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Diss Factsheets

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1987

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Only 2 dose levels were tested rather than 3. No interim sacrifice satellite group was included. Frequency of treatment was 5 days a week, not daily Food and water consumption were not recorded).
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Haematology, urine, clinical chemistry and organ weight were not assessed. Aorta, caecum, rectum, muscle and peripheral nerve were not preserved following necropsy and therefore not histopathologically examined.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrakis(hydroxymethyl)phosphonium chloride
EC Number:
204-707-7
EC Name:
Tetrakis(hydroxymethyl)phosphonium chloride
Cas Number:
124-64-1
Molecular formula:
C4H12O4P.Cl
IUPAC Name:
tetrakis(hydroxymethyl)phosphonium chloride
Details on test material:
- Name of test material (as cited in study report): Tetrakis(hydroxymethyl)phosphonium chloride (THPC) from Aceto Chemical Company (Flushing, New York)
- Analytical purity: 75 % (determined by iodate-thiosulfate titration, elemental analysi, and thin -layer chromatographic analyses)
- Storage condition of test material: 23°C
- Lot/batch No.: ON2
No other data

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Portage, MI)
- Age at study initiation: 7 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5 per Polycarbonate cage (Lab Products, Inc., Rochelle Park, NJ)
- Diet: NIH 07 Rat and Mouse Ration (Zeigler Bros., Gardners, PA); available ad libitum
- Water: ad libitum, Automatic watering system (Edstrom Industries, Waterford, WI)
- Acclimation period: 17 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-60
- Air changes (per hr): 15
- Photoperiod: 12 hrs dark /12 hrs light


IN-LIFE DATES: From: 15 september 1980 To: 3 september 1982

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: deionized water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: THPC added to appropriate volume of deionized water and mixed by inverting 20 times. The study material was diluted with deionized water to give a stock solution containing THPC at the desired concentration for the high dose. Other concentrations were prepared by dilution of an appropriate portion of the stock solution with deionized water.

MAXIMUM STORAGE TIME: 14 days

STORAGE CONDITIONS: 23°C
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Formulations of THPC in water were periodically selected at random and analyzed in duplicate by the study laboratory to determine the accuracy with which formulations were prepared over the course of the studies. Sets of samples were analyzed at approximately 8-week intervals. In addition to the analyses of the dose mixtures performed by the study laboratory, referee analyses af a split sample were performed by the analytical chemistry laboratory twice each year during the 2-year studies.
Duration of treatment / exposure:
103 week
Frequency of treatment:
5 days per week
Post exposure period:
none
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 3.75, 7.5 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Because of the hepatocellular necrosis observed at 15 mg/kg during thirteen-week study, THPC doses selected for rats for the 2-year studies were 3.75 and 7.5 mg/kg administered by gavage in water 5 days per week.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily from month 4 to month 21 and monthly at other times

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights by cage were recorded once per week for 12 weeks of the studies and once per month thereafter.

HAEMATOLOGY: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Necropsy and histologic examination performed on all animals; the following tissues examined: gross lesions and tissue masses, regional lymph nodes, mendibular or mesenteric lymph node, salivary gland, sternum or femur or vertebrae including marrow, thyroid gland, parathyroids, small intestine, colon, liver, prostate/testis or ovaries/uterus, heart, esophagus, stomach, brain, thymus, trachea, pancreas, spleen, skin, lungs and mainstem bronchi, kidneys, adrenal glands, urinary bladder, pituitary gland, eyes, mammary gland.
Other examinations:
None
Statistics:
Survival analyses: The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Trone's (1975) life table test for a dose-related trend. When significant survival differences were detected, additional analyses using these procedures were carried out to determine the time point at which significant differences in the survival curves were first detected.
Analysis of Tumor incidence: Three statistical methods are used to analyzed tumor incidence data. the two that adjust for intercurrent mortality employ the classical method for combining contingency tables developed by Mentel and Haenszel (1959). Tests of significance included pairwise comparisons of high dose and low dose groups with vehicle controls and tests for overall dose-response trends.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Haematological findings:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
Compound-related clinical signs consisted primarily of rough hair coats and diarrhea. The survival of the high dose group of female rats was significantly lower than that of the vehicle controls (after week 70) and that of the low dose group (P=0.013).

BODY WEIGHT AND WEIGHT GAIN
Mean body weights of dosed and vehicle control male and female rats were comparable throughout most of the studies


HAEMATOLOGY
Hematopoietic system: the incidence of mononuclear cell leukemia in low dose male rats was significantly greater than that in the vehicle controls by the life table test.
Spleen: hematopoiesis of the red pulp was observed at increased incidences in dosed female rats (male: vehicle control, 1/50; low dose, 5/50; high dose, 3/49; female: 3/50; 9/50; 15/50)


GROSS PATHOLOGY
Lung: acute congestion and edema were observed at increased incidences in dosed rats that died during the studies (- acute congestion male: vehicle control, 0/50; low dose, 1/50; high dose, 9/50; female: 3/50; 2/50; 12/50; - edema male: 1/50; 1/50; 6/50; female: 0/50; 2/50; 11/50)

HISTOPATHOLOGY: NON-NEOPLASTIC
Liver: Cytoplasmic vacuolization was observed at increased incidences in dosed male and female rats. This lesion was characterized by large, generally homogeneous, eosinophilic droplets in the cytoplasm of hepatocytes near triads. The nuclei of those cells were either not apparent or were displaced to one side. Cystic degeneration was observed at increased incidences in dosed male rats.

Relevance of carcinogenic effects / potential:
There was not a treatment related increase in tumor incidence as compared to controls.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
3.75 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: hepatotoxicity
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
7.5 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: hepatotoxicity
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
7.5 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Highest tested dose
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Applicant's summary and conclusion

Conclusions:
Under the conditions of this test, there was no evidence of carcinogenicity of THPC in either sex of F344/N rats given 3.75 or 7.5 mg/kg.
Executive summary:

Two-year study was conducted in F344/N rats (NTP, 1982) by administering 0, 3.75, or 7.5 mg/kg THPC in deionized water by gavage to groups of 50 animals of each sex, 5 days per week for 103 weeks. Results showed that survival of the high dose group of female rats given THPC was lower after week 70 than that of the vehicle controls (survival at terminal kill: 37/50; 34/50; 21/50). Mean body weights of rats dosed with THPC were comparable to those of the vehicle controls. Compound-related clinical signs consisted primarily of rough hair coats and diarrhea. A nonneoplastic effect to 2 -year exposure to THPC was an increase in the incidence of hepatocellular lesions, primarily cytoplasmic vacuolization. The incidence of this lesion was dose related. Moreover, the incidences of mononuclear cell leukemia in low dose male rats administered THPC was somewhat greater than those in the vehicle controls (THPC: 19/50; 25/50; 16/50). Nevertheless, these marginal increases in the incidences of hematopoietic system tumors were not considered related to chemical exposure, since they were significant only by the life table tests and were not dose related. Under the conditions of this test, there was no evidence of carcinogenicity of THPC in either sex of F344/N rats given 3.75 or 7.5 mg/kg.