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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
10/16/1979 - 9/3/1980
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

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1987
Report Date:
1987
Reference Type:
secondary source
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Principles of method if other than guideline:
13 week agavage study in rats.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: Tetrakis(hydroxymethyl)phosphonium chloride (THPC)
Molecular formula: C4H12O4P.Cl
Structure: [Cl-].OC[P+](CO)(CO)CO
Molecular weight: 190.56
Substance type: ionic substance
Physical state: solid
Further details (analytical purity etc): THPC 80% (nominal) aqueous solution.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Animals were housed five per cage. Feed and water were avaliable ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
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 13 weeks
Frequency of treatment:
once per day (Mo-Fr)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 3.75, 7.5, 15, 30 or 60 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
2 observations per day
weighed once per week

Examinations

Sacrifice and pathology:
Necropsy performed on all animals; histologic examinations performed on the following tissues from all rats that died before end of
studies in the vehicle control, 30 mg/kg. and 60 mg/kg groups. and from 2 rats/sex in 15 mg/kg group; from all mice that died before end
ofstudies. from vehicle control.4S mg/kg, and 135 mg/kg groups. and from 2 mice/sex in 15 mg/kg group: skin, mandibular
lymph node, mammary gland, salivary gland, skeletal muscle, sciatic nerve, bone marrow, thymus, trachea, lungs and bronchi, heart,
thyroid gland, parathyroids, esophagus, stomach, small intestine, large intestine, mesenteric lymph node, iver, pancreas, spleen, kidneys,
adrenal glands. urinary bladder, prostate, testis or ovaries/uterus, brain, pituitary gland, spinal cord.
Liver, stomach, and skeletal muscle examined from all rats in 3.75, 7.5, and 15 mg/kg groups and kidneys from female rats in 3.75, 7.5, and 15
mg/kg groups.

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
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 examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
All males and 5/10 females that received 60 mg/kg THPC and 2/10 males and 1/10 females that received 15 mg/kg died before the end of the studies (Table 10). Deaths in the 15 mg/kg groups may have been due to gavage error.
The final mean body weight of males that received 30 mg/kg was 89% that of the vehicle controls. The final mean body weight of females that received 60 mg/kg was 80% that of the vehicle controls.
Rough coats, hunched backs, diarrhea, lethargy, and paresis and hyperextension of the rear limbs were observed for rats that received 60 mg/kg.

Periportal hepatocellular necrosis was observed in 9/10 males and 7/10 females that received 15 mg/kg, 10/10 males and 10/10 females that received 30 mg/kg, and 7/10 males and 8/10 females that received 60 mg/kg. (The severity at 15 mg/kg was minimal.)
Periportal cytoplasmic vacuolization was observed in 8/10 males that received 7.5 mg/kg, 9/10 males and 8/10 females that received 15 mg/kg, and all rats that received 30 or 60 mg/kg.
Degeneration of the axons was found in 2/10 females that received 60 mg/kg but not in any of the rats that received 30 mg/kg.

Effect levels

open allclose all
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: Periportal hepatocellular necrosis at 15 mg/kg/day
Dose descriptor:
NOAEL
Effect level:
> 3.75 - < 7.5 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: Periportal cytoplasmic vacuolization in males at 7.5 mg/kg/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
When rats received 0, 3.75, 7.5, 15, 30, or 60 mg/kg THPC by gavage for 13 weeks, treatment-related death occurred at 60 mg/kg
in both sexes (NTP 1987). Periportal hepatocellular necrosis was observed beginning at 15 mg/kg THPC and periportal cytoplasmic
vacuolization was observed in males beginning at 7.5 mg/kg THPC (NTP 1987).
For each sex the maximal tolerated dose was set at 7.5 mg/kg bw/day, to be used in the consecutive chonic study.