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Acute Toxicity: oral

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acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study conducted in accordance with GLP. However, no data on test substance purity were given.

Data source

Reference Type:
study report

Materials and methods

Principles of method if other than guideline:
A study was performed to determine the acute oral median lethal dose (LD50) of the test material, administered as a solution in distilled water, in the Sprague-Dawley CFY strain rat. The method used followed that described in the OECO Guidelines forTesting of Chemicals (1981) No.
401 "Acute Oral Toxicity". Four groups, each of ten fasted animals (five males and five females), were given a single oral dose of test material preparation at dose levels of 250 to 2000 mg/kg bodyweight. Animals were observed for 14 days.
GLP compliance:
Test type:
standard acute method
Limit test:

Test material

Test material form:
solid: particulate/powder
migrated information: powder
Details on test material:
Bronopol, supplied by Dynamit Nobel AG, no purity given. White crystalline powder.

Test animals

Details on test animals and environmental conditions:
Males, weight at study initiation: 100 - 144 g
Females, weight at study initiation: 97 - 148 g
All animals were about 5 to 8 weeks old.
Twenty-.four male and twenty-four female Sprague-Dawley CFY strain rats were supplied by Interfauna (UK) Limited, Wyton, Huntingdon, Cambridgeshire.
Acclimatisation period: five days.
The animals were housed in groups of up to five by sex in solid-floor polypropylene cages with sawdust bedding. With the exception of an overnight
fast immediately before dosing and for approximately two hours after dosing, free access to mains drinking water and food (Rat and Mouse Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, U.K.) was allowed throughout the study.
The animal room was maintained at a temperature of 19 - 23°C and relative humidity of 60 - 70%. The rate of air exchange was approximately 15
changes per hour and the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.

Administration / exposure

Route of administration:
oral: gavage
Details on oral exposure:
Observation period: 14 days.
Limit test: 2000 mg/kg bw
Range finding test: 100, 250, 500, and 1000 mg/kg bw
Main test: 250, 500, 1000, and 2000 mg/kg bw
Administered Volume: 10 ml/kg bw
No. of animals per sex per dose:
Limit test: 5 males + 5 females.
Range finding test: 1 male + 1 female.
Main test: 5 males + 5 females.
Control animals:
Details on study design:
The 2000 mg/kg bw was tested alone within a limit test, prior to the range finding test. The test substance was applied as single dose by gavage, using distilled water as vehicle; the administration volume was 10 ml/ kg bw. Following treatment, the animals were regularly examined for mortality and clinical signs of toxicity over an observation period of 14 days; body weights were recorded at test starting and during the observation period. All rats that died during the observation period as well as the surviving rats, which were sacrificed at the end of the observation period, were subjected to necropsy.
The LD50 and the 95% confidence limits were calculated by means of the method of Weil CS (Tables for convenient calculation of median-effective dose (LD50 or ED50) and instructions in their use. Biometrics 8: 249 - 263, 1952).

Results and discussion

Effect levelsopen allclose all
Dose descriptor:
Effect level:
305 mg/kg bw
95% CL:
>= 167 - <= 556
Dose descriptor:
Effect level:
273 mg/kg bw
95% CL:
>= 142 - <= 522
Dose descriptor:
Effect level:
354 mg/kg bw
95% CL:
>= 127 - <= 981
Limit test: death occured
Range finding test: 1000 mg/kg bw: 2/2; 500 mg/kg bw: 1/2; 250 mg/kg bw: 0/2; 100 mg/kg bw: 0/2.
Main Test:
250 mg/kg: male: 1/5 dead after 1 hour; female: 1/5 dead after 1 hour and 1/5 dead after 2 hours.
500 mg/kg: male: 3/5 dead after 1 hour, 1/5 after 2 hours, and 1/5 after 1 day; female: 1/5 dead after 1 hour and 1/5 dead after 2 hours.
1000 mg/kg: male/female: 4/5 dead after 1 hour, 1/5 dead after 4 hours
2000 mg/kg: male: 3/5 dead after 1 hour, 2/5 after 4 hours; female: 2/5 dead after 1 hour and 3/5 dead after 4 hours.
see table 1 in section Remarks on results.
Clinical signs:
Common abnormalities noted in both decedents and surviving animals, one and four hours after dosing, were hunched posture, pilo-erection,
lethargy and decreased respiratory rate. Occasional of isolated signs of noisy respiration, ataxia, ptosis, pallor of the extremities and coma were also noted during this period. All surviving animais were normal two or three days after dosing except one female treated with 500 mg/kg which continued to show hunched posture and pilo-erection up to eleven days after treatment. This animal also showed uncontrolled
side to side and up and down head movement three to five days after dosing. This animal recovered and appeared normal twelve days after
dosing. One low dose male also showed signs of toxicity four to nine days after dosing but was normal on day ten (see details table 2).
Body weight:
A small number of surviving animals showed reduced bodyweight gain
over the first week; all surviving animals showed expected gains in
bodyweight over the second week.
Gross pathology:
Common abnormalities noted at necropsy of decedents were dark livers and kidneys, severe haemorrhage or ulceration of the gastric mucosa
and haemorrhage of the small and large intestines. Abnormally red lungs were noted at necropsy of decedents treated with dose levels of
500 mg/kg or greater. Dark spleens and sloughing of the non-glandular region of the stomach were also noted at necropsy of animals treated with 2000 mg/kg.

Any other information on results incl. tables

Table 1: Mortality of male and female animals in the main test of the study:

Dose level














 1000  5/5 5/5  10/10   
 2000  5/5 5/5  10/10   

Table 2: Clinical signs and observations after dosing of animals with bronopol:

 Dose level (mg/kg)  Clinical observation Number showing effects during day of dosing (hour)          Number showing effects during day of observation                 
     1  4  1 8 -14 
 250 Hunched posture   8
   Pilo-erection  8
   Lethargy  8
   Decreased respiratory rate  8
   Noisy respiration  1
   Ataxia  1
   Pallor of the extremities  0
   Distended abdomen  0 1
   Comatose  1
   No abnormalities detected  0 6/7 
 500 Hunched posture   5
   Pilo-erection  5
   Lethargy  5
   Decreased respiratory rate  5
   Ataxia  2
   Ptosis  2
   Comatose  1
   Uncontrolled head movements  0
   No abnormalities detected  0 2/3 
 1000 Hunched posture   2  
   Pilo-erection  2  
   Lethargy  2  
   Decreased respiratory rate  2  
   Ataxia  2  
   Ptosis  2  
 2000 Hunched posture   3  1  
   Pilo-erection  3  1  
   Lethargy  3  1  
   Decreased respiratory rate  3  1  
   Ataxia  3 1  
   Pallor of the extremities  3 1  
   Ptosis  1 1  
   Comatose  2 1  

Applicant's summary and conclusion