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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well documented GLP-guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Remarks:
- only minor deviation (relative humidity sometimes outside of the target ranges specified in the protocol). This minor deviation was not considered to comprise the validity or integrity of the study.
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
Remarks:
- only minor deviation (relative humidity sometimes outside of the target ranges specified in the protocol). This minor deviation was not considered to comprise the validity or integrity of the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material: 1,2,3-Propanetriol, glycidyl ethers
- Substance type: organic
- Physical state: liquid
- Storage condition of test material: at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS - Sprague-Dawley ICO: OFA-SD (IOPS Caw)
- Source: Iffa Credo, L'Arbresle, France
- Age at study initiation: on the day of treatment, the animals were approximately 6 weeks old
- Weight at study initiation: mean body weight +/- standard deviation of 191 +/- 6 g for the males and 144 +/- 7 g for the females.
- Fasting period before study: overnight (approximately 18 hours, but had free access to water. Food was given back approximately 4 hours after administration of the test substance
- Housing: The animals were housed in polycarbonate cages (48 cm * 27 cm * 20 cm). Each cage contained four to seven animals of the same sex during the acclimatization period and five rats of the same sex during the treatment period. Each cage contained dust-free sawdust. Bacterial and chemical analyses of the sawdust, including the detection of possible contaminants (pesticides, heavy metals), are performed regularly by external laboratories.
- Diet (e.g. ad libitum): All animals had free access to A04C pelleted diet (UAR, Villemoisson-sur-Orge, France), except as noted above for fasting purposes. Each batch of food was analysed by the supplier for composition and contaminant levels.
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided at libitum. Bacteriological and chemical analyses of the water and diet, including the detection of possible contaminantes (pesticided, heavy metals and nitrosamines), are performed regularly by external laboratories.
No contaminants are known to be present in the diet, drinking water or bedding material at levels which may be expected to interfere with or prejudice the outcome of the study.
- Acclimation period: at least 5 days
- Identification. the animals were identified individually by earmarks of earmotches

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2°C
- Humidity (%): 30 - 70 %
- Air changes (per hr): approximately 12 cycles/hours of filtered, non-recycled air.
- Photoperiod (hrs dark / hrs light): 12 h/ 12 h

The temperature and relative humidity were under continuous control and recording. The records were checked daily and retained. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: unchanged for 2000 mg/kg bw, corn oil in the dose-levels 1415 mg/kg and 1000 mg/kg
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 141,5 mg/mL or 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: commonly used and well established
- Lot/batch no. (if required): 86H0059

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg
Doses:
2000 (undiluted), 1415 (diluted in corn oil), and 1000 mg/kg (diluted in corn oil)
No. of animals per sex per dose:
2000mg/kg dose-level: 5 males and females
1415mg/kg dose-level: 5 females
1000mg7Kg dose-level: 5 females
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
The animals were observed frequently during the hours following administration of the test substance, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day until day 15. Type, time of onset and duration of clinical signs were recorded for each animal individually. Time of death was recorded individually, in terms of the number of hours or days after dosing.
Body weight - the animals were weighed individually just before administration of the test substance on day 1 and then on days 8 to 15. Individual weights of animals found dead during the study were measured at necropsy when survival exceeded 24 hours and if no signs of "cannibalism" were present. The body weight gain of the treated animals was compared to that of CIT control animals wi9th the same initial body weight.
- Necropsy of survivors performed: yes
The animals found dead during the study were subjected to a macroscopic examination as soon as possible. On day 15, all surviving animals were killed by carbon dioxide asphyxiation and a macroscopic examination was performed.
After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed. In case of macroscopic lesions, organ samples were taken and preserved in 10 % buffered formalin. No microscopic examination was performed.
- Other examinations performed: clinical signs, body weight,organ weights
Statistics:
Evaluation of the toxicity of the test substance following a single oral administration in rats should include the relationship, in any, between the animals' exposure to the test substance and the incidence and severity of all abnormalities including behavioural and clinical abnormalities, macroscopic lesions, body weight changes,mortality and any other toxic effects.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
no animals died in the 1000 and 1415 mg/kg dose groups. 3 of 5 males and 2 of 5 females died in the 2000 mg/kg dose group.
Clinical signs:
At the 2000 mg/kg dose-level, hypoactivity or sedtion and piloerection were observed in all animals from day 1 up to day 3 at the latest; coma was also observed prior to death in one female. Recovery was complete in the surviving animals on day 2. At the 1415 mg/kg dose-level, hypoactivity and piloerection were noted in 3/5 females on day 1. At the 1000 mg/kg dose-level, hypoactivity was noted in all females on day 1.
Body weight:
The body weight gain of the surviving animals was not affected by treatment with the test substance.
Gross pathology:
macroscopic examinations of the main organs of the animlas revealed no apparent abnormalities

Any other information on results incl. tables

Table 1:Individual clinical signs and mortality
Dose Time Animals Mortality Clinical signs
(mg/kg)   Males Females    
1000 30 min   02-03 No Hypoactivity
01-04 -05 No None
1h-2h-4h 01-02-03-04-05 No Hypoactivity
D2 to D 15 01-02-03-04-05 No None
1415 30 min - 1 h   01-02-03-04-05 No None
2h 01-02-05 No Hypoactivity, piloerection
03-04 No None
4h 01-02-03-04-05 No None
D 2 to D 15 01-02-03-04-05 No None
2000 30 min - 1 h 01-02-03-04-05 01-02-03-04-05 No None
2h 01-02-03-04-05 01-02-03-04-05 No Sedation, piloerection
4h 02 Yes
01 No Piloerection, coma
01-03-04-05 02-03-04-05 No Hypoactivity, piloerection
6h 01 No Piloerection, coma
01-03-04-05 02-03-04-05 No Hypoactivity, piloerection
D2 (morning) 01 Yes
03-04 No Hypoactivity, piloerection
01 -05 02-03-04-05 No None
D2 (afternoon) 03-04 No Hypoactivity, piloerection
01-05 02-03-04-05 No None
D3 (morning) 03 03 Yes
04 No Hypoactivity
01-05 02-04-05 No None
D3 (afternoon) 04 No Hypoactivity
01-05 02-04-05 No None
D4 (morning) 04 Yes
01-05 02-04-05 No None
D > 4 (afternoon) to D 15 01-05 02-04-05 No None
min:minutes
h  :hour
D  :day

Table 2: Individual and mean body weight and weekly body weight change of treated rats (g) 
Dose Volume Sex Animals Days
mg/kg ml/kg 1 (1) 8 (1) 15 At death
1000 10 Female 01 131 38 169 21 190 -
02 136 35 171 23 194 -
03 149 48 197 41 238 -
04 136 42 178 43 221 -
05 141 29 170 22 192 -
M 139 38 177 30 207 -
SD 7 7 12 11 21 -
1415 10 Female 01 152 36 188 22 210 -
02 147 45 192 22 214 -
03 149 50 199 26 225 -
04 146 39 185 28 213 -
05 147 39 186 24 210 -
M 148 42 190 24 214 -
SD 2 6 6 3 6 -
2000 1.67 Male 01 183 59 242 66 308 -
02 188 -
03 192 174
04 200 -
05 194 72 266 60 326 -
M 191 66 254 63 317
SD 6 9 17 4 13
2000 1.67 Female 0! 156 -
02 149 42 191 27 218 -
03 148 147
04 140 35 175 21 196 -
05 140 31 171 25 196 -
M 347 36 179 24 203
SD 7 6 11 3 13  
(1)  -Body weight gain
M   -Mean
SD  -Standard Deviation
 - = not applicable
Animals found dead during the study not mentioned

Table 3: Individual macroscopic examinations at necropsy
Dose Time Animals Macroscopic abnormalities
mg/kg Males Females
1000 D15   01-02-03-04-05 None
1415 D15   01-02-03-04-05 None
2000 D1 02   No apparent abnormalities
D2 01 Advanced autolysis
D3 03 03 Advanced autolysis
D4 04 Cannibalized animal
D15 01-05 02-04-05 No apparent abnormalities
D: day

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
LD50 is near 2000 mg/kg bw. C&L is required.
Executive summary:

The test substance was administered via oral gavage to groups of five male and/or female fasted Sprague-Dawley rats. In the first instance, the test substance was administered undiluted, at the dose of 2000 mg/kg (dose volume 1.67 ml/kg, taking into consideration that its specific gravity was 1.2. As 50 % mortality occurred in this limit test, the test substance was then prepared in corn oil and administered to other animals at lower doses (1415 mg/kg and 1000 mg/kg in corn oil (dose volume 10 ml/kg) to 5 females each). Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test substance. All animals were subjected to necropsy. At the 2000 mg/kg dose-level 3/5 males and 2/5 females died between days 1 and 4. Hypoactivity or sedation and piloerection were observed in all animals from day 1 up to day 3 at the latest, coma was observed prior to death in one female. Recovery was complete in the surviving animals on day 2. At the 1415 mg/kg dose-level, no mortality was observed. Hypoactivity and piloerection were noted in 3/5 females on day 1. At the 1000 mg/kg dose-level, no mortality was observed. Hypoactivity was noted in all females on day 1. The body weight gain of the surviving animals was not affected by treatment with the test substance. No apparent abnormalities were observed in all the animals at necropsy. In conclusion and under the experimental conditions, the oral LD50 of the test substance is near 2000 mg/kg. In accordance with ethic and scientific recommendations concerning the LD50, a more precise determination was not conducted. According to the classification criteria laid down in Commission Directive 93/21/EEC, concerning the potential toxicity by the oral route, the test substance should be assigned the symbol Xn, the indication of danger "Harmful" an the risk phrase R 22 " Harmful if swallowed".