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EC number: 204-707-7 | CAS number: 124-64-1
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 987
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- no ophtalmoscopic examination, no haemathology were performed.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- 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
Constituent 1
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 Breeding Laboratories
- Age at study initiation: 7 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5 per cage. Polycarbonate cages (Lab Products, Inc., Rochelle Park, NJ), with bedding (Absorb-Dri* (Lab Products, Inc.. Garfield, 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: 18 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 16 october 1979 to 14 january 1980
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: deionized water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Mixed on a w/v basis with distilled water and stirred mechanically for 5-10 min.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Formulation 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.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 5 days per week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 3.75, 7.5, 15, 30, or 60 mg/kg
Basis:
actual ingested
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- No data
- Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes, twice a day.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
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
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- All males and 5/10 females that received 60 mg/kg and 2/10 males and 1/10 females that received 15 mg/kg died before the end of the studies (See Table 1 for more details).
Deaths in the 15 mg/kg groups may have been due to gavage error.
- Rough coats, hunched backs, diarrhea, lethargy, and paresis and hyperextension of the rear limbs were observed for rats that received 60 mg/kg.
BODY WEIGHT AND WEIGHT GAIN
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.
GROSS PATHOLOGY
At necropsy, 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.
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: histopathology (hepatocellular necrosis)
- Dose descriptor:
- LOAEL
- Effect level:
- 15 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: histopathology (hepatocellular necrosis)
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Survival and mean body weights of rats in the thirteen-week gavage studies of THPC
Sex |
Dose (mg/kg) |
Mean Survival (a) |
Initial mean BW (g) (b) |
final mean BW (g) |
Change mean BW (g) (c) |
Final weight relative to controls (percent) |
male |
0 |
10/10 |
150 +/-6 |
350 +/-7 |
+ 200 +/-2 |
- |
3.75 |
10/10 |
150 +/-4 |
343 +/-10 |
+ 193 +/- 9 |
98 |
|
7.5 |
10/10 |
151 +/-5 |
326 +/- 8 |
+ 175 +/-5 |
93 |
|
15 |
(d) 8/10 |
149 +/-4 |
335 +/-6 |
+ 188 +/-4 |
96 |
|
30 |
10/10 |
153 +/-5 |
313 +/- 9 |
+ 159 +/-7 |
89 |
|
60 |
(e) 0/10 |
151 +/-4 |
(f) |
(f) |
(f) |
|
female |
0 |
10/10 |
116 +/-2 |
191 +/-2 |
+ 75 +/-2 |
- |
3.75 |
10/10 |
115 +/-2 |
196 +/-3 |
+81 +/-2 |
103 |
|
7.5 |
10/10 |
113 +/-3 |
197 +/-4 |
+ 84 +/-3 |
103 |
|
15 |
(g) 9/10 |
114 +/-2 |
197 +/-2 |
+82+/-2 |
103 |
|
30 |
10/10 |
114 +/-2 |
197 +/-4 |
+83 +/-4 |
103 |
|
60 |
(h) 5/10 |
114 +/-2 |
152 +/-9 |
+ 39+/-11 |
80 |
(a) number surviving/number initially in group
(b) initial mean group body weight +/- standard error of the mean. Subsequent calculations are based on those animals surviving to the end of the study
(c) mean body weight change of the survivors of the group +/- standard error of the mean
(d) Week of death: 5, 8
(e) Week of death: 4, 5, 7, 8, 8, 8, 9, 9, 10
(f) No data are reported due to the 100% mortality in this group
(g) Week of death: 5
(h) Week of death: 4, 6, 8, 10, 11
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this test, deaths were observed in both sex at the highest dose level (60 mg/kg bw/day), and hepatocellular necrosis was observed as soon as 15 mg/kg bw/ day. A NOAEL of 7.5 mg/kg bw/ day was identified.
- Executive summary:
In a thirteen-week studies (NTP, 1987), F344/N rats (10 per sex) were administered 3.75, 7.5, 15, 30 and 60 mg/kg THPC in deionized water by gavage 5 days per week for 13 weeks. Controls were untreated.
All males and 5/10 females that received 60 mg/kg and 2/10 males and 1/10 females that received 15 mg/kg died before the end of the studies. Deaths in the 15 mg/kg groups may have been due to gavage error. Rough coats, hunched backs, diarrhea, lethargy, and paresis and hyperextension of the rear limbs were observed for rats that received 60 mg/kg.
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. At necropsy, 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. 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.
Based on these results, the LOAEL is 15 mg/kg bw/ day and the NOAEL is 7.5 mg/kg bw/ day.
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