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Toxicological information

Carcinogenicity

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Administrative data

Endpoint:
carcinogenicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
9/15/1980 - 9/3/1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The read-across approach is based on the assumption, that Tetrakis(hydroxymethyl)phosphonium chloride (THPC, CAS 124-64-1), as part of the technical product 'Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea' (THPC-urea, CAS 27104-30-9), is the relevant, most hazardous compound. The (local) mode of action based on direct chemical reactivity is the same in both compounds. Additionally the read-across approach is based on the worst-case assumption that the reaction mixture THPC-urea is as reactive as THPC. In the confirmatory information it becomes obvious, that THPC is at least 6 times more hazardous than THPC, oligomeric reaction products with urea. For the detailed justification of the read-across hypothesis see “overall remarks, attachments”. When considering both the read-across hypotheses, the direct read-across from data obtained with technical THPC (80%) onto technical THPC-urea (65-68%) do not lead to an underestimation of the hazard. No further uncertainty factor, e.g. AF=2 for read-across, is considered to be necessary for deriving a DNEL(THPC-urea) from NOAEL(THPC). Reliability: Published test report from National Toxicology Program (US). Evaluated data from a reliable secondary source (US-CPSC).

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Principles of method if other than guideline:
chronic (two-year) agavage study in rats.
Only two dose levels were tested: 0, 3.75, 7.5 mg/kg bw/day
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Tetrakis(hydroxymethyl)phosphonium chloride (THPC)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on analytical verification of doses or concentrations:
The same method was used to analyze THPC doses in water at both the analytical chemistry (100% and 80% level) and the study laboratories ( 36-1 mg/mL). It involved oxidation of the cation of THPC with potassium iodate and back-titration with sodium thiosulfate (Frank, 1977).
Duration of treatment / exposure:
5 days/week for 104 weeks
Frequency of treatment:
once per day (Mo-Fr)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 3.75, 7.5 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Positive control:
no

Examinations

Observations and examinations performed and frequency:
2 observations per day
weighed once per week for 12 weeks and then monthly
Sacrifice and pathology:
Necropsy and histologic examination performed on all animals; the following tissues examined: gross lesions and tissue masses,
regional lymph nodes, mandibular 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.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Details on results:
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.
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.
No neurotoxicity or any other signs of clinical toxicity were observed.
A nonneoplastic effect common to 13-week and 2-year exposure to THPS or THPC was an increase in the incidence of hepatocellular lesions, primarily cytoplasmic vacuolization. The incidences of this lesion in the 2-year studies were dose related.
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.
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.
Relevance of carcinogenic effects / potential:
There is no evidence that THPC is carcinogenic in animals after oral exposure.

Effect levels

Dose descriptor:
NOAEL
Effect level:
7.5 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: There is no evidence that THPC is carcinogenic in animals after oral exposure.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Applicant's summary and conclusion