Tetrakis(hydroxymethyl)phosphonium chloride

Carcinogenicity

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

Reference

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)

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.

Conclusions:

No eveidence for carcinogenicity of THPC.

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

Reference

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.

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.

Conclusions:

There is no evidence that THPC is carcinogenic in animals after oral exposure.

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).