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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
Study period:
22 May - 08 June 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
Appearance: Off-white powder
Test item storage: At room temperature
Specific details on test material used for the study:
No correction factor required

Test animals

Species:
rat
Strain:
other: Crl:WI (Han)
Sex:
female
Details on test animals and environmental conditions:
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: 176 to 184 g
- Fasting period before study: overnight (maximum of 20 hours).
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages.
- Diet: Free access to 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.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 – 24 (actual 21 - 22)
- Humidity (%): 40 - 70 (actual 45 - 74)
- Air changes (per hr): approx 10
- Photoperiod (hrs dark / hrs light): 12/12

Deviations from the maximum level of daily mean target humidity occurred on several days during the study (highest value was 74%). This study plan deviation is considered not to have affected the integrity of the study because it did not noticeably affect the clinical condition of the animals or the outcome of the study.

IN-LIFE DATES: From: 23 May to 08 June 2018

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
GAVAGE METHOD: plastic feeding tubes.

Frequency: single dosage, on Day 1.

VEHICLE: Propylene glycol
- Justification for choice of vehicle: Trial preparations were performed at the Test Facility to select the suitable vehicle and to establish a suitable formulation procedure. Trial preparation formulations were not used for dosing and were discarded after the assessment is complete. These trial preparations have a non-GLP status and were carried out in the quality assured environment of the Test Facility.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (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. The dosing formulations were stirred until and during dosing. Adjustment was made for specific gravity of the vehicle. No correction was made for the purity/composition of the test item. Any residual volumes were discarded.
Doses:
2000 mg/kg body weight


No. of animals per sex per dose:
6 (2 groups of three females in a stepwise manner)
Control animals:
no
Details on study design:
Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum.

- Duration of observation period following administration: 14 days
- Mortality/Viability: Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day.
- Body weights: Animals were weighed individually on day 1 (predose), 8 and 15. A fasted weight was recorded on the day of dosing.
- Clinical signs: At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15.
- Necropsy of survivors performed: All animals were sacrificed by oxygen/carbon dioxide procedure at the end of the observation period. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded.
- Other examinations performed: none.
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture and/or piloerection were noted for the animals on days 1 and/or 2.
Body weight:
The body weight gain shown by the 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:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:
other: Not classified
Remarks:
according to EC 1272/2008
Conclusions:
The oral LD50 value of D6-NORETH in Wistar rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.
Executive summary:

An acute oral toxicity test was performed in Wistar rats according to OECD/EC guidelines and in accordance with GLP priniples. D6-NORETH was administered by oral gavage to two consecutive groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations, weekly determination of body weight and post mortem macroscopic examination. No mortality occurred during the observation period (15 days). Hunched posture and/or piloerection were noted for the animals on days 1 and/or 2. The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals.

The oral LD50 value of D6-NORETH in Wistar rats was established to exceed 2000 mg/kg body weight.

These results were evaluated according to:

- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments).

- Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

The LD50 cut-off value was considered to exceed 5000 mg/kg body weight, based on the OECD 423 test guideline. Based on these results, D6-NORETH does not have to be classified and has no obligatory labelling requirement for acute oral toxicity.