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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 1993 to April 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study, performed according to standard method.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: the US EPA Pesticide Assessment Guidelines, Subdivision F, § 82-2,
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: the TSCA Health Effects Testing Guidelines; Subpart B, Section 98.1175
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
1992-06-11
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrakis(hydroxymethyl)phosphonium sulphate(2:1)
EC Number:
259-709-0
EC Name:
Tetrakis(hydroxymethyl)phosphonium sulphate(2:1)
Cas Number:
55566-30-8
Molecular formula:
C4H12O4P.1/2O4S
IUPAC Name:
tetrakis(hydroxymethyl)phosphonium sulphate(2:1)
Test material form:
other: liquid stored at room temperature
Details on test material:
- Test material: Named in the report as Tolcide THPS 75%.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source of animals: Charles River Ltd., UK
- Age at study initiation:: 5-8 weeks old
- Weight at study initiation: weight ranging from 137 to 180 g, with male mean weight of 159 g and female mean weight of 150 g.
- Fasting period before study: overnight
- Housing: 5 per cage
- Diet: Rat and Mouse Expanded Diet No. 1 Special Diets Services Limited, Witham, Essex, U.K
- Water: Domestic water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS:
- Temperature 19-23 deg. C, 
- Relative  humidity 42-64%, 
- Air changes (per hr): air exchange rate approximately 15 volumes per hour, 
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark.

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50.0, 59.5 and 70.7 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg

MAXIMUM DOSE VOLUME APPLIED: 530 mg/kg bw, as main ingredient

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: a range finding study was performed using 3 dose levels: 500, 707 and 1000 mg/kg bw, with one male and one female per dose.
Animals treated with 707 or 1000 mg/kg bw and the male treated with 500 mg/kg bw were found dead four hours or one day after dosing.
Common signs of systemic toxicity noted were ataxia, hunched posture, lethargy and decreased respiratory rate with additional signs of piloerection and ptosis.
Based on this information, dose levels of 500, 595 and 707 mg/kg bw were selected for the main study.
Doses:
500, 595 and 707 mg/kg bw, as active substance
375, 446 and 530 mg/kg bw, as main ingredient
No. of animals per sex per dose:
10 (5 males and 5 females)/sex/dose
Control animals:
no
Details on study design:
Duration of observation period following administration: 14 days

- Frequency of observations: death and clinical observations: 1/2, 1,2 and 4h after dosing and once daily for 14 days
- weighing: on day 0, days 7 and 14 or at death
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight and gross necrospsy examination.


Statistics:
The LD50 and their 95% confidence limits were estimated with Finney's method and were expressed as active substance (i.e. test substance) and as main ingredient (considering THPS concentration of 100%)

Results and discussion

Preliminary study:
Not applicable.
Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LD50
Effect level:
431 mg/kg bw
Based on:
act. ingr.
95% CL:
389 - 478
Sex:
female
Dose descriptor:
LD50
Effect level:
388 mg/kg bw
Based on:
act. ingr.
95% CL:
290 - 520
Sex:
male
Dose descriptor:
LD50
Effect level:
466 mg/kg bw
Based on:
act. ingr.
95% CL:
418 - 520
Mortality:
- At 500 mg/kg bw, 2 female rats were found dead at the first day following dosing (see Table 8.7.1/ 1: Mortality data).
- At 595 mg/kg bw, 2 female rats were found dead 4 hours following dosing and 2 others were found dead at the first day following dosing. Three male rats were found dead at the second day following dosing.
- At 707 mg/kg bw, for each sex 3 animals died during the 6 first hours after dosing, with 2 by hour 4 and 1 by hour 6.
Clinical signs:
- Ataxia, hunched posture, lethargy and decreased respiratory rate were observed in all treated groups.
- Laboured respiration was commonly noted in animals treated with 595 or 707 mg/kg bw.
- Additional or isolated incidents of systemic toxicity were noted in animals treated with 595 mg/kg bw were pallor of the extremities, pilo-erection, ptosis and tiptoe gait (see Table 8.7.1/2: Clinical and pathological findings).
- Animals alive after 14 days of experiment recovered, judged by external appearance and behaviour, between days 3 to 5 after dosing.
Body weight:
Surviving animals showed expected gain in bodyweight during the study except for 1 male treated with 500 mg/kg bw with a bodyweight loss during the second week of the study, and 1 male and 1 female treated with 707 mg/kg bw characterised by bodyweight decrease during the first week of the study.
Gross pathology:
- Common abnormalities in animals that died during the study were haemorrhagic lungs, dark liver, dark kidneys and slightly haemorrhagic, thickened or hardened gastric mucosa (see Table 8.7.1/2: Clinical and pathological findings).
- Slight haemorrhage of the small intestine was also noted in 2 males and 2 females treated with 707 mg/kg bw.
- No abnormalities were noted at necropsy of animals that were killed at the end of the study.
Other findings:
No data.

Any other information on results incl. tables

The LD50 and their 95% confidence limits estimated with Finney's method are expressed as active substance ( i.e. test substance) and as main ingredient (considering THPS concentration of 100%) and presented in the table below:

______________________________________________
                                Active substance        main ingredient
LD 50 combined             575                              431
(95% CI)                      (519-637)                    (389-478)

LD50 males                    622                               466
(95% CI)                      (558-694)                      (418-520)

LD50 females                  518                               388
(95% CI)                      (387-693)                      (290-520)
______________________________________________
95% CI: Confidence limits at 95%
table 8.7.1/1: Mortality data

Dose level (mg/kg bw)

Sex

Number of treated animals

Time of death following dosing

Total deaths

0.5 h

1 h

2 h

4 h

6 h

1 d

2 d

3-14 d

500

M

5

0

0

0

0

0

0

0

0

0/5

F

5

0

0

0

0

0

2

0

0

2/5

595

M

5

0

0

0

0

0

0

3

0

3/5

F

5

0

0

0

2

0

2

0

0

4/5

707

M

5

0

0

0

2

1

1

0

0

4/5

F

5

0

0

0

2

1

1

0

0

4/5

LD50value

575 (519-637) mg/kg bw

table 8.7.1/2: Clinical and pathological findings

Dose level (mg/kg bw)

Number of deaths/group

Time of death (range)

Observations

Pathology findings
in dead animals

500

2/10

24 h

Ataxia, hunched posture, lethargy and decreased respiratory rate

Haemorrhagic lungs, dark liver, dark kidneys and thickened gastric mucosa.

595

7/10

4 - 48 h

Ataxia, hunched posture, lethargy, decreased respiratory rate, pilo-erection, ptosis and laboured respiration

Haemorrhagic lungs, dark liver, dark kidneys and slightly haemorrhagic, thickened or hardened gastric mucosa.

707

8/10

4 - 24 h

Ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration

Haemorrhagic lungs, dark liver, dark kidney, thickened gastric mucosa and slight haemorrhage of the small intestine


Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the test conditions of this study, the combined acute median lethal dose (LD50) of the active substance (THPS 75% in water) in rat was 575 mg/kg bw ,
and combined rat LD50= 431 mg/kg bw, for the main ingredient (THPS 100%). Based on these results, THPS (75% or 100%) is considered as harmful if swallowed according to EU criteria.
Executive summary:

The acute oral toxicity of THPS 75% in water was assessed in a study according to the US EPA Pesticide Assessment Guidelines, Subdivision F, § 82 - 2 in compliance with the EPA OPPTS 870.1100 and OECD Guideline 401 and in accordance with GLP.

In this study, five animals/sex/dose were dosed once at three doses 500, 595 and 707 mg/kg bw (active substance) corresponding to 375, 446 and 530 mg/kg bw as main ingredient by gavage.

Mortality and clinical signs were recorded daily. Necropsy and body weight measurement were performed on each dead rats or on the surviving rats after 14 days of experiment, after sacrifice.

 

The LD50 after 14 days was for the active substance (THPS 75% in water) = 575 mg/kg bw , and for the main ingredient (THPS 100%) = 431 mg/kg bw.

Most relevant results were the appearance of the first clinical signs during the first day after dosing, with mainly hunched posture, ataxia and respiratory disturbance. If death had to occured, it was in the first 2 days, otherwise rats recovered a normal behaviour and no anatomical disruption was noticed. Under the test conditions of this study, the combined acute median lethal dose (LD50) of the active substance (THPS 75% in water) in rat was 575 mg/kg bw , and the combined rat LD50= 431 mg/kg bw for the main ingredient (THPS 100%).

Based on these results, THPS (75% or 100%) are considered as harmful if swallowed according to EU criteria.

This acute oral study is classified as acceptable. It satisfies the guideline requirement for an acute oral study in the rats.