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EC number: 204-707-7 | CAS number: 124-64-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Carcinogenicity
Administrative data
Description of key information
THPC has not been shown to be carcinogenic in rodents after oral administration in well conducted studies using two species.
THPC does not appear to be carcinogenic by the dermal route of exposure, but these data are sparse.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Published test report from National Toxicology Program (US). Evaluated data from a reliable secondary source (US-CPSC).
- GLP compliance:
- not specified
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- not specified
- 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:
- http://ntp.niehs.nih.gov/?objectid=0707718C-C765-87B3-5E7E0D39B7253CD1
- Dose descriptor:
- NOAEL
- Effect level:
- > 7.5 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- NOAEL
- Effect level:
- > 15 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- female
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Conclusions:
- No eveidence for carcinogenicity of THPC.
Reference
Toxicology and carcinogenesis studies of tetrakis(hydroxymethyl)phosphonium chloride (THPC) were conducted because of the widespread use of these chemicals as flame retardants in cotton fabrics. THPC was available as a 75% aqueous solution. Short-term gavage studies with a range of doses were conducted first to identify toxic effects and affected sites and to determine doses for the 2-year studies. The doses selected for the 14-day studies ranged from 9.4 to 150 mg/kg THPC for rats, and 18.8 to 300 mg/kg THPC for mice. Mortality and reduction in body weight gain occurred at the two highest doses in the 14-day studies. There was hind limb paralysis in some rats and mice dosed at the highest concentrations of THPC.
In the 13-week studies, doses of THPC ranged from 3.75 to 60 mg/kg in rats and from 1.5 to 135 mg/kg in mice. Mortality and reduction in body weight gain occurred at the two higher doses for both sexes and species. Vascular degeneration of hepatocytes or hepatocellular necrosis was a common histopathologic finding. Hind limb paralysis was noted in rats and mice receiving the highest dose of THPC, and axonal degeneration, characterized by swollen axon sheaths, missing or fragmented axons, and some proliferation of neurolemma cells, was observed in rats. These lesions were found in the sciatic nerve, dorsal roots of the caudal spinal nerves, and the tracts of the spinal cord, particularly in the dorsal column of the lumbar cord.
Two-year studies were conducted in F344/N rats by administering 0, 3.75, or 7.5 mg/kg THPC in deionized water by gavage to groups of 49 or 50 animals of each sex, 5 days per week for 103 or 104 weeks. Groups of 49 or 50 B6C3F1mice were administered 0, 7.5, or 15 mg/kg THPC (males), or 0, 15, or 30 mg/kg THPC (females).
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. There was no difference in survival or mean body weights between the vehicle controls and mice dosed with either THPC. No neurotoxicity or any other signs of clinical toxicity were observed.
A nonneoplastic effect common to 13-week and 2-year exposure to THPC was an increase in the incidence of hepatocellular lesions, primarily cytoplasmic vacuolization. The incidences of this lesion in the two-year studies were dose related for all studies. Other lesions observed included follicular cell hyperplasia of the thyroid gland in high dose female mice given THPC. The increased incidences of hematopoietic system lesions observed in these studies were not considered biologically related to chemical exposure because the increases were marginal, no dose-response relationship was observed, and the incidences of these lesions are highly variable in untreated rats and mice.
The incidences of mononuclear cell leukemia in low dose male rats administered THPC were somewhat greater than those in the vehicle controls (THPC: 19/50; 25/50; 16/50). 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.
THPC demonstrated no mutagenic activity inSalmonella typhimuriumstrains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. THPC induced forward mutations in mouse lymphoma L5178Y cells without metabolic activation; neither was tested in the presence of S9. THPC increased the frequency of sister-chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in the presence and absence of exogenous metabolic activation.
An audit of the experimental data was conducted for the 2-year studies of THPC. No discrepancies were found that influenced the final interpretations.
Under the conditions of these 2-year gavage studies, there was no evidenceof carcinogenicity of THPC in either sex of F344/N rats given 3.75 or 7.5 mg/kg, in male B6C3F1mice given 7.5 or 15 mg/kg, or in female B6C3F1mice given 15 or 30 mg/kg.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 7.5 mg/kg bw/day
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Link to relevant study records
- Endpoint:
- carcinogenicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1978
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Published test report with experimental data from a peer reviewed journal. Evaluated data from a reliable secondary source (US-CPSC).
- GLP compliance:
- not specified
- Species:
- mouse
- Strain:
- ICR
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- random-bred female ICR/Ha Swiss mice (ARS/Sprague-Dawley Division, The Mogul Corp., Madison, Wis.) were acclimated to laboratory conditions
for 2 weeks, and treatments were begun when they were 6 to 8 weeks old. The mice were housed 6/cage on sterile hardwood chips (Betta Chip; Fisher & Son, Bound Brook, N. J.) in stainless steel cages, fed Purina laboratory chow and water ad libitum, and weighed monthly. The animal rooms were maintained at 22 to 24°C. - Route of administration:
- dermal
- Vehicle:
- other: aceton-water (9:1)
- Details on exposure:
- external dose: 2 mg THPC per 0.2 ml aceton-water (9:1)
The dosages used in all experiments were based on short-term toxicity evaluations (4 to 6 weeks); the highest possible doses that gave minimal
cytotoxic effects, as determined by histopathological examination, were used for the chronic exposures.
In the skin application experiments, the dorsal skin of the mice was shaved initially and, when necessary, throughout the test. All compounds were
applied in 0.1 or 0.2 ml of solvent to the shaved dorsal skin 3 times/week with a micropipet (Biopette; Carworth Farms, Inc.,New City, N. Y.) - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- skin application 3 times weekly for 496 days
- Frequency of treatment:
- skin application 3 times weekly for 496 days
- Remarks:
- Doses / Concentrations:
2 mg/application
Basis:
nominal in water - No. of animals per sex per dose:
- one treatment group of 60 female mice (limit test at MTD, dermal)
four no-treatment control groups that were used for these tests as well as for other concurrent experiments (249 mice). - Control animals:
- yes, concurrent no treatment
- yes, concurrent vehicle
- Positive control:
- No addition of tumor inductor or promotor.
Study hypothesis is, the possible liberation of formaldehyde and hydrochloric acid from free THPC in the fabric. Formaldehyde and hydrochloric acid are known to be in equilibrium with the animal and human carcinogen bis(chloromethyl)ether (Van Duuren 1978). - Observations and examinations performed and frequency:
- All compounds were used in well-ventilated hoods, and the mice were housed there for at least 2 hr after treatment. All skin treatments were
continued for the duration of the experiment. Animals were examined regularly and scored, and the findings were charted once monthly. - Sacrifice and pathology:
- Animals in poor health or with large tumor masses were killed. Except for the cranial region, animals were completely autopsied at the end of the
experiment or at death. Samples of all abnormal-appearing tissues and organs were excised for histopathological diagnosis. In addition, routine
histopathology was performed on skin, liver, and kidney in all animals dying during the test period and in 20% of all animals killed at the end of the
test. All tissue sections were fixed in 10% formalin, proc essed, blocked in paraffin, and stained with hematoxylin and eosin for histopathological
examination. Included in the protocols were groups given vehicle only; no treatment groups were included in the protocols. - Other examinations:
- Skin lesions were diagnosed clinically as papillomas when they reached 1 cu mm in size and per
sisted for 30 days or more or when they were confirmed histopathologically. - Statistics:
- The p values given in the table were assigned by means of computation of x2 analyses in which the tumor
incidences in the test groups were compared with a composite of 4 no-treatment control groups that were used for
these tests as well as for other concurrent experiments (249 mice). - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- 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:
- THPC was inactive in induction of skin tumors in skin painting studies.
THPC is a quaternary compound. Such compounds do not cross membranes very readily, therefore, they are not absorbed via the skin and poorly
absorbed from mucuous membranes. The chloride salts of quaternary bases are not likely to generate active chloride ions that could then help to
form bischloromethyl ether from the THPC. - Conclusions:
- There is no evidence that THPC is carcinogenic in animals after oral exposure.
Reference
THPC was inactive in induction of skin tumors in skin painting studies.
THPC is a qua·ternary compound. Such compounds do not cross membranes very readily, therefore, they are not absorbed via the skin and poorly absorbed from mucuous membranes. The chloride salts of quaternary bases are not likely to generate active chloride ions that could then help to form bischloromethyl ether from the THPC.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 mg/kg bw/day
Justification for classification or non-classification
Oral and dermal tests at MTD were negative for carcinogenicity. No classification necessary.
Additional information
NTP (1987) concluded that there was no evidence of carcinogenicity after gavage administration (at MTD) to rats (7.5 mg/kg THPC, both sexes) or mice (15 or 30 mg/kg THPC in male and female mice, respectively). IARC (1990) concluded that tetrakis(hydroxymethyl)phosphonium salts are not classifiable as to carcinogenicity in humans (Group 3) based on insufficient evidence for the carcinogenicity in experimental animals and a lack of human carcinogenicity data.
Insufficient data are available to judge the carcinogenicity of THPC by the dermal route of exposure. Although squamous cell skin carcinoma was observed in 1/20 mice when THPC in DMSO was applied to the skin without an initiator or promotor, as well as after DMBA initiation in 3/20 animals, these results were not significantly different compared to controls (Loewengart and Van Duuren 1977). In another study, THPC in acetone:water (2 mg/application =MTD) did not cause tumors (Van Duuren et al. 1978).
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