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Description of key information

Assessment of subchronic exposure by oral route is discussed below.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
other: Published study
Adequacy of study:
key study
Study period:
December 1982 to March 1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented published GLP study.
Qualifier:
no guideline followed
Principles of method if other than guideline:
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 for 5 days per week for 13 weeks..
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female F344/N rats were obtained from Simonsen Laboratories, Inc. (Gilroy, CA); rats were 40 days old upon receipt. Rats were quarantined 27 to 30 days before dosing began. At this time, five males and five females o f each species were randomly selected and evaluated for evidence of disease. At the end of the study, serology samples were collected from five male and five female control rats for murine virus antibody
determinations.
Average age when studies began: 10 weeks
Rats were housed five per cage; Feed and water were available ad libitum.
Temperature: 21-23 degrees C
Relative humidity: 40% to 60%
Fluorescent light: 12 hours/day
Room air changes: 15 changes/hour
Bedding: Ab-Sorb-Dri hardwood chips (Ab-Sorb-Dri. Inc.), changed twice weekly
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
The dose formulation suspensions for the gavage studies were prepared by mixing tricresyl phosphate in USP grade corn oil.
Dose formulations were prepared once. The stability of the gavage dose formulations was confirmed, based on the four major components, for at least 2 weeks at room temperature when stored in the dark, and for 3 hours when exposed to air and light.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of all of the dose formulations of tricresyl phosphate were conducted by the study laboratory with ultraviolet spectroscopy. For ultraviolet spectroscopy, samples were extracted with methanol; then after centrifugation the extracts were diluted with methanol and the absorbance determined at 265 nm. During the 13-week studies, the dose formulations were analyzed at the beginning, the midpoint, and end of the studies.
Determined concentrations differed form target concentrations by -4% to +7%.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days per week for 13 weeks.
Remarks:
Doses / Concentrations:
0,50,100, 200, 400, or 800 mg/kg body weight
Basis:
actual ingested
No. of animals per sex per dose:
10 male + 10 female per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale:
Due to reduced survival and the occurrence of lymphoid depletion of the spleen and thymus in male and female mice receiving 1,450, 2,900, and 5,800 mg/kg in the 16 day gavage study in mice, these doses were considered too high for the high dose in a 13-week gavage study. Therefore, 800 mg/kg was selected as the high dose for the 13-week gavage study, with the remaining doses being 50, 100, 200, and 400 mg/kg.
Animals randomized according to body weight using a table of random numbers.
Positive control:
None
Observations and examinations performed and frequency:
Clinical findings were recorded once weekly. The animals were weighed at study initiation and weekly thereafter.

Clinical Pathology
Blood was collected from the vena cava for hematology and clinical chemistry.
Haematology:erythrocytes, hemoglobin, hematocrit, mean erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration. mean erythrocyte volume, and total and differential leukocyte counts
Clinical Chemistry: Cholinesterase

Neurobehavioural examination
Spontaneous motor activity, forelimb and hindlimb grip strength, startle response and paw-lick latency were measured in all rats one week before dosing began and on the day before necropsy.
Sacrifice and pathology:
Method of sacrifice: Pentobarbital injection
Necropsy was performed on all animals.Organ weights were recorded for brain, heart, right kidney, liver, lung, left testis, and thymus.

Histopathology
Tissues for microscopic examination were embedded in paraffin, sectioned to a thickness of 4 to 6 um, and stained with hematoxylin and eosin.
Complete histopathology was performed on all controls, all animals dying early, and all rats receiving 800 mg/kg. In addition to gross lesions, the tissues examined included: adrenal gland, bone (including marrow). brain, clitoral gland (rats), epididymis, esophagus, gallbladder (mice), heart, kidney, large intestine (cecum. colon. rectum). liver, lung, mandibular and mesenteric lymph node, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland (rats), prostate gland, salivary gland. sciatic nerve, seminal vesicle, skin, small intestine (duodenum, jejunum, ileum), spinal cord, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder and uterus. In addition. the adrenal gland, ovary, and spinal cord and sciatic nerve of all dosed rats and and testis of dosed rats were examined.
Statistics:
Calculation of Incidence
The incidences of nonneoplastic lesions are given as the number of animals bearing such lesions at a specific anatomic site and the number of animals with that site examined microscopically. For calculation of statistical significance, the incidences of all nonneoplastic lesions are given as the ratio of the number of affected animals to the number of animals with the site examined microscopically.

Analysis of Nonneoplastic Lesion Incidences
Because all nonneoplastic lesions in these studies were considered to be incidental to the cause of death or not rapidly lethal, the primary statistical analysis used was a logistic regression analysis in which lesion prevalence was modeled as a logistic function of chemical exposure and time. For lesions detected at the interim evaluation, the Fisher exact test was used, a procedurebased on the overall proportion of affected animals.
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:
no adverse effect observed
Dose descriptor:
LOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
mouse

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The following studies are available for inspection:

 

NTP Studies:

 

Substance tested: Mixed isomer preparation of 79% tricresyl phosphate esters (consisting of 21% tri-m-cresyl phosphate, 4% tri-p-cresyl phosphate, less than 1% tri-o-cresyl phosphate, and other unidentified tricresyl phosphate esters). Refer to original NTO report page 21 http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr433.pdf

 

Key, K1, National Toxicology Program (NTP) (1994) - NTP mouse 13 week feed

 

Endpoint

Effect level

Based on

Sex

Basis for effect level / Remarks

no NOAEL identified

test mat.

female

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

LOAEL

250 ppm

test mat.

female

Cytoplasmic vacuolation of the adrenal cortex occurred in all groups of female dosed animals. 250 ppm is estimated to deliver average daily dose of 65 mg/kg bw

LOAEL

250 ppm

test mat.

male

Cytoplasmic vacuolization of the adrenal cortex occurred in all exposed groups of male and female mice with the exception of 250 ppm males. 250 ppm is estimated to deliver average daily dose of 45 mg/kg bw

 

Groups of 10 male and 10 female mice were fed diets containing 0, 250, 500, 1,000, 2,100, or 4,200 ppm of tricresyl phosphate. All mice survived to the end of the study. Mean body weights of 4,200 ppm males and of females exposed to 2,100 and 4,200 ppm were lower than those of controls throughout the study. Feed consumption by females exposed to 1,000, 2,100, or 4,200 ppm was lower than that by controls during week 12. Dietary levels of 250, 500, 1,000, 2,100, or 4,200 ppm tricresylphosphate were estimated to deliver average daily doses of 45,110, 180, 380, or 900 mg/kg body weight (males) and 65, 130, 230, 530, or 1,050 mg/kg (females). Interpretation of grip strength changes observed in groups receiving 2,100 or 4,200 ppm were confounded by the reduced body weights of these groups.

 

Cytoplasmic vacuolization of the adrenal cortex occurred in all exposed groups of male and female mice with the exception of 250 ppm males. Papillary hyperplasia of the gallbladder mucosa occurred in male mice exposed to 500 ppm or more and in female mice exposed to 1,000 ppm or more. Axonal degeneration occurred in males and females exposed to 2,100 and 4,200 ppm and females exposed to 1,000 ppm. Renal tubule regeneration occurred in all 4,200 ppm male mice.

 

Key, K1, National Toxicology Program (NTP) (1994) - NTP rat 13 week feed

 

Endpoint

Effect level

Based on

Sex

Basis for effect level / Remarks

no NOAEL identified

test mat.

male/female

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

LOAEL

900 ppm

test mat.

male/female

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)

 

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 occurred in 6,600 and 13,000 ppm males.

 

Key, K1, National Toxicology Program (NTP) (1994) - NTP mouse 13 week gavage

 

Endpoint

Effect level

Based on

Sex

Basis for effect level / Remarks

no NOAEL identified

test mat.

male/female

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

LOAEL

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

test mat.

male/female

Cytoplasmic vacuolation of the adrenal cortex occurred in all dosed animals and the severity increased with dose.

 

Groups of 10 male and 10 female mice received tricresyl phosphate in corn oil by gavage at doses of 0, 50, 100,200, 400, or 800 mg/kg bodyweight. All mice survived to the end of the study. Final mean body weights of male mice receiving 200 mg/kg and of male and female mice receiving 400 and 800 mg/kg were significantly lower than those of the controls. Cytoplasmic vacuolization of the adrenal cortex occurred in all dosed groups of mice and the severity increased with dose. Ovarian interstitial cell hypertrophy was present in all dosed groups of female mice. Multifocal degeneration of the spinal cord occurred in males and females that received 100, 200, 400, and 800 mg/kg, and multifocal degeneration of the sciatic nerve occurred in males that received 200, 400, and 800 mg/kg and females that received 100, 200,400, and 800 mg/kg. Hindlimb grip strengths of male mice that received 200, 400, or 800 mg/kg were significantly lower than that of the controls at the end of the study.

 

Key, K1, National Toxicology Program (NTP) (1994) - NTP rat 13 week gavage

 

Endpoint

Effect level

Based on

Sex

Basis for effect level / Remarks

no NOAEL identified

test mat.

male/female

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

LOAEL

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

test mat.

male/female

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 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.

 

Sup, K1, National Toxicology Program (NTP) (1994)- NTP rat 16 day gavage

 

Endpoint

Effect level

Based on

Sex

Basis for effect level / Remarks

NOAEL

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

test mat.

male

Clinical finding related to chemical administration (diarrhea), which occurred in six males receiving 730 mg/kg.

NOAEL

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

test mat.

female

Diarrhoea considered related to chemical administration in all females receiving 1450, 2900, or 5800 mg/kg. The final mean body weights and mean body weight gains of female rats that received 1450, 2900, and 5800 mg/kg were significantly lower than those of the controls. Absolute and relative thymus weights of females that received 1450 mg/kg were significantly lower than those of controls.

 

A 16 day 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, 360, 730, 1450, 2900 or 5800 mg/kg bodyweight (highest dose was administered undiluted), five days per week for a total of 13 or 14 doses in a 16-day period. The only clinical finding related to chemical administration was diarrhea, which occurred in six males receiving 730 mg/kg and all males and females receiving 1450, 2900, or 5800 mg/kg. One female receiving 1450 mg/kg and five males and eight females receiving 2900 mg/kg died before the end of the study. Final mean body weights of animals receiving 1450 mg/kg or more were significantly lower than controls. Necrosis of the mandibular lymph node, spleen and thymus occurred primarily in rats receiving 2900 and 5800 mg/kg. Diffuse aspermatogenesis occurred in male rats receiving 2900 and 5800 mg/kg.

 

Sup, K1, National Toxicology Program (NTP) (1994) - NTP mouse 16 day gavage

 

Endpoint

Effect level

Based on

Sex

Basis for effect level / Remarks

no NOAEL identified

test mat.

male/female

Absolute liver weights of males that received 360 or 730 mg/kg and all dosed groups of females were significantly greater than those of the controls. Hindlimb grip strengths of 360 mg/kg males (lowest dose tested) were significantly lower than those of the controls on day 14 of the study.

LOAEL

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

test mat.

male/female

Absolute liver weights of males that received 360 or 730 mg/kg and all dosed groups of females were significantly greater than those of the controls. Hindlimb grip strengths of 360 mg/kg males, 730 mg/kg males and females, 1450 mg/kg males, and 5800 mg/kg males and females were significantly lower than those of the controls on day 14 of the study.

 

Groups of 10 male and 10 female mice received tricresyl phosphate in corn oil by gavage at doses of 0, 360, 730, 1450, 2900, or 5800 mg/kg body weight, 5 days per week, for a total of 13 or 14 doses in a 16-day period. Five males and all females that received 1450 mg/kg, all mice that received 2900 mg/kg, and four males and one female that received 5800 mg/kg died before the end of the study. Final mean body weights of male mice that received 1450 and 5800 mg/kg were significantly lower than that of the controls. Final mean body weights of female mice that received 360, 730, or 5800 mg/kg were significantly greater than that of the controls. Necrosis of the mandibular lymph node, thymus, and spleen occurred primarily in mice receiving 2900 and 5800 mg/kg. Hindlimb grip strengths of male mice that received 360 and 1450 mg/kg and male and female mice that received 730 and 5800 mg/kg were significantly lower than those of the controls at the end of the study.

 

Sup, K2, Saito et al (1974) - Test of Subacute toxicity of tricresyl phosphate

 

Endpoint

Effect level

Based on

Sex

Basis for effect level / Remarks

NOAEL

1000 mg/kg bw/day (actual dose received)

male/female

All of the above changes observed were comparatively slight and, even in the 1000 mg/kg group, the correlation of the changes with the pathohistologic tests showed that the changes were not severe. It is deemed appropriate to allocate a NOAEL at the highest dose level.

 

An experiment was performed with the oral administration of doses of 30, 100, 300, and 1000 mg/kg TCP continuously for three months to male and female SD-SLC rats and the following results obtained: 1) As a symptom of intoxication throughout the period of administration of TCP, transient excessive salivation was seen but no other abnormalities appeared. 2) A slight suppression in body weight was seen in both the males and females of th 1000 mg/kg group. 3) The results of the hematologic tests in the females showed a tendency to increased leukocyte count but no other abnormalities were seen. 4) Decreased albumin values and increased potassium concentrations were seen in both the males and females in the results of a serum biochemical tests. Increased blood urea nitrogen was seen in only the females. 5) The slight increases in the liver weight manifested a correlation with the dose administered. In addition, the kidney weight was increased in the females and the weight of the adrenal gland was increased in the females of the 1000 mg/kg group.

 

All of the above changes were comparatively slight and, even in the 1000 mg/kg group, the correlation of the changes with the pathohistologic tests showed that the changes were not severe.

 

Sup, K2, MacKellar D G (1975) - ACUTE AND SUBACUTE TOXICITY TESTS KRONITEX TCP: TRICRESYL PHOSPHATE

 

Endpoint

Effect level

Based on

Sex

Basis for effect level / Remarks

NOEL

0.1 % in food

test mat.

male/female

No effects noted at this concentration.

 

During a 28-day study period, Kronitex K-TCP was fed to weanling albino rats at dietary levels of 1.0, 0.5 and 0.1% to assess its effect on behavior, mortality, body weight and food consumption, hematological, biochemical and uranalytical parameters and vital organ weights.

No toxic effects were observed in the group of animals receiving 0.1% K-TCP in their diet, although significant treatment-related toxic effects, including mortality and elevated liver weight to body weight ratios were observed in animals receiving 0.5% and 1.0% K-TCP in their diets.

 

Sup, K3, Oishi, H. et al. (1982) - TOXICITY OF SEVERAL PHOSPHORIC ACID ESTERS IN RATS

no NOAEL identified

 

Oishi et al. (1982) conducted a 9-week feeding study in which male JCL-Wistar rats were fed a pellet diet containing a mixture of tricresyl phosphate isomers, of unspecified composition, at 5 g/kg diet and found increased absolute and relative liver weights with associated histopathological changes (cytoplasmic vacuolation, increases in the number of binucleated cells and enlargement of cell size) and, in the plasma, significantly increased total protein, urea, cholesterol and glutamate pyruvate transaminase in TCP-treated rats compared with controls.

 

Additional data from the Carcinogenicity studies:

 

Key, K1, National Toxicology Program (NTP) (1994) - Carcinogenicity NTP rat 2 year feed

 

Endpoint

Effect type

Effect level

Based on

Sex

Basis for effect level / Remarks

NOAEL

carcinogenicity

300 ppm

test mat.

male/female

There were no chemical-related increased incidences of neoplasms in rats. 300 ppm estimated to deliver average daily doses of 13 mg/kg (males) 15 mg/kg (females), respectively.

NOAEL

toxicity

300 ppm

test mat.

male

Cytoplasmic vacuolization of the adrenal cortex was observed in 600 ppm males. 300 ppm estimated to deliver average daily dose 13 mg/kg

 

Groups of 95 male and 95 female rats were fed diets containing 0, 75, 150, or 300 ppm of tricresyl phosphate. An additional group of 95 male and 95 female rats were fed diets containing 600 ppm of tricresyl phosphate for 22 weeks and then received only control feed. After 3, 9, and 15 months of chemical exposure,up to 15 males and 15 females per group were evaluated for forelimb and hindlimb grip strength, then necropsied and evaluated for histopathologic lesions.

 

Survival, Mean Body Weights, and Feed Consumption

Survival of exposed rats was similar to that of controls. The final mean body weights of all exposed groups of males and females were similar to those of the controls. Feed consumption by exposed groups of male and female rats was similar to that by the controls. Dietary levels of 75, 150, or 300 ppm tricresyl phosphate were estimated to deliver average daily doses of 3, 6, or 13 mg/kg body weight (males) and 4, 7, or 15 mg/kg (females).

 

Pathology Findings

There were no chemical-related increased incidences of neoplasms in rats. Cytoplasmic vacuolization of the adrenal cortex occurred i n 600 ppm males and 150, 300, and 600 ppm females at the 3-month interim evaluation. At 9 and 15 months, cytoplasmic vacuolization occurred only in female rats, primarily in the 300 ppm group. Cytoplasmic vacuolization of the adrenal cortex and ovarian interstitial cell hyperplasia occurred in female rats exposed to 300 ppm throughout the 2-year study and the incidence and severity were significantly increased at the end of the study.

 

Under the conditions of this 2-year feed study, there was no evidence of carcinogenic activity of tricresylphosphate in male or female F344/N rats that received 75, 150,or 300 ppm.

 

Key, K1, National Toxicology Program (NTP) (1994) - Carcinogenicity NTP mouse 2 year feed

 

Endpoint

Effect type

Effect level

Based on

Sex

Basis for effect level / Remarks

NOAEL

carcinogenicity

250 ppm

test mat.

male/female

There were no chemical-related increased incidences of neoplasms in mice. 250 ppm estimated to deliver average daily doses of 27 mg/kg (males) 37 mg/kg (females), respectively.

LOAEL

toxicity

60 ppm

test mat.

male

At the end of the 2-year study, the incidences of clear cell focus, fatty change, and ceroid pigmentation were significantly increased in male mice receiving 125 and 250 ppm. 60 ppm estimated to deliver average daily dose of 7 mg/kg

 

Groups of 95 male and 95 female mice were fed diets containing 0, 60, 125, or 250 ppm of tricresyl phosphate. After 3, 9, and 15 months of chemical exposure, up to 15 males and 15 females per group were evaluated for forelimb and hindlimb grip strength, then necropsied and evaluated for histopathologic lesions.

 

Survival, Mean Body Weights, and Feed Consumption

Survival of exposed groups of male and female mice was similar to that of the controls.The final mean body weights of males and females receiving tricresyl phosphate were similar to those of controls. Feed consumption by exposed groups of male and female mice was similar to that by the controls. Dietary levels of 60,125, or 250 ppm tricresyl phosphate were estimated to deliver average daily doses of 7, 13, or 27 mg/kg body weight (males) and 8, 18, or 37 mg/kg (females).

 

Pathology Findings

There were no chemical-related increased incidences of neoplasms in mice. Ceroid pigmentation of the adrenal cortex occurred in all groups of mice throughout most of the 2-year study, with the exception of 60 and 125 ppm females at the 3-month interim evaluation; however, the severity was markedly increased in female mice receiving 250 ppm. Incidences of clear cell foci, fatty change, and ceroid pigmentation of the liver were significantly increased in male mice that received 125 or 250 ppm.

 

Under the conditions of this 2-year feed study, there was no evidence of carcinogenic activity in male or female B6C3Fl mice that received 60, 125, or 250 ppm.

 

Conclusions

 

It is well established that tricresyl phosphate is toxic. However it should be noted that due to the age of the studies, these are likely to have been conducted on TCP that may have contained higher % content of ortho-TCP than is currently marketed. In particular, there is comprehensive evidence that tri-o-cresyl phosphate, rather than the other isomers of tricresyl phosphate, is neurotoxic to humans and animals after repeated oral or dermal (and potentially also inhalation) exposure. However, neurotoxicity effects are not considered in the context of these repeated dose studies, as explained elsewhere within the dossier, these are attributable to the ortho isomer of TCP, which is not significantly present in current commercial TCP products. There were no significant changes in neurobehavioral measurements among any groups of rats at the 9- and 15-month evaluations.

 

A number of pathological changes have been observed following repeat dose exposure to tricresyl phosphate including effects in the liver, lymph nodes, spleen and thymus, testis, seminiferous tubules, ovaries, adrenal, kidney, gall bladder, sciatic nerve and spinal cord. The LOAEL for any treatment-related effect (cytoplasmic vacuolation of the adrenal cortex) in the 13-week studies was 250 ppm in the feed (in mice; equivalent to 45 mg/kg/bw or 65 mg/kg/bw for males and females respectively).

 

In the two-year NTP feeding studies, the LOAEL for any treatment-related effect (pigmentation of the adrenal cortex) was 60 ppm in the feed (in mice; equivalent to 7 mg/kg/bw or 8 mg/kg/bw for males and females respectively).

 

Ceroid pigmentation of the adrenal cortex was noted for all groups of mice, including controls, throughout most of the two-year study. However, control mice and treated females receiving 60 or 125 ppm were not affected at the 3-month interim evaluation; the extent of the adrenal change appears to have been minor below 125 ppm. The incidence of clear cell foci, fatty change and ceroid pigmentation of the liver was significantly increased in male mice at 125 or 250 ppm, but not at 60 ppm.

 

Triaryl phosphates are known to block the action of neutral cholesterol ester hydrolase with minimal inhibition of acyl coenzyme A cholesterol acyltransferase in rodents (Rosol et al 2001; seehttp://tpx.sagepub.com/content/29/1/41.full.pdf, Pg 45). This results in an accumulation of cholesterol esters in the fat vacuoles in all layers of the adrenal cortex, which accounts for the ceroid pigmentation effects noted. However, corticosterone concentrations are normal since synthesis of cholesterol is not disrupted, thereby providing adequate cholesterol to serve as a precursor for steroid hormone synthesis.

 

While the LOAEL can be considered to be 60 ppm (adrenal changes, particularly in males, equivalent to 7 mg/kg bw/day), this is considered to probably represent a minor effect of uncertain significance to human health. As such, the effects associated with this LOAEL is disregarded with regards to classification and labelling.  This is in accordance withRegulation (EC) No 1272/2008, section3.9.2.8.1. (c) and (e) which states as follows:

 

3.9.2.8.Effects considered not to support classification for specific target organ toxicity following repeated exposure

 

3.9.2.8.1. It is recognised that effects may be seen in humans and/or animals that do not justify classification. Such effects include, but are not limited to:

 

(c) changes in organ weights with no evidence of organ dysfunction;

(e) substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

 

The LOAEL derived is considered appropriate for derivation of DNEL however, to allow for suitable margins of safety.

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Various studies are available via gavage and feed.  The results are equivalent.  The gavage test is selected as this provides a definitive result rather than a range.  Note that the 2 year chronic study endpoint is taken as the definitive value for DNEL derivation.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

This study is waivered.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

This study is waivered.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

This study is waivered.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

This study is waivered.

Justification for classification or non-classification

The above results triggered no classification under the CLP Regulation (EC No 1272/2008) on the basis that the effects noted are not considered to represent a minor effect of uncertain significance to human health

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