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Endpoint summary

Description of key information

For CDP (phenyl dicresyl phosphate) a 28 day repeated dose toxicity study equivalent or similar to OECD 407 and an OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) screening study according to OECD 422 are available. No sub-chronic study for CDP is available.

Based on the similar chemical structure and a trend in biological activity a category has been defined. The category consists of CDP (Diphenyl cresyl phosphate), TPP (Triphenyl phosphate) and TCP (Tricresyl phosphate). Structurally CDP (diphenyl cresyl phosphate) is more similar to TPP (triphenyl phosphate) than to TCP (tricresyl phosphate) because CDP (diphenyl cresyl phosphate) has only one cresyl group, whereas TPP (tricresyl phosphate) has 3 cresyl groups. A category justification document is attached in chapter 13.

Based on the category approach a read-across to studies from TPP and TCP is justified to fill the data gap of CDP concerning the sub-chronic study.

The following studies are available for category members.

In a 28 day 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 hair loss. 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 were 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 leukocyte 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 (BG Chemie, 1995).

Diphenyl cresyl phosphate was studied for oral toxicity in rats in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test at doses of 12, 60 and 300 mg/kg/day. In the 300 mg/kg group, increased salivation, suppression in body weight gain and an increase in water intake in both sexes, and an increase in food consumption in male rats were noted. At necropsy, enlargement of the adrenals and liver were observed in both sexes. Histopathological examination showed cortical vacuolation of the adrenals, enlargement of the liver and fatty change of the proximal tubular epithelium in kidneys in both sexes. In addition, a reduction of fatty change of the hepatocytes, an increase in hyaline droplets and basophilia change in the proximal tubular epithelium in the kidneys, erosion or focal necrosis of the mucosa in the stomach, and atrophy of seminiferous tubules in the testes were observed in males. Increased glycogen of hepatocytes, atrophy of the thymus and interstitial cell hypertrophy and hyperplasia in the ovaries were also observed in female rats. Hematological hypertrophy and hyperplasia in the ovaries were also observed in female rats. Hematological examination of males showed anemia and an increase of leukocytes in the 300 mg/kg group. Blood chemical examination revealed an increase in GPT, gamma-GTP, total cholesterol and calcium, and decreases in GOT, albumin, the A/G ratio and triglycerides in males of the 300 mg/kg group. A decrease of cholinesterase activities in the brain, serum and erythrocytes at 60 and 300 mg/kg/day is regarded as equivocal because the decrease was only slight compared to control (5.8%, 22.65%, 35%, respectively) and it is assumed that this slight inhibition of cholinesterase activities is not biologically significantly adverse. This can be justified by the Biological Tolerance Value (BAT) of reduced acetylcholinesterase activity to 70% of reference value for samples collected at the end of exposure or end of shift; for long-term sampling, sample after several shifts. This value of 70% was recommended by the German Commission for the Investigation of health Hazards of Chemical Compounds in the Work Area (MAK, 2009) as well as the respective organization in the USA (ACGIH, 2001). Additionally no neurotoxic effects were observed in the rat study according to OECD 422 or the subacute toxicity study at any dose. Overall, the slightly decreased cholinesterase activity observed at 60 and 300 mg/kg/day is not regarded as adverse. Furthermore, potential contamination with o-cresyl residues can not be excluded as no information on the o-cresyl content of the test compound is available. (Neurotoxicity is reported for o-cresyl phosphates as a result from esterase inhibition by cyclic phosphate metabolites – cyclisation is only possible for o-cresyl residues, not for m- or p-cresyl residues) [for further details on o-cresyl isomers see chapter ´Other effects- specific investigations]. On urinalysis, decreases in pH and specific gravity, and an increase of urine volume were found in males of the 300 mg/kg group. In the 60 mg/kg group, the similar histopathological changes in the adrenals were noted in both sexes. In addition, increases in food consumption and total cholesterol, a decrease in cholinesterase activity, and enlargement of the liver were found in male rats, and suppression in body weight gain as well as histopathological changes in the liver, kidneys and the thymus were noted in females. The NOEL for the repeat dose toxicity is considered to be 12 mg/kg/day for both sexes and the LOAEL is 60 mg/kg/day based on the effects observed in the adrenals, liver and kidneys (JETOC, 1997; Matsuura et. al., 1995).

Wistar rats were treated with triphenyl phosphate for 90 consecutive days by dietary administration at dose levels of 0, 300, 1500 and 7500 ppm according to OECD 408. The mean test article intake over the study period was 0, 20, 105, and 583 mg/kg bw/d for males and 0, 22, 117, and 632 mg/kg bw/d for females. All groups consisted of 10 male and 10 female rats.

Treatment with the test substance up to 7500 ppm was well tolerated by the animals. No treatment-related mortality occurred, and no toxicologically relevant clinical signs were noted. Slight changes in body weight and food intake were not considered adverse in nature. A treatment-related increase in liver weight at 7500 ppm (approximately 30 and 21% for males and females, respectively) was considered adverse in nature, although no supportive adverse histopathological changes were noted in the liver. Histopathological findings in the stomach and adrenal glands were not considered to be adverse as these can also be found in control animals at similar severities and incidences.

Based on the liver weight increase at 7500 ppm, a No Observed Adverse Effect Level (NOAEL) for Triphenyl phosphate of 1500 ppm (corresponding to an actual test article intake of 105 and 117 mg/kg for males and females, respectively) was established.

Groups of 10 male and 10 female rats received tricresyl phosphate in corn oil by gavage at doses of 0, 50, 100, 200, 400, or 800 mg/kg bodyweight. All rats survived to the end of the study. Final mean body weights of male rats receiving 200,400, and 800 mg/kg were significantly lower than that of the controls. Cytoplasmic vacuolization of the adrenal cortex occurred in all dosed groups and the severity increased with dose. Ovarian interstitial cell hypertrophy occurred in all dosed groups of females.

Atrophy of the seminiferous tubules occurred in male rats that received 400 and 800 mg/kg. There were no biologically significant changes in neurobehavioral parameters in rats. No NOAEL was identified. The LOAEL was 50 mg/kg bw due to cytoplasmic vacuolization of the adrenal cortex occurred in all dosed groups and the severity increased with dose.

Groups of 10 male and 10 female rats were fed diets containing 0, 900, 1700, 3300, 6600, or 13000 ppm of tricresyl phosphate. All rats survived to the end of the study. Final mean body weights of males and females exposed to 6600 and 13000 ppm and females exposed to 3300 ppm were significantly lower than those of controls. Feed consumption by male and female rats exposed to 13000 ppm was lower than that by controls during the first week of the study.

Dietary levels of 900, 1700, 3300, 6600 or 13000 ppm tricresyl phosphate were estimated to deliver daily doses of 55, 120, 220,430, or 750 mg/kg bodyweight (males) and 65, 120, 230, 430, or 770 mg/kg (females).There were no biologically significant changes in neurobehavioral parameters in rats.

Cytoplasmic vacuolization of the adrenal cortex occurred in all exposed groups of rats. Hyperplasia of ovarian interstitial cells and inflammation of the ovarian interstitium occurred in all exposed groups of females. Renal papillary edema and renal papillary necrosis occurred in 13000 ppm males and females and in 6600 ppm females. Basophilic hypertrophy of the pituitary gland pars distalis and atrophy of the seminiferous tubules occurred in 6600 and 13000 ppm males. No NOAEL was identified. The LOAEL was 900 ppm (55 mg/kg bodyweight (males) and 65  mg/kg bodyweight (females)) due to cytoplasmic vacuolation of the adrenal cortex occurred in all groups of dosed animals.

For risk assessment, the 28 day repeated dose toxicity study and the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) screening study according to OECD 422 are considered:

As a starting point for the risk assessment the NOEL of 12 mg/kg/day reported in the combined repeat dose and reproductive/developmental toxicity screening test is too conservative because: 1) the dosing interval is high (factor of 5) and consequently the no-effect-level is likely to be higher than the NOEL. 2) the subacute study has to be taken into account in a weight-of-evidence approach (BG Chemie, 1995). In both studies adrenals, liver and kidney were identified as target organs. No adverse effects were observed in the sub-acute toxicity study at 62.5 mg/kg but some effects were observed in the combined repeat dose and reproductive/developmental toxicity screening test at 60 mg/kg/day. Overall, it can be concluded that the LOAEL of 60 mg/kg/day reported in the an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test is a dose close to the NOAEL reported in the subacute toxicity study similar to OECD 407.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

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

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

Species:

rat

Strain:

other: CD

Sex:

male/female

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

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

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.

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.

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

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.

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.

Reference 2

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:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

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

Principles of method if other than guideline:

Diphenyl cresyl phosphate was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 12, 60, and 300 mg/kg/day.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

olive oil

Duration of treatment / exposure:

Male, 45 days; Female from 14 days before mating to day 3 of lactation

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0 (vehicle), 12, 60, 300 mg/kg/day
Basis:
other: gavage

No. of animals per sex per dose:

10 male and 10 female rats/dose

Control animals:

yes, concurrent vehicle

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

In the 300 mg/kg group, increased salivation and suppression in body weight gain and an increase were noted.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In the 300 mg/kg group suppression in body weight gain and an increase were noted.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In the 300 mg/kg group an increase in water intake in both sexes, and an increase in food consumption in male rats were noted.

Food efficiency:

not specified

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

effects observed, treatment-related

Description (incidence and severity):

In the 300 mg/kg group an increase in water intake in both sexes, and an increase in food consumption in male rats were noted.

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Hematological examination of males showed anemia, and an increase of leukocytes in the 300 mg/kg group. Blood chemical examination revealed a decrease of cholinesterase activities in the brain, serum and erythrocytes, increases in GPT, gamma-GTP, total cholesterol and calcium, and decreases in GOT, albuminum, the A/G ratio and triglycerides in males of the 300 mg/kg group. On urinalysis, decreases in pH and specific gravity, and an increase of urine volume were found in males of the 300 mg/kg group.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Blood chemical examination revealed a decrease of cholinesterase activities in the brain, serum and erythrocytes, increases in GPT, gamma-GTP, total cholesterol and calcium, and decreases in GOT, albuminum, the A/G ratio and triglycerides in males of the 300 mg/kg group. On urinalysis, decreases in pH and specific gravity, and an increase of urine volume were found in males of the 300 mg/kg group.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

On urinalysis, decreases in pH and specific gravity, and an increase of urine volume were found in males of the 300 mg/kg group.

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):

At necropsy, at a dose of 300 mg/kg/bw enlargement of the adrenals and liver were observed in both sexes.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathological examination showed cortical vacuolation of the adrenals, enlargement of the liver and fatty change of the proximal tubular epithelium in kidneys in both sexes. In addition, a reduction of fatty change of the hepatocytes, an increase in hyaline droplets and basophilia change in the proximal tubular epithelium in the kidneys, erosion or focal necrosis of the mucosa in the stomach, and atrophy of seminiferous tubules in the testes were observed in males. Increased glycogen of hepatocytes, atrophy of the thymus and interstitial cell hypertrophy and hyperplasia in the ovaries were also observed in female rats. n the 60 mg/kg group, the similar histopathological changes in the adrenals were noted in both sexes. In addition, increases in food consumption and total cholesterol, a decrease in cholinesterase activity, and enlargement of the liver were found in male rats, and suppression in body weight gain as well as histopathological changes in the liver, kidneys and the thymus were noted in females.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Key result

Dose descriptor:

NOEL

Effect level:

ca. 12 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

60 mg/kg bw/day (nominal)

System:

hepatobiliary

Organ:

kidney

liver

other: adrenals

Treatment related:

yes

Dose response relationship:

yes

The NOEL for the repeat dose toxicity is considered to be 12 mg/kg/day for both sexes.

Conclusions:

Histopathological examination showed various changes in in the adrenals, liver, kidneys, stomach, testes, thymus and ovaries. Various blood parameters and clinical chemical paramaters were elevated.

Executive summary:

Diphenyl cresyl phosphate was studied for oral toxicity in rats in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test at doses of 12, 60 and 300 mg/kg/day.

In the 300 mg/kg group, increased salivation, suppression in body weight gain and an increase in water intake in both sexes, and an increase in food consumption in male rats were noted. At necropsy, enlargement of the adrenals and liver were observed in both sexes. Histopathological examination showed cortical vacuolation of the adrenals, enlargement of the liver and fatty change of the proximal tubular epithelium in kidneys in both sexes. In addition, a reduction of fatty change of the hepatocytes, an increase in hyaline droplets and basophilia change in the proximal tubular epithelium in the kidneys, erosion or focal necrosis of the mucosa in the stomach, and atrophy of seminiferous tubules in the testes were observed in males. Increased glycogen of hepatocytes, atrophy of the thymus and interstitial cell hypertrophy and hyperplasia in the ovaries were also observed in female rats. hematological hypertrophy and hyperplasia in the ovaries were also observed in female rats. Hematological examination of males showed anemia, and an increase of leukocytes in the 300 mg/kg group. Blood chemical examination revealed a decrease of cholinesterase activities in the brain, serum and erythrocytes, increases in GPT, gamma-GTP, total cholesterol and calcium, and decreases in GOT, albuminum, the A/G ratio and triglycerides in males of the 300 mg/kg group. On urinalysis, decreases in pH and specific gravity, and an increase of urine volume were found in males of the 300 mg/kg group. In the 60 mg/kg group, the similar histopathological changes in the adrenals were noted in both sexes. In addition, increases in food consumption and total cholesterol, a decrease in cholinesterase activity, and enlargement of the liver were found in male rats, and suppression in body weight gain as well as histopathological changes in the liver, kidneys and the thymus were noted in females.

The NOEL for the repeat dose toxicity is considered to be 12 mg/kg/day for both sexes.

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

See attached justification.

Observations and examinations performed and frequency:

in line with Guideline requirements

Details on results:

Treatment with the test substance up to 7500 ppm was well tolerated by the animals. No treatment-related mortality occurred, and no toxicologically relevant clinical signs were noted. The only in-life findings of note were a lower body weight (gain) in both sexes at 7500 ppm (approximately 21% and 12% lower for males and females at 7500 ppm, respectively), along with a slightly higher food intake (approximately 16% and 12% higher for males and females at 7500 ppm, respectively). Body weights of males showed an apparent slight dose-related decrease over the dose groups. Since these changes in body weight and food intake were considered slight in nature, these were not considered adverse in nature.

An apparent higher motor activity was recorded for males at 7500 ppm, which was not considered to be adverse in nature. Based on individual values, no clear dose-related group-response was noted, both in total mean counts and counts per interval. Also, all groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period. Also, these results were not supported by clinical observations or other functional observation tests and had no supportive morphological correlates in examined neuronal tissues.

There were treatment-related morphologic alterations in the liver, thyroid gland (males only), adrenal glands (both sexes) and stomach (females only), starting at 1500 ppm.

Histopathological findings in the liver consisted of centrilobular hepatocellular hypertrophy of the liver in males at 1500 and 7500 ppm and in females at 7500 ppm (up to slight degree). This was not considered to be adverse at the recorded severities and since degenerative changes in the liver were absent. This finding was accompanied by enlargement and red brown discolouration of the liver and higher liver weight at necropsy at 7500 ppm. The magnitude of liver weight increase at 7500 ppm (approximately 30 and 21% for males and females, respectively) was considered adverse in nature, although no supportive adverse histopathological changes were noted in the liver.

Morphological findings in the thyroid consisted of an increased incidence and/or severity of follicular cell hypertrophy of the thyroid gland in males at 1500 and 7500 ppm (up to slight degree), which might be secondary to the hepatocellular hypertrophy and is not considered to be adverse (Ref. 5). Necropsy of males at 7500 ppm showed enlargement and higher weight of the thyroid gland.

Histopathological findings in the stomach and adrenal glands were not considered to be adverse as these can also be found in control animals at similar severities and incidences. These lesions consisted of vacuolation of the limiting ridge of the stomach in females at 1500 and 7500 ppm (up to slight degree), hyperplasia and hyperkeratosis of the limiting ridge in a single female at 7500 ppm (at minimal degree), and increased vacuolation of the zona fasciculata or zona glomerulosa of the adrenal glands in males and females respectively at 7500 ppm (up to slight degree).

Changes in clinical biochemistry parameters consisted of higher total protein and calcium in males at 7500 ppm, and higher cholesterol in males and females at 7500 ppm, and in males also at 1500 ppm. These changes occurred in the absence of any correlating adverse histopathological changes, and were therefore not considered adverse in nature.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks:

(test material intake of 1500 ppm treated males)

Sex:

male

Basis for effect level:

other: liver weight increase in males of the 7500 ppm group

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks:

(test material intake of 1500 ppm treated females)

Sex:

female

Basis for effect level:

other: liver weight in crease in females of the 7500 pm group

Critical effects observed:

not specified

Mean test article intake over the study period was as follows:

 

group	Nominal dietary inclusion level [ppm]	Average intake [mg test substance/kg body weight] (range indicated within brackets)
		males		females
2	300	20	(16-29)	22	(18-28)
3	1500	105	(81-151)	117	(97-147)
4	7500	583	(448-853)	632	(520-798)

 

Conclusions:

Wistar rats were treated with Triphenyl phosphate for 90 consecutive days by dietary administration at dose levels of 0, 300, 1500 and 7500 ppm according to OECD 408. The mean test article intake over the study period was 0, 20, 105, and 583 mg/kg bw/d for males and 0, 22, 117, and 632 mg/kg bw/d for females. All groups consisted of 10 male and 10 female rats.
Treatment with the test substance up to 7500 ppm was well tolerated by the animals. No treatment-related mortality occurred, and no toxicologically relevant clinical signs were noted. Slight changes in body weight and food intake were not considered adverse in nature. A treatment-related increase in liver weight at 7500 ppm (approximately 30 and 21% for males and females, respectively) was considered adverse in nature, although no supportive adverse histopathological changes were noted in the liver. Histopathological findings in the stomach and adrenal glands were not considered to be adverse as these can also be found in control animals at similar severities and incidences.
Based on the liver weight increase at 7500 ppm, a No Observed Adverse Effect Level (NOAEL) for Triphenyl phosphate of 1500 ppm (corresponding to an actual test article intake of 105 and 117 mg/kg for males and females, respectively) was established.

Executive summary:

Wistar rats were treated with Triphenyl phosphate for 90 consecutive days by dietary administration at dose levels of 0, 300, 1500 and 7500 ppm according to OECD 408. The mean test article intake over the study period was 0, 20, 105, and 583 mg/kg bw/d for males and 0, 22, 117, and 632 mg/kg bw/d for females. All groups consisted of 10 male and 10 female rats.

Treatment with the test substance up to 7500 ppm was well tolerated by the animals. No treatment-related mortality occurred, and no toxicologically relevant clinical signs were noted. Slight changes in body weight and food intake were not considered adverse in nature. A treatment-related increase in liver weight at 7500 ppm (approximately 30 and 21% for males and females, respectively) was considered adverse in nature, although no supportive adverse histopathological changes were noted in the liver. Histopathological findings in the stomach and adrenal glands were not considered to be adverse as these can also be found in control animals at similar severities and incidences.

Based on the liver weight increase at 7500 ppm, a No Observed Adverse Effect Level (NOAEL) for Triphenyl phosphate of 1500 ppm (corresponding to an actual test article intake of 105 and 117 mg/kg for males and females, respectively) was established.

Reference 4

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

See attached justification.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Mortality:

mortality observed, treatment-related

Description (incidence):

see below for details

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

see below for details.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Details on results:

CLINICAL SIGNS
The only chemical related clinical finding was emaciation, which was observed by day 23 in males and by day 10 in females exposed to 13,600ppm.

MORTALITY
All rats survived to the end of the study.

BODY WEIGHT AND WEIGHT GAIN
Final mean body weights and mean body weight gains of females exposed to 3,300 ppm and males and females exposed to 6,600 or 13,000 ppm were significantly lower than those of the controls.

FOOD CONSUMPTION
During the first week of the study feed consumption by groups of male and female rats exposed to 13,000 ppm was 58% and 50% lower than that by the controls and remained somewhat lower than the controls throughout the study, indicating reduced palatability of feed containing tricresyl phosphate at this concentration. Feed consumption by males exposed to 6,600 ppm was 16% lower than that by controls during the first week of the study.

HAEMATOLOGY
There were no differences inthe hematological parameters which were considered to be related to chemical exposure.

CLINICAL CHEMISTRY
Significant and dose-related decreases in the serum cholinesterase activity was present in all exposed groups of rats.

NEUROBEHAVIOUR
There were no biologically significant changes in the neurobehavioral measurements of rats exposed to tricresyl phosphate.

ORGAN WEIGHTS
Relative liver weights of males and females exposed to 1,700, 3,300, 6,600, and 13,000 ppm and absolute liver weights of 6,600 ppm males and females and of 13,000 ppm females were significantly greater than those of controls. Absolute and relative right testis weights of males exposed to 6,600 and 13,000ppm were significantly lower than those of the controls. Other organ weight differences were most likely due to the reduced body weights of groups exposed to 3,300, 6,600, and 13,000 ppm.

GROSS PATHOLOGY AND HISTOPATHOLOGY
At necropsy adrenal gland enlargement was observed in two males and four females exposed to 6,600 ppm and four males and six females exposed t o 13,000 ppm. In addition, small testes were observed in one 6,600ppm and four 13,000 ppm males.
Microscopic lesions asssociated with chemical exposure were present in the testis, epididymis, adrenal gland, pituitary gland, and kidney of males, and the ovary, adrenal gland, and kidney of females.
The lesions in the testis, ovary, and adrenal gland were similar to those observed in the 13-week gavage study. Cytoplasmic vacuolation of the adrenal cortex occurred in all groups of dosed animals. Small focal accumulations of mononuclear inflammatory cells (chronic inflammation) were also observed in the ovary of some exposed females but the incidence and severity did not increase with dose. Small groups of lymphocytes were also observed in the adrenal cortex of some male and female rats exposed to tricresyl phosphate.
Hypertrophy of basophils of the pars distalis of the pituitary gland was observed in several males exposed to 3,300, 6,600, or 13,000 ppm tricresyl phosphate. Scattered individual basophils were enlarged and had pales taining or clear cytoplasm. This effect is consistent with the testicular atrophy observed in males, and may be due to loss of feedback inhibition of secretion of gonadotropin releasing hormone (GnRH) in the hypothalamus with aconsequent stimulation of pituitary secretion of gonadotropins. A similar effect has been observed in castrated males.
Edema and/ornecrosis of the renal papilla was observed in nearly all male and female rats exposed to 13,000 ppm and most rats exposed to 6,600 ppm. The interstitium was distended, presumably from edema, and there was coagulative necrosis of the epithelium lining the papillary ducts and thin limbs of the loop of Henle with no accompanying inflammatory response. One or a few scattered foci of tubule regeneration consistent with an early stage of nephropathy were also observed in the kidney of most rats in the 13,000 ppm groups, but not in the controls.

Dose descriptor:

NOAEL

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Cytoplasmic vacuolation of the adrenal cortex occurred in all groups of dosed animals.

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Dose descriptor:

LOAEL

Effect level:

900 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Cytoplasmic vacuolation of the adrenal cortex occurred in all groups of dosed animals. 900 ppm estimated to deliver 55 mg/kg bodyweight (males) and 65 mg/kg bodyweight (females)

Critical effects observed:

not specified

Conclusions:

A 13-week feeding study was conducted in which groups of ten male and ten female rats were fed diets containing 0, 900, 1,700, 3,300, 6,600 or 13,000 ppm tricresyl phosphate (estimated to deliver 0, 55, 120, 220, 430 or 750 mg/kg bodyweight (males) and 0, 65, 120, 230, 430 or 770 mg/kg bodyweight (females)). All rats survived to the end of the study. Mean bodyweights of males and females receiving 6,600 and 13,000 ppm and females exposed to 13,000 ppm were significantly lower than controls during the first week of the study. Cytoplasmic vacuolation of the adrenal cortex occurred in all groups of dosed animals. Hyperplasia of ovarian interstitial cells and inflammation of the ovarian interstitium occurred in all exposed groups of females. Renal papillary oedema and renal papillary necrosis occurred in males and females receiving 13,000 ppm and in females receiving 6600 ppm. Basophilic hypertrophy of the pituitary gland pars distalis and atrophy of the seminiferous tubules occurred in males receiving 6,600 and 13,000 ppm.

Executive summary:

Groups of 10 male and 10 female rats were fed diets containing 0, 900, 1,700, 3,300, 6,600,or 13,000 ppm of tricresyl phosphate. All rats survived to the end of the study. Final mean body weights of males and females exposed to 6,600 and 13,000 ppm and females

exposed to 3,300 ppm were significantly lower than those of controls. Feed consumption by male and female rats exposed to 13,000 ppm was lower than that by controls during the first week of the study.

Dietary levels of 900, 1,700, 3300,6600 or 13,000 ppm tricresyl phosphate were estimated to deliver daily doses of 55, 120, 220,430, or 750 mg/kg bodyweight (males) and 65, 120, 230, 430, or 770 mg/kg (females).There were no biologically significant changes in neurobehavioral parameters in rats.

Cytoplasmic vacuolization of the adrenal cortex occurred in all exposed groups of rats. Hyperplasia of ovarian interstitial cells and inflammation of the ovarian interstitium occurred in all exposed groups of females. Renal papillary edema and renal papillary necrosis occurred in 13,000 ppm males and females and in 6,600 ppm females. Basophilic hypertrophy of the pituitary gland pars distalis and atrophy of the seminiferous tubules ocurred in 6,600 and 13,000 ppm males.

Reference 5

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

See attached justification.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

see below for details

Details on results:

CLINICAL SIGNS
There were no clinical findings clearly related to tricresyl phosphate administration.

MORTALITY
All rats survived to the end of the study.

BODY WEIGHT AND WEIGHT GAIN
Mean body weights of male rats that received 800 mg/kg were lower than those of the controls throughout the received 800 mgkg study, whereas mean body weights of males that received 200 or 400 mg/kg were lower than those of controls during the latter half of the study. The final mean body weights and mean body weight gains of males receiving 200, 400,and 800 mg/kg were significantly lower than those of the controls.The final mean body weights of dosed groups of female rats were similar to that of the controls.

FOOD CONSUMPTION
Average daily feed consumption by male and female rats that received 800 mg/kg was slightly greater than feed consumption by controls; however, feed consumption by groups receiving lower doses was similar to consumption by controls.

HAEMATOLOGY
Hemoglobin concentration and erythrocyte counts in males that received 400 or 800 mg/kg and the hemoglobin concentration in females that received 200 or 800 mg/kg were significantly lower than those of the controls. However, the magnitude of the decreases were small and not indicative of toxicity to the blood or hematopoietic system.

CLINICAL CHEMISTRY
There were also significant, dose-related decreases in the serum cholinesterase activity in all dosed groups of males and females.

NEUROBEHAVIOUR
The only neurobehavioral measure affected by chemical exposure in the 13-week gavage study was hind limb grip strength, which was significantly
reduced in female rats that received 400 or 800 mg/kg. However, the magnitude of the reduction was small, and the difference between group mean
grip strength recorded on study day 0 and that recorded at week 13 did not differ significantly from the corresponding difference measured for the
control group.

ORGAN WEIGHTS
Absolute and relative liver weights of male rats that received 800 mg/kg and female rats that received 400 or 800 mg/kg were significantly greater than those of controls,whereas the absolute and relative thymus weights of males and females and the absolute and relative testis weights of males decreased with dose. Several organ weight to body weight ratios of males receiving 200,400, or 800 mg/kg were significantly different from controls; however, the lower final mean body weights of these groups tend to obscure any possible association between these differences and a toxic response.

GROSS PATHOLOGY AND HISTOPATHOLOGY
The principal lesions associated with administration of tricresyl phosphate by gavage for 13 weeks occurred in the testis, ovary, and adrenal gland. Atrophy of the testis was observed in all males receiving 400 or 800 mg/kg and was characterized by focal to diffuse loss of spermatogenic cells from the seminiferous tubules. The most severely affected tubules had only a thin layer of Sertoli cells remaining.
Hypertrophy of ovarian interstitial cells occurred in all female rats receiving tricresyl phosphate. The interstitial cells were enlarged by abundant foamy cytoplasm, apparently due to lipid accumulation. While the change primarily appeared to be enlargement of the interstitial cells, it was uncertain if there was also an increased number of cells (hyperplasia).
Diffuse vacuolization of the zona glomerulosa and zona fasciculata of the adrenal cortex also occurred in all male and female rats receiving tricresyl phosphate, and the degree of vacuolization increased with dose.

Dose descriptor:

NOAEL

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Cytoplasmic vacuolation of the adrenal cortex occurred in all dosed animals.

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Dose descriptor:

LOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Cytoplasmic vacuolization of the adrenal cortex occurred in all dosed groups and the severity increased with dose.

Critical effects observed:

not specified

Conclusions:

A 13-week oral study was conducted in which groups of ten male and ten female rats received tricresyl phosphate in corn oil by gavage at doses of 0, 50, 100, 200, 400 or 800 mg/kg body weight. All rats survived to the end of the study. Final mean bodyweights of male rats receiving 200 mg/kg or more were significantly lower than controls. Cytoplasmic vacuolation of the adrenal cortex occurred in all dosage groups and the severity increased with dose. Ovarian interstitial cell hypertrophy occurred in all dosed groups of females. Atrophy of the seminiferous tubules occurred in male rats that received 400 and 800 mg/kg

Executive summary:

Groups of 10 male and 10 female rats received tricresyl phosphate in corn oil by gavage at doses of 0, 50, 100, 200, 400, or 800 mg/kg bodyweight. All rats survived to the end of the study. Final mean body weights of male rats receiving 200,400, and 800 mg/kg were significantly lower than that of the controls. Cytoplasmic vacuolization of the adrenal cortex occurred in all dosed groups and the severity increased with dose. Ovarian interstitial cell hypertrophy occurred in all dosed groups of females.

Atrophy of the seminiferous tubules occurred in male rats that received 400 and 800 mg/kg. There were no biologically significant changes in neurobehavioral parameters in rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

60 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Equivalent or similar to guideline studies

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

As a starting point for the risk assessment the NOEL of 12 mg/kg/day reported in the combined repeat dose and reproductive/developmental toxicity screening test is to conservative because: 1) the dosing interval is high (factor of 5) and consequently the no-effect-level is likely to be higher than the NOEL. 2) the subacute study has to be taken into account in a weight-of-evidence approach (BG Chemie, 1995). In both studies adrenals, liver and kidney were identified as target organs. No adverse effects were observed in the sub-acute toxicity study at 62.5 mg/kg but some effects were observed in the combined repeat dose and reproductive/developmental toxicity screening test at 60 mg/kg/day. Overall, it can be concluded that the LOAEL of 60 mg/kg/day reported in the an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test is a dose close to the NOAEL reported in the sub acute toxicity study similar to OECD 407.

Justification for classification or non-classification

There is a trend in the repeated dose toxicity of the category members (see category justification document).

In the available repeated dose toxicity studies triphenyl phosphate (TPP) only affected the liver as target organ. Diphenyl cresyl phosphate in addition showed microscopic changes on kidneys and adrenals and changes in hematological  parameters in high dose animals. Additional organs were affected in a repeated dose/reproductive/developmental screening test with a diphenyl cresyl phosphate test material with a purity of 41.9%, especially effects on the testes were observed.  With tricresyl phosphate testes toxicity was a main effect observed in repeated dose toxicity studies, especially with test substance with a low purity related to ortho-cresly content. Additional target organs observed were adrenals, ovaries, kidneys and pituitary gland.

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification for CDP (diphenyl cresyl phosphate) is not justified.