Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996-12-31 to 1997-01-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): POLYRAM SL
- Physical state: yellow viscous liquid
- Analytical purity: 100 % (expressed in complex substance)
- Certificate of analysis date: 1996/03/04
- Lot/batch No.: 5788
- Expiration date of the lot/batch: 1997/03
- Storage condition of test material: in dark and at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA- CREDO (69210 L'ARBRESLE, FRANCE)
- Age at study initiation: about 6 weeks
- Weight at study initiation: between 184g and 212g (males) and 170g and 183g (females)
- Fasting period before study: overnight prior to administration of the test substance
- Housing: 5 animals by sex in polypropylene cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: the test substance was prepared in Carboxymethyl cellulose (0.5%) at concentrations of 100 and 400 mg/mL for the 500 and the 2000 mg/kg bw dose groups respectively.
- Amount of vehicle (if gavage): 5 mL/kg bw for the 500 and the 2000 mg/kg bw dose groups
- Justification for choice of vehicle: solubility
- Lot/batch no. (if required): Cooper Batch B09710
- Purity:

MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg bw

Doses:
2 groups of 10 animals (5 of each sex)
Doses : Group 1 : 500mg/kg
Group 2 : 2000mg/kg
These doses were chosen according to a preliminary "sighting" study performed on a few number of animals.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- The animals were observed daily for 14 days after treatment.
- Mortalities were checked twice a day during all the observation period.
- A clinical examination was carried out one hour after treatment and frequently during the five hours following treatment and then at least once a day for 14 days.
- Body weights of the animals were recorded just prior to treatment (D1) and then on days 3, 7 and 14 after treatment.
- The animals found dead during the test were immediately necropsied.
- At the end of the 14 observation days, surviving animals were sacrified after barbituric anaesthia, then autopsied.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 500 - < 2 000 mg/kg bw
Mortality:
A mortality rate of 70% was induced with the dose of 2000mg/kg. The time of death chiefly occured between 6 hours and 72 hours following treatment. There were no death amongst animals treated at the dose of 500mg/kg (See table 1 in results and discussion free-text for details).
Clinical signs:
- At the 500 mg/kg bw dose-level, except a slight piloerection that appeared 30 minutes after the treatment and disappeared in less than 24 hours, no clinical signs were observed.
- At the 2000 mg/kg bw dose-level, all the animals showed an important piloerection on the day of treatment. The next morning, two males and one female were found dead. The other deaths occured on days 4 (2 females) to 6 (1 male). On Day 10, a moribund male was killed for humane reasons. From Day 2 to Day 8, the surviving animals showed an important piloerection, a slight abdominal meteorism and a dirty urogenital area. Watery stools were found on the litter. They recovered after about a week.
Body weight:
- At the 500 mg/kg bw dose-level, The body weight of gain was normal and regular for this species.
- At the 2000 mg/kg bw dose-level, all animals lost weight at 72 hours. Females but not males, recovered at day 8 (See tables 2 ,3, 4 and 5 in results and discussion free-text for details).
Gross pathology:
- Necropsy of animals found dead revealed some changes in lungs, liver, kidneys, spleen (congestion), stomach (distension) and intestine (distension).
- Necropsy of the male sacrified on D10 showed stomach adhesions with liver, spleen and abdominal wall and intestine distended with presence of liquid.
- Necropsy of the surviving animals, on day 15, revealed no significant macroscopic abnormality.

Any other information on results incl. tables

Table 1: Mortality at the 500 and 2000 mg/kg bw dose-levels

 Dose  Male  Female  Total
 500 mg/kg  0  0  0
 2000 mg/kg 2/5 (24 hours = Day 2)1/5 (Day 6)1/5 (Day 10) 1/5 (24 hours = Day 2)2/5 (72 hours = Day 4)  7/10 (end of study)

Table 2: Bodyweight of male animals dosed with 500 mg/kg bw

 Animal#  4481 4482  4483 4484  4485   Mean  S.D.
 D1 206 184  195  198  197  196 7.9
 D4 244 218  231  228  238  231.8 9.9
 D8 293 259  273 266 277 273.6 12.8
 D15 355 316  310  310  330  324.2 19.1
 D15 -D1 149 132  115  112  133  128.2  15.1 

Table 3: Bodyweight of female animals dosed with 500 mg/kg bw

 Animal#  4486 4487 4488 4489 4490  Mean  S.D.
 D1 171 180 179  175 170  175 4.5
 D4 191 202 199 185 199 195.5 7.0
 D8 205 220 222 192 206 209 12.3
 D15 202 229 223 210 220 216.8 10.8
 D15 -D1  31 49  44  35  50  41.8  8.5 

Table 4: Bodyweight of male animals dosed with 2000 mg/kg bw

 Animal# 4491 4492  4493 4494 4495  Mean S.D.
 D1 195 196 212 206 189 199.6 9.2
 D4 162 159 186 - 169 14.8
 D8 153 158 - 155.5 3.5
 D15 - 250 - 250  -
 D15 -D1  -  - 38  -  - 38  -

Table 5: Bodyweight of female animals dosed with 2000 mg/kg bw

 Animal#  4496 4497  4498 4499  4500   Mean  S.D.
 D1 177 175 177  172 183  176.8 4.0 
 D4 170 168  169 1.4
 D8 218 217 217.5 0.7
 D15 233 240 236.5 4.9
 D15 -D1 56 57  5605  0.7 

 

Applicant's summary and conclusion

Interpretation of results:
other: Toxicity category 4 / Harmful
Remarks:
Criteria used for interpretation of results: other: CLP (Reg. 1272/2008/EC) and Directive 67/548/EEC
Conclusions:
Under these experimental conditions, the oral LD50 of the test item was comprised between 500 and 2000 mg/kg in rats.
Executive summary:

The acute oral toxicity of the test item was evaluated in rats according to OECD guideline 401. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.  

The test item was prepared in Carboxymethyl cellulose at 05% and was administered by oral route (gavage), under a volume of 5 mL/kg bw, to groups of five fasted male and female Sprague-Dawley rats. The dose-levels of 500 and 2000 mg/kg bw were selected on the basis of the results obtained in a preliminary sighting study.

In the main study, clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test item. All animals were subjected to necropsy.

At the 500 mg/kg bw dose-level, no mortality occured. A slight piloerection that appeared 30 minutes after the treatment and disappeared in less than 24 hours was the only clinical sign. The body weight gain of the animals was not affected by treatment with the test item and no apparent abnormalities were observed in any animal at necropsy.

At the 2000 mg/kg bwdose-level, 70% (4/5 males and 3/5 females) of the animals died within the study period. Most of the deaths occured 24 to 72 hours after treatment . An important piloerection, a slight abdominal meteorism and a dirty urogenital area were noted in the surviving animals from day 2 to day 8. All animals lost weight at 72 hours but females (not males) recovered at day 8. Necropsy of animals found dead revealed changes in liver, spleen, kidney, lung, intestine and abdominal wall. Necropsies of animals surviving until end of study did not reveal any changes.

Under these experimental conditions, the oral LD50of the test item was comprised between 500 and 2000 mg/kg in rats.