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Description of key information

LD50 oral cut-off(rat): 2000 mg/kg bw [report, Schüngel 2004]

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June to November 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
17 December 2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Strain: Hsd Cpb:WU (SPF)
- Age at study initiation: 10-14 weeks
- Mean weight at study initiation: 166-205 g
- Housing: in groups of 3 animals. The animals were group caged conventionally in polycarbonate cages on low dust wood granulate bedding (J. Rettenmaier & Söhne, 73479 Ellwangen-Holzmühle,
Germany). The cages of the animals were placed on racks, in ascending group number order.
- Diet: ad libitum, standard diet “Provimi Kliba 3883.0.15 Maus/Ratte Haltung, Kaiseraugst Switzerland”
- Water: ad libitum, tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 5
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
other: formulated in demineralized water with the aid of 2% Cremophor EL
Details on oral exposure:
- Application volume: 10 mL/kg bw

- Rationale for the selection of the starting dose:
As described in the flow charts of Annex 2, OECD guideline 423, the starting dose level should be that which is most likely to produce mortality in some of the dosed animals. Therefore, the limit dose 2000 mg/kg bw was chosen as starting dose.

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Purity: demineralized water with 2% Cremophor

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
300 and 2000 mg/kg
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at least once daily (clinical signs, mortality) or once weekly (weight gain)
- Necropsy of survivors performed: yes

- Clinical signs including body weight: yes, please refer to results
- Other examinations performed: clinical signs, body weight, gross pathology
Statistics:
none (limit test)
Key result
Sex:
female
Dose descriptor:
other: LD50 cut-off
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
At the dose 2000 mg/kg bw 4 out of 6 animals died within 2 days after treatment. The dose 300 mg/kg bw was tolerated by all 6 females without mortalities.
Clinical signs:
other: At 2000 mg/kg bw decreased motility, uncoordinated gait, narrowed palpebral fissure, lateral position, spasmodic state, tachypnea, abdominal position, labored breathing, temporary lateral position, poor reflexes, lacrimation/increased lacrimation and dysp
Gross pathology:
No gross pathological findings were observed in animals that died during the observation period and at the end of the study.
Other findings:
none
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
According to OECD TG 423 the LD50 cut-off of Picolinamid-Phenylether is 2000 mg/kg bw (Category 4 of the Globally Harmonized Classification System). At the limit-dose 2000 mg/kg bw 4 out of 6 animals died within 2 days after treatment. The dose 300 mg/kg bw was tolerated by all 6 females without mortalities. At 2000 mg/kg bw decreased motility, uncoordinated gait, narrowed palpebral fissure, lateral position, spasmodic state, tachypnea, abdominal position, labored breathing, temporary lateral position, poor reflexes, lacrimation/increased lacrimation and dyspnea were observed up to day 2 after treatment. The dose 300 mg/kg bw was tolerated by all animals without clinical signs. In both doses neither effects on body weight gain nor gross pathological findings were observed.


Executive summary:

In an acute oral toxicity study similar to OECD TG 423 (adopted 17 December 2001), groups of fasted, female Wistar rats, weighing 166-205 g, (3/treatment) were given a single oral dose of Picolinamid phenyletherin 2% Cremophor in demineralized water at a doses of 300 and 2000 mg/kg bw and observed for 14 days.


Oral LD50 Combined = 2000 mg/kg bw cut-off


Limit test


At the dose 2000 mg/kg bw 4 out of 6 animals died within 2 days after treatment. The dose 300 mg/kg bw was tolerated by all 6 females without mortalities.


There were no treatment related clinical signs, necropsy findings or changes in body weight in all animals of the 300 mg/kg bw group. At 2000 mg/kg bw decreased motility, uncoordinated gait, narrowed palpebral fissure, lateral position, spasmodic state, tachypnea, abdominal position, labored breathing, temporary lateral position, poor reflexes, lacrimation/increased lacrimation and dyspnea were observed up to day 2 after treatment.


The test item exhibited a LD50 cut off in female Wistar rats of 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
The study is GLP compliant and is of high quality (Klimisch score=1)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In an acute oral toxicity study similar to OECD TG 423 (adopted 17 December 2001), groups of fasted, female Wistar rats, weighing 166-205 g, (3/treatment) were given a single oral dose of Picolinamid phenyletherin 2% Cremophor in demineralized water at a doses of 300 and 2000 mg/kg bw and observed for 14 days.


Oral LD50 Combined = 2000 mg/kg bw cut-off


Limit test


At the dose 2000 mg/kg bw 4 out of 6 animals died within 2 days after treatment. The dose 300 mg/kg bw was tolerated by all 6 females without mortalities.


There were no treatment related clinical signs, necropsy findings or changes in body weight in all animals of the 300 mg/kg bw group. At 2000 mg/kg bw decreased motility, uncoordinated gait, narrowed palpebral fissure, lateral position, spasmodic state, tachypnea, abdominal position, labored breathing, temporary lateral position, poor reflexes, lacrimation/increased lacrimation and dyspnea were observed up to day 2 after treatment.


The test item exhibited a LD50 cut off in female Wistar rats of 2000 mg/kg bw.

Justification for classification or non-classification

Based on the study results (oral LD50 cut-off value: 2000 mg/kg bw ) a classification with Acute Toxicity Cat. 4 (H302:harmful if swallowed) according to Regulation (EC) No.1272/2008 (CLP) is required.