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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1980-10-21 to 1981-02-26
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (very few information on the tested substance reported and only male rats used)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method

Test material

Constituent 1
Reference substance name:
No IUPAC name
EC Number:
614-637-2
Cas Number:
68603-75-8
Molecular formula:
R-N(CH2CHOHCH3)xCH2CH2CH2N(CH2CHOHCH3)y with x+y=3 and where R = alkyl
IUPAC Name:
No IUPAC name
Details on test material:
- Name of test material (as cited in study report): DINORAM SL
- Physical state: dark brown liquid
- Lot/batch No.: 2852
No other data available

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Centre d'elevage Charles River France, 76410 Saint Aubin les Elbeuf
- Age at study initiation: not reported
- Weight at study initiation: Male : 120-140 g
- Fasting period before study: 16 h before dosing
- Housing: polycarbonate cages , 5 animals per cage.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 3 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 25 °C
- Humidity (%): 60 ± 20 %
- Air changes (per hr): 11
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
- no vehicle used

MAXIMUM DOSE VOLUME APPLIED: 25 mL/kg bw . The administered volume was not constant starting from 25 ml/ kg bw to 0.5 ml/kg bw for the lowest dose-level administered.
Doses:
preliminary experiment: 5, 10, 15, 20 and 25 mL/kg bw ( 2 rats per dose) then 1, 3, 4, 5 and 10 mL/kg bw (10 rats per dose)
main experiment: 0.5, 1.0, 1.5, 2.0 and 3.0 mL/kg bw (10 rats per dose)
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for clinical signs immediately upon dosing, 3 hours after dosing and daily thereafter for a total of 14 days. Body weights were measured immediately prior to dosing (Day 0) and on Days 4, 7 and 14.
- Necropsy of survivors performed: yes
Statistics:
LD50 and confidence intervals: Litchfield & Wilcoxon (J. Pharmacol. Exp. Therap., 1949, 96, 99-113)

Results and discussion

Preliminary study:
5, 10, 15, 20 and 25 mL/kg bw ( 2 rats per dose): all animals died between days 2 and 3. Prostration, piloerection, diarrhoea and abdominal swelling were noted prior to death.
3, 4, 5, 10 mL/kg bw (10 rats per dose): all animals died between days 2 and 3. Prostration, piloerection, diarrhoea and abdominal swelling were noted prior to death.
1 mL/kg bw (10 rats per dose): no fatalities
Effect levels
Sex:
male
Dose descriptor:
LD50
Effect level:
1 255 mg/kg bw
Based on:
test mat.
95% CL:
> 1 031 - < 1 534
Remarks on result:
other: All administered doses were expressed in volume. The final result (ie LD50) was expressed in weight taking into account that the relative density of the test item was 0.897 (see relative density chapter 4.4).
Mortality:
At 0.5 ml/kg bw : no deaths occured.
At 1 ml/kg bw : 2 rats died on day 4.
At 1.5 ml/kg bw : 4 rats died on day 7.
At 2 ml/kg bw : 7 rats died on day 4 and 2 additional rats died on day 7.
At 3 ml/kg bw : all rats died on day 4
Clinical signs:
- At 0.5 ml/kg bw : no clinical effects were noted all along the study.
- At 1 ml/kg bw : a slight drowsiness was in all animals observed 1h and 3h after administration. 24 hours later (day 1) , drowsiness was still observed and mucoid diarrhoea was noted. From days 2 to 4, drowsiness, thinness and kyphosis were observed. All symptoms disappeared on day 5.
- At 1.5 and 2 ml/kg bw : a slight drowsiness was observed in all animals 1h after administration. Prostration and piloerection appeared in all animals 3h after administration and persisted until day 1. On days 2 to 4, prostation and kyphosis are observed. All symptoms disappeared on day 6.
- At 3 ml/kg bw : animals are apathetic 15 minutes after administration, prostration and piloerection are noted in all animals at 30 minutes. Those symptoms persisted all the day long. On days 1 and 2, mucoid diarrhoea, abdominal swelling, apathy, piloerection, prostration, kyphosis and dizziness were observed. All rats were found dead on day 3.
Body weight:
- Normal body weight development in the 0.5 mL/kg bw group
- In the 1 and 1.5 mL/kg bw group, the body weight gain of the survivors was reduced up to day 4 but became normal on day 7.
- In the 2 mL/kg bw group, a decrease in the body weight of the survivors was recorded up to day 7 and grew thereafter.
Gross pathology:
No macroscopic abnormalities were observed at necropsy.

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 1255 (1031 - 1534) mg/kg bw in male rats with 95% confidence interval limits
Executive summary:

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

The test item was administered undiluted by oral route (gavage) to groups of ten male fasted Sprague-Dawley rats. In the preliminary experiment, the test item was administered at the dose-levels of 1, 3,4, 5, 10, 15, 20 and 25 mL/kg bw (relative density 0.897) and the animals were observed for 7 days. Based on these results, the dose-levels selected for the main experiment were 0.5, 1.0, 1.5, 2.0 and 3.0 mL/kg bw of the undiluted test item.

Clinical signs, mortality and body weight were checked for a period of up to 14 days following the single administration of the test item. All animals were subjected to necropsy. The LD50 was calculated according to Litchfield & Wilcoxon (J. Pharmacol. Exp. Therap., 1949, 96, 99-113).

No deaths occured at 0.5 ml/kg bw. At 1, 1,5 and 2ml/kg bw, 2, 4 and 9 rats died from day 4 to day 7 respectively. At 3 ml/kg bw, all rats died on day 4.

Generally clinical signs were drowsiness and mucoid diarrhoea (at 1 mL/kg bw and higher), prostration and piloerection (at 1.5 ml/kg bw and higher), abdominal swelling and dizziness (at 3 ml/kg bw). no clinical sighns were observed at 0.5 ml/kg bw.

No macroscopic abnormalities were observed at necropsy in any dose-groups.

Under these experimental conditions, the oral LD50 of the test item was 1255 (1031 - 1534) mg/kg bw in male rats with 95% confidence interval limits