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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:
from 1991-07-30 to 1991-08-28
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study however no information was provided on purity.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(version 1987)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
(version EU Directive 84/449/EEC)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
1989-10-24
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Test material form:
other: liquid stored at room temperature
Details on test material:
- Substance type: multi-component substance
- Lot/batch No.: no data
- Analytical purity: no data
- Physical state: colourless liquid
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Ltd., Manston, Kent, UK
- Age at study initiation: 5-8 weeks
- Weight at study initiation: 137-159g (males) and 127-154 g (females)
- Fasting period before study: 12 hours
- Housing: by sex and in groups of up to 5, in propylene cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25 °C
- Humidity (%): 47-64%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 1991-07-30 To: 1991-08-28

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 1.53 ml/kg

Doses:
500, 1000 and 2000 mg test material/kg bw
325, 650 and 1300 mg Active ingredient (AI)/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
* Mortality and clinical signs: 30 minutes after administration of the treatment, then at 1, 2 and 4 hours, and daily thereafter
* weighing: 0, 7 and 14 after dosing
- Necropsy of survivors performed: yes
Statistics:
Using the mortality data obtained the acute oral median lethal dose (LD50) and 95 confidence limits of the test material were calculated using the method of Thompson (Bact. Reviews, 11, 115-145 (1947)). The LD50 and 95% confidence limits were calculated for males and females separately.

Results and discussion

Preliminary study:
3 groups each composed of 1 male and 1 female were treated under the same conditions as those employed in the main study at the dose levels of 500, 1000 and 2000 mg test material/kg:
- At 2000 mg/kg, all animals died.
- At 1000 or 500 mg/kg, females were found dead during the day of dosing or up to two days after dosing.
- Clinical signs: laboured, gasping, noisy respiration and decreased respiratory rate, hunched posture, pilo-erection, lethargy, ptosis, pallor of the extremities and ataxia.
Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
1 000 mg/kg bw
Based on:
test mat.
95% CL:
632 - 1 582
Sex:
male
Dose descriptor:
LD50
Effect level:
933 mg/kg bw
Based on:
test mat.
95% CL:
664 - 1 310
Sex:
male/female
Dose descriptor:
LD50
Effect level:
962 mg/kg bw
Based on:
test mat.
95% CL:
734 - 1 261
Sex:
female
Dose descriptor:
LD50
Effect level:
650 mg/kg bw
Based on:
act. ingr.
95% CL:
410 - 1 027
Sex:
male
Dose descriptor:
LD50
Effect level:
606 mg/kg bw
Based on:
act. ingr.
95% CL:
431 - 851
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
625 mg/kg bw
Based on:
act. ingr.
95% CL:
477 - 820
Mortality:
- At 500 mg/kg: one female was died at one day after dosing. No mortality was observed in the male goups
- At 1000 mg/kg: 2 males and 2 females were died at 1 and 2 days after dosing. one male was killed in extremis at 5 days after treatment
- At 2000 mg/kg: all males and 3 females were died within 24 hours.
Clinical signs:
- At 1000 or 2000 mg/kg (Common signs): hunched posture, lethargy, ptosis, decreased respiratory rate and occational body tremors.
- At 2000 mg/kg: Isolated incidents of laboured respiration and red/brown stains around the eyes were noted.
- At 1000 mg/kg: emaciation, pilo-erection, dehydration, red/brown stains around the snout and pallor of the extremities.
- At 500 mg/kg: no clinical signs was observed.
Surviving animals appeared normal throughout the study and five to twelve days after dosing.
Body weight:
Surviving animals showed expected gain in bodyweight during the study except for two animals treated with 1000 mg/kg, which showed body weight loss during the first week.
Gross pathology:
- At 500 (one animal only), 1000 and 2000 mg/kg: Common abnormalities noted were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, dark kidneys, haemorrhagic or sloughing of the gastric mucosa.
- At 1000 mg/kg and 2000: other abnormalities observed were fissuring of the stomach, fissuring and/or hardening/thickening of the gastric mucosa, haemorrhage of the non-glandular epithelium of the stomach and haemorrhage of the small and large intestines.
- At 2000 mg/kg: additional abnormalities observed were gross hardening/thickening of the kidneys, possible necrosis of the stomach, yellow discolouration of the small intestine was also noted.
- At 1000 mg/kg: the male killed in extremis showed patchy pallor of the kidneys and gaseous distension of the stomach. Pale liver and hardening/thickening of the stomach (3 females), yellow discolouration of the liver (1 male).
No abnormalities were noted at necropsy of one male treated with 1000 mg/kg and nine animals treated with 500 mg/kg.
Other findings:
none

Any other information on results incl. tables

Table 7.2.1/2: Number of animals dead [and with evident toxicity] [and time range within which mortality occurred]

 

Dose
(mg test material/kg bw)

Mortality (# dead/total)

Time range of deaths (hours)

Number with evident toxicity(#/total)

Male

Female

Combined

Male

Female

Combined

500

 0/5

 1/5

 1/10

 24

 0/5

1/5 

 1/10

1000

2 +1*/5

 2/5

4 (1*)/10

 24 -48 and 120 **

4/5

 5/5

 9/10

2000

5/5 

 5/5

 10/10

 6 -24

5/5 

 5/5

10/10

*: animal killed in extremis

**: one male treated at 1000 mg/kg killed in extremis 5 days after dosing

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, Oral LD50 Combined Males/Females = 625 mg AI/kg bw. Tetrakis (hydroxy methyl) phosphonium chloride, oligomeric reaction products with urea (THPC-urea) is classified in category 4, H302 according to the CLP regulation (1272/2008) and as HARMFUL if swallowed (Xn R22) according to the Directive 67/548/EEC.
Executive summary:
In an acute oral toxicity study (OECD 401, method B1 in the Directive 84/449/EEC) and in compliance with GLP, groups of fasted, 5 -7 weeks old Sprague-Dawley rats (5/sex) were given a single oral dose of a water solution of THPC-urea at doses of 500, 1000 and 2000 mg test material/kg bw (equivalent to 325, 650 and 1300 mg AI/kg bw) and observed for 14 days. Signs of intoxication were hunched posture, ataxia, lethargy, ptosis, laboured respiration, piloerection, dehydratation, and occasional body tremors. At necropsy, abnormalities were observed in the liver, lungs, kidneys, stomach and gastrointestinal tract Oral LD50 Female = 650 mg AI/kg bw (410 -1027), Oral LD50 Male = 606 mg AI/kg bw (431 - 851) and Oral LD50 Combined Males/Females = 625 mg AI/kg bw (477 -820). Based on the results of this study, THPC-urea is classified in category 4, H302 according to the CLP regulation (1272/2008) and as HARMFUL if swallowed (Xn R22) according to the Directive 67/548/EEC. This acute oral study is classified as acceptable. It does satisfy the guideline requirements for an acute oral study (OECD 401) in the rat.