 mg/kg/day and as there were no treatment-related microscopic changes at this dosage, it is concluded that the no-observed-adverse effect level (NOAEL) was 62.5 mg/kg/day.
There were no treatment-related histopathological changes in the brain, sciatic nerve, spinal cord, testes, epididymides or ovaries.
In the absence of any major disturbances in the clinical pathology parameters of animals that received 62.5 mg/kg/day and as there were no treatment-related microscopic changes at this dosage, it is concluded that the no-observed-adverse effect level (NOAEL) was 62.5 mg/kg/day.

Executive summary:

In a repeated dose toxicity study three groups of five male and five female CD rats received Diphenyl Cresyl Phosphate at dosages of 62.5, 250 or 1000 mg/kg/day by oral gavage administration for four weeks. A similarly constituted control group received the vehicle alone (maize oil).

Four males and two females receiving 1000 mg/kg/day died during the last week of treatment. Necropsy findings included abnormal kidneys in one male and thickened wall or abnormal contents of the urinary bladder in two males. Histopathology indicated changes in the liver, kidneys and adrenals. These deaths were considered to be directly related to the administration of the test material.

From Day 4 of treatment, salivation associated with dosing was observed among animals receiving 1000 mg/kg/day and occasionally among animals receiving 250 mg/kg/day.

Other signs include, at 1000 mg/kg/day, ungroomed coat and for females, general hairloss.

There were no neurological changes in behavior.

Bodyweight gains were lower for males receiving 1000 mg/kg/day when compared with controls.

Lower food intake was recorded for high dosage males and females during the last week of treatment.

The food conversion efficiencies of males receiving 1000 mg/kg/day was low throughout the study, whereas females at this dosage were similarly affected only during the last week of treatment.

When compared with control values, the water intake of animals receiving 1000 mg/kg/day was high and that for females receiving 250 mg/kg/day was slightly high.

After 24 days of treatment reduced mean cell volumes and mean cell haemoglobin were recorded for males and females receiving 1000 mg/kg/day with marginally low packed cell volume and haemoglobin concentrations also recorded for high dosage females. High total leucocyte and monocyte counts were recorded for males and females receiving 1000 mg/kg/day with high lymphocyte counts in all treated males and females receiving 1000 mg/kg/day.

Biochemical analysis of animals receiving 1000 mg/kg/day revealed high creatinine concentrations, low chloride concentrations and changes in plasma protein concentrations; high calcium and phosphorus concentrations and high aspartate alanine amino-transferase activities for high dosage males. Other findings included high phosphorus concentrations for females receiving 250 mg/kg/day and changes in plasma protein concentrations for males receiving 62.5 or 250 mg/kg/day.

After 22 days of treatment, high urinary volumes and slightly low specific gravities for males and females receiving 1000 mg/kg/day; increased protein concentrations for treated males and females receiving 250 and 1000 mg/kg/day. In addition, the number of crystals detected for high dosage animals was low when compared with controls and epithelial cells or polymorphonuclear leucocytes were present in the urine of a number of animals receiving 250 or 1000 mg/kg/day.

There were no changes in the sperm numbers, motility or morphology of treated animals.

Organ weight analysis indicated high absolute and bodyweight-relative, liver, kidney and adrenal weights for males and females that received 1000 mg/kg/day and slightly high absolute and bodyweight-relative liver weights for males that received 250 mg/kg/day.

Microscopic changes comprised a high incidence of basophilic cortical tubules, hyaline casts and tubular dilatation in the kidneys of males that received 250 mg/kg/day and for males and females that received 1000 mg/kg/day with intracellular debris also recorded in the kidneys of high dosage animals; diffuse hypertrophy in the liver of animals that received 250 or 1000 mg/kg/day; increased incidence of cortical fatty vacuolation in the adrenals of high dosage animals.

As a conclusion it can be assumed that oral administration of Diphenyl Cresyl Phosphate to CD rats for four weeks at dosages of 250 mg/kg/day and above was associated with a number of toxic findings which included changes in renal function and, at 1000 mg/kg/day, change in the adrenals and mortality.

There were no treatment-related histopathological changes in the brain, sciatic nerve, spinal cord, testes, epididymides or ovaries.

In the absence of any major disturbances in the clinical pathology parameters of animals that received 62.5 mg/kg/day and as there were no treatment-related microscopic changes at this dosage, it is concluded that the no-observed-adverse effect level (NOAEL) was 62.5 mg/kg/day.