Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28 Feb 2019 - 23 Apr 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
December 2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
December 2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Appendix to Director General Notification, No. 12-Nousan-8147. Agricultural Production Bureau, Ministry of Agriculture, Forestry and Fisheries of Japan (JMAFF), November 2000, including the most recent revisions.
Version / remarks:
November 2000
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(S)-2-(5-Oxo-3-propyl-1,2-dihydropyrrol-1-yl) butyramide
Cas Number:
357338-13-7
Molecular formula:
C11H18N2O2
IUPAC Name:
(S)-2-(5-Oxo-3-propyl-1,2-dihydropyrrol-1-yl) butyramide
Test material form:
solid: particulate/powder
Details on test material:
- Appearance: Off-white powder
- Storage condition of test material: In refrigerator protected from light

Test animals

Species:
rat
Strain:
other: Crl:WI (Han)
Sex:
female
Details on test animals or test system and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at the initiation of dosing: Young adult animals (approx. 8-10 weeks old)
- Weight at the initiating of dosing: 147 to 187 g
- Fasting period before study: Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item.
- Housing: Group housing of 3 animals of the same dosing group in polycarbonate cages (Macrolon MIV type),
containing sterilized sawdust as bedding material equipped with water bottles. For psychological/environmental enrichment, animals were provided with paper.
- Diet: Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days before the commencement of dosing

ENVIRONMENTAL CONDITIONS (set to maintain)
- Temperature (°C): 18 – 24 (actual: 20 - 21)
- Humidity (%): 40 - 70 (actual: 38 - 52)
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
GAVAGE METHOD: syringe with a plastic gavage cannula attached

Frequency: single dosage, on Day 1.

VEHICLE
The vehicle was selected based on trial preparations.

DOSE VOLUME APPLIED
10 mL/kg body weight

DOSAGE PREPARATION
Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. The dosing formulations were kept at room temperature until dosing and were used within 4 hours after preparation. The dosing formulations were stirred until and during dosing. Adjustment was made for specific gravity of the vehicle (1.036).
Doses:
- 2000 mg/kg bw
- 300 mg/kg bw
No. of animals per sex per dose:
- 2000 mg/kg bw: 6 (2 groups of 3 females in a stepwise manner)
- 300 mg/kg bw: 6 (2 groups of 3 females in a stepwise manner)
Control animals:
no
Details on study design:
The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups. The first group was treated at a dose level of 2000 mg/kg bw. Based on the results, one additional group was dosed at 2000 mg/kg bw. Based on the results, two additional groups were dosed at 300 mg/kg bw.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Moribundity checks: Twice daily, in the morning and at the end of the working day.
Body weights: Days 1 (pre-administration), 8 and 15
Clinical signs: At periodic intervals on the day of dosing (at least 3 times) and once daily thereafter, until Day 15.
- Necropsy of survivors performed: All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.
- Other examinations performed: none.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
- At 2000 mg/kg bw, for the first dose group, 1 animal was found dead on Day 1. For the second dose group, all animals were killed in extremis on Day 1.
- At 300 mg/kg bw, no mortality occurred.
Clinical signs:
- At 2000 mg/kg bw, lethargy, flat and hunched posture, uncoordinated movements, shallow respiration, piloerection and/or ptosis were noted for the animals between Days 1 and 4.
- At 300 mg/kg bw hunched, uncoordinated movements and piloerection were noted for the animals between Days 1 and 3.
Body weight:
The body weight gain shown by the surviving animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
Abnormalities of the thymus (several reddish foci on the left side) were found in one animal at 2000 mg/kg bw that was sacrificed for humane reasons during the study. No further macroscopic abnormalities were noted in any of the animals.

Applicant's summary and conclusion

Interpretation of results:
other: Category 4 based on GHS and CLP criteria
Conclusions:
In an acute oral toxicity study with the substance in female rats, performed according to OECD/EC test guidelines, an LD50 of > 300 - < 2000 mg/kg bw was determined. Based on this result, the substance is classified for acute toxicity by the oral route (Category 4) with Harmful if swallowed (H302). According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 2000 mg/kg body weight.
Executive summary:

The acute oral toxicity of the substance was determined in accordance with OECD 423 (2001) and according to GLP principles. The substance was administered by oral gavage, initially to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure three additional groups of three females were dosed at 2000, 300 and 300 mg/kg body weight.

At 2000 mg/kg bw, for the first dose group, one animal was found dead on Day 1 and the other two animals survived the observation period. At 2000 mg/kg bw, for the second dose group, all animals were killed in extremis on Day 1. At 300 mg/kg bw, no mortality occurred.

At 2000 mg/kg bw, lethargy, flat and hunched posture, uncoordinated movements, shallow respiration, piloerection and/or ptosis were noted for the animals between Days 1 and 4. At 300 mg/kg bw hunched, uncoordinated movements and piloerection were noted for the animals between Days 1 and 3. Abnormalities of the thymus (several reddish foci on the left side) were found in one animal at 2000 mg/kg bw that was sacrificed for humane reasons during the study. No further macroscopic abnormalities were noted in any of the animals.

The acute oral toxicity (LD50) was determined to be > 300 - < 2000 mg/kg bw. Based on this result, the substance is classified for acute toxicity by the oral route (Category 4) with Harmful if swallowed (H302). According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 2000 mg/kg body weight.