[No public or meaningful name is available]

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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:

1996

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

In an OECD 414 study diphenyl cresyl phosphate was administered by gavage at dosages of 100, 300 or 900 mg/kg/day to groups of 22 pregnant rats from Day 6 to 15 of gestation inclusive. All females were killed on Day 20 of gestation. The aim of the study was to assess the effects of oral administration of diphenyl cresyl phosphate during the organogenesis phase of gestation upon the progress and outcome of pregnancy in the rat.

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:

22.8% Triphenyl Phosphate,
32.3 Fiphenyl-p-cresyl-phosphate,
12.1% Diphenyl-m-cresyl phosphate,
14.3% Phenyl-di-m-cresyl phosphate,
10.0% Phenyl-m, p-cresyl phosphate,
1.7% Phenyl-di-p-cresyl phosphate,
3.1% Tri-m-cresyl phosphate,
2.9% Di-m, p-cresyl phosphate,
0.8% Di-p, m-cresyl phosphate,
0.1% Tri-p-cresyl phosphate,
<0.1% Unknown products,
99.9% Total

Test animals

Species:

rat

Strain:

other: CD

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

maize oil

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

Females were paired on a one-to-one basis with stock males of the same strain. Each morning following pairing, the trays beneath the cages were checked for ejected copulation plugs and a vaginal smear was prepared from each female and examined for the presence of spermatozoa. The day on which a sperm positive vaginal smear or at least three copulation plugs were found was designated Day 0 of gestation.

Duration of treatment / exposure:

From day 6 to Day 15 of gestation inclusive.

Frequency of treatment:

daily

Duration of test:

All females were killed on Day 20 of gestation for examination of their uterine content.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day

Remarks:

Control

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

300 mg/kg bw/day

Doses / concentrations 4

Dose / conc.:

900 mg/kg bw/day

No. of animals per sex per dose:

Groups of 22 female rats/dose

Control animals:

yes

Examinations

Maternal examinations:

Serial: Clinical signs, maternal body weight, food consumption, water consumption.
Terminal: Haematology, blood chemistry.

Ovaries and uterine content:

Number of corpora lutea, number of implantation sites, number of resorption sites, number and distribution of foetuses in each uterine horn.

Fetal examinations:

External and internal examination at necropsy. Skeletal examination at necropsy.

Statistics:

The significance of sugestive inter-group differences was tested using appropriate statistical tests.

Indices:

Pre-implantation loss, post-implantation loss, foetal observations.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Post-dose salivation was observed on a regular basis at 300 and 900 mg/kg/day in a doseage-related manner. Other signs observed at 900 mg/kg/day included brown staining, hailoss, urogenital staining, piloerection and ungroomed coat. The general condition of females receiving 100 and 300 mg/kg/day was similar to that of the Controls.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No deaths occurred.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Bodyweight stasis or loss was observed over Days 7 to 10 of gestation at 900 mg/kg/day, although the deficit was recouped by Day 20 of gestation. Weight gains at 100 and 300 mg/kg/day were unaffected by treatment.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was reduced at 900 mg/kg/day for the first few days of the treatment period. Food consumption at 100 and 300 mg/kg/day was similar to that of the controls.

Food efficiency:

not specified

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

effects observed, treatment-related

Description (incidence and severity):

Water consumption showed a marked increase throughout the treatment period, and up to termination, for females receiving 300 and 900 mg/kg/day. Water consumption at 100 mg/kg/day was unaffected by treatment.

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

On day 16 of gestation, packed cell volume, haemoglobin concentration and red blood cell count were lower for all treated groups, although females receiving 100 mg/kg bw were only marginally affected. Increased total leucocyte counts, neutrophil and platelet counts were recorded at 300 and 900 mg/kg/day. Polychromasia and/ or hypochromasia were observed for all females at 900 mg/kg/day.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Blood chemistry of females receiving 300 and 900 mg/kg/day revealed low albumin concentrations, slightly high alpha-globulin and high beta-globulin concentrations, and a lower albumin to globulin ratio. At 900 mg/kg/day, there were high alanine and aspartate amino-transferase activities, and marginally low plasma glucose concentrations.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

With the exception of four females exhibiting hairloss at 900 mg/kg/day, necropsy of females on Day 20 of gestation, revealed no macroscopic findings that were considered to be an effect of treatment.

Neuropathological findings:

not specified

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

no effects observed

Details on maternal toxic effects:

It was concluded from this investigation that oral administration of diphenyl cresyl phosphate to pregnant rats during the period of organogenesis at a dosage of 900 mg/kg/day resulted in several findings indicative of toxicity. These included reduced weight gain, increased water consumption and an effect on erythrocytic parameters. The liver was identified as a possible target organ.
At a dosage of 300 mg/kg/day, water consumption was increased, and erythrocytic parameters were affected as for the highest dosage, but to a lesser degree.
At the lowest dosage of 100 mg/kg/day, diphenyl cresyl phosphate was well tolerated with no signs of overt toxicity, and this was considered to be the maternal NOAEL.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Key result

Abnormalities:

effects observed, treatment-related

Description (incidence and severity):

A dosage of 900 mg/kg/day resulted in several findings indicative of toxicity. These included reduced weight gain, increased water consumption and an effect on erythrocytic parameters. The liver was identified as a possible target organ.
At a dosage of 300 mg/kg/day, water consumption was increased, and erythrocytic parameters were affected as for the highest dosage, but to a lesser degree.

Results (fetuses)

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Litter survival, growth and development in utero was unaffected by treatment with diphenyl cresyl phosphate at all dosages. Litter parameters growth and development were unaffected by treatment at all dosages, and the NOEL for foetuses was therefore considered to be 900 mg/kg/day.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Litter survival, growth and development in utero was unaffected by treatment with diphenyl cresyl phosphate at all dosages. Litter parameters growth and development were unaffected by treatment at all dosages, and the NOEL for foetuses was therefore considered to be 900 mg/kg/day.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Litter survival, growth and development in utero was unaffected by treatment with diphenyl cresyl phosphate at all dosages. Litter parameters growth and development were unaffected by treatment at all dosages, and the NOEL for foetuses was therefore considered to be 900 mg/kg/day.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Litter survival, growth and development in utero was unaffected by treatment with diphenyl cresyl phosphate at all dosages. Litter parameters growth and development were unaffected by treatment at all dosages, and the NOEL for foetuses was therefore considered to be 900 mg/kg/day.

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Litter survival, growth and development in utero was unaffected by treatment with diphenyl cresyl phosphate at all dosages. Litter parameters growth and development were unaffected by treatment at all dosages, and the NOEL for foetuses was therefore considered to be 900 mg/kg/day.

Effect levels (fetuses)

Key result

Dose descriptor:

NOEL

Effect level:

ca. 900 mg/kg bw/day

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

Satellite females, five per group, were similarly treated and killed on Day 16 of gestation, for determination of haematology and blood chemistry parameters.

Post-dose salivation was observed on a regular basis at 300 and 900 mg/kg/day in a doseage-related manner. Other signs observed at 900 mg/kg/day included brown staining, hailoss, urogenital staining, piloerection and ungroomed coat. The general condition of females receiving 100 and 300 mg/kg/day was similar to that of the Controls. No deaths occurred.

Bodyweight stasis or loss was observed over Days 7 to 10 of gestation at 900 mg/kg/day, although the deficit was recouped by Day 20 of gestation. Weight gains at 100 and 300 mg/kg/day were unaffected by treatment.

Food consumption was reduced at 900 mg/kg/day for the first few days of the treatment period. Food consumption at 100 and 300 mg/kg/day was similar to that of the Controls.

Water consumption showed a marked increase throughout the treatment period, and up to termination, for females receiving 300 and 900 mg/kg/day. Water consumption at 100 mg/kg/day was unaffected by treatment.

With the exception of four females exhibiting hairloss at 900 mg/kg/day, necropsy of females on Day 20 of gestation, revealed no macroscopic findings that were considered to be an effect of treatment.

Litter survival, growth and development in utero was unaffected by treatment with Diphenyl cresyl phosphate at all dosages.

On day 16 of gestation, packed cell volume, haemoglobin concentration and red blood cell count were lower for all treated groups, although females receiving 100 mg/kg bw were only marginally affected. Increased total leucocyte counts, neutrophil and platelet counts were recorded at 300 and 900 mg/kg/day. Polychromasia and/ or hypochromasia were observed for all females at 900 mg/kg/day.

Blood chemistry of females receiving 300 and 900 mg/kg/day revealed low albumin concentrations, slightly high alpha-globulin and high beta-globulin concentrations, and a lower albumin to globulin ratio. At 900 mg/kg/day, there were high alanine and aspartate amino-transferase activities, and marginally low plasma glucose concentrations.

Females receiving 100 mg/kg/day were considered to be unaffected by treatment.

Applicant's summary and conclusion

Conclusions:

It was concluded from this investigation that oral administration of Diphenyl Cresyl phosphate to pregnant rats during the period of organogenesis at a dosage of 900 mg/kg/day resulted in several findings indicative of toxicity. These included reduced weight gain, increased water consumption and an effect on erythrocytic parameters. The liver was identified as a possible target organ. At a dosage of 300 mg/kg/day, water consumption was increased, and erythrocytic parameters were affected as for the highest dosage, but to a lesser degree. At the lowest dosage of 100 mg/kg/day, Diphenyl cresyl phosphate was well tolerated with no signs of overt toxicity, and this was considered to be the maternal NOAEL.

Litter survival, growth and development in utero was unaffected by treatment with Diphenyl cresyl phosphate at all dosages. Litter parameters growth and development were unaffected by treatment at all dosages, and the NOEL for foetuses was therefore considered to be 900 mg/kg/day.

Executive summary:

The influence of Diphenyl cresyl phosphate upon the progress and outcome of pregnancy was assessed in sexually mature rats of the CD strain in accordance with the guidelines of the OECD 414. For this purpose , Diphenyl cresyl phosphate was administered by gavage at dosages of 100, 300 or 900 mg/kg/day to groups of 22 pregnant rats from Day 6 to 15 of gestation inclusive. Control animals received the vehicle, maize oil, throughout the same period. All females were killed on Day 20 of gestation for examination of their uterine contents.

Satellite females, five per group, were similarly treated and killed on Day 16 of gestation, for determination of haematology and blood chemistry parameters.

Post-dose salivation was observed on a regular basis at 300 and 900 mg/kg/day in a doseage-related manner. Other signs observed at 900 mg/kg/day included brown staining, hailoss, urogenital staining, piloerection and ungroomed coat. The general condition of females receiving 100 and 300 mg/kg/day was similar to that of the Controls. No deaths occurred.

Bodyweight stasis or loss was observed over Days 7 to 10 of gestation at 900 mg/kg/day, although the deficit was recouped by Day 20 of gestation. Weight gains at 100 and 300 mg/kg/day were unaffected by treatment.

Food consumption was reduced at 900 mg/kg/day for the first few days of the treatment period. Food consumption at 100 and 300 mg/kg/day was similar to that of the Controls.

Water consumption showed a marked increase throughout the treatment period, and up to termination, for females receiving 300 and 900 mg/kg/day. Water consumption at 100 mg/kg/day was unaffected by treatment.

With the exception of four females exhibiting hairloss at 900 mg/kg/day, necropsy of females on Day 20 of gestation, revealed no macroscopic findings that were considered to be an effect of treatment.

Litter survival, growth and development in utero was unaffected by treatment with Diphenyl cresyl phosphate at all dosages.

On day 16 of gestation, packed cell volume, haemoglobin concentration and red blood cell count were lower for all treated groups, although females receiving 100 mg/kg bw were only marginally affected. Increased total leucocyte counts, neutrophil and platelet counts were recorded at 300 and 900 mg/kg/day. Polychromasia and/ or hypochromasia were observed for all females at 900 mg/kg/day.

Blood chemistry of females receiving 300 and 900 mg/kg/day revealed low albumin concentrations, slightly high alpha-globulin and high beta-globulin concentrations, and a lower albumin to globulin ratio. At 900 mg/kg/day, there were high alanine and aspartate amino-transferase activities, and marginally low plasma glucose concentrations.

Females receiving 100 mg/kg/day were considered to be unaffected by treatment.

It was concluded from this investigation that oral administration of Diphenyl Cresyl phosphate to pregnant rats during the period of organogenesis at a dosage of 900 mg/kg/day resulted in several findings indicative of toxicity. These included reduced weight gain, increased water consumption and an effect on erythrocytic parameters. The liver was identified as a possible target organ.

At a dosage of 300 mg/kg/day, water consumption was increased, and erythrocytic parameters were affected as for the highest dosage, but to a lesser degree.

At the lowest dosage of 100 mg/kg/day, Diphenyl cresyl phosphate was well tolerated with no signs of overt toxicity, and this was considered to be the maternal NOAEL.

Litter parameters were unaffected by treatment at all dosages, and the NOEL for foetuses was therefore considered to be 900 mg/kg/day.