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Description of key information

In an acute oral toxicity study (acute toxic class method, ATC) according to OECD guideline 423 an LD50 of above 2000 mg/kg bw was determined (corresponding to > 2280 mg product/kg bw).

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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:
December 07, 2016 - March 16, 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
17th December 2001
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
SPF
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: TOXI COOP ZRT. Cserkesz u. 90. 1103 Budapest, Hungary
- Females nulliparous and non-pregnant: yes
- Age at study initiation: young adult rat, 8 weeks old in first and second step
- Weight at study initiation:
at starting (first step): 205 - 214 g
at starting (second step): 207 - 213 g
- Fasting period before study: The day before treatment.
- Housing: Group caging (3 animals/cage) in Type II polypropylene/polycarbonate cages.
- Diet: ssniff® SM R/M-Z+H complete diet for rats and mice produced (ssniff Spezialdiäten GmbH, 59494 Soest Germany) ad libitum.
- Water: tap water from municipal supply, as for human consumption from bottle ad libitum.
- Acclimation period: 6 days in the first step and 7 days in the second step

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): above 10 air exchanges/hour by central air-condition system.
- Photoperiod (hrs dark / hrs light): 12/12 from 6.00 a.m. to 6.00 p.m.

In life phase: January 11-27, 2017





Route of administration:
oral: gavage
Vehicle:
other: Aqua purificata Ph.Hg. VIII.
Remarks:
Parma Produkt Kft.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle: 10 mL/kg bw
- Batch no: 1608-5511

DOSAGE PREPARATION
The test item was applied in a concentration of. The correction factor was taken into consideration in the course of the making of solution. Formulations were prepared just before the administration and were stirred continuously during the treatment.

CLASS METHOD
- Rationale for the selection of the starting dose: Starting dose (2000 mg/kg bw) was selected on the basis of the available information about the test item.








Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 female animals (3 in the first step, 3 in the second step)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed individually after dosing at least once during the first 30 minutes, then 1 h, 2 h, 3 h, 4 h after the treatment and twice each day for 14 days thereafter. The body weights were recorded on day 0 (just before the treatment), on day 7 and on day 15 with a precision of 1 g.
- Necropsy of survivors performed: yes, After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed, and any abnormality was recorded with details of its location, colour, shape and size.
- Sacrifice: At the end of the observation period all surviving rats were sacrificed under isofluran anaesthesia.
- Other examinations performed: Individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Statistics:
The method used is not intended to allow the calculation of a precise LD50 value.
Key result
Sex:
female
Dose descriptor:
LD50
Remarks:
corre
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No death occurred at 2000 mg/kg bw single oral dose of the test item. All female rats in step 1 and step 2 survived until the end of the 14-day observation period.
Clinical signs:
In group 1 and 2 treated with 2000 mg/kg bw dose no treatment related symptoms were observed throughout the 14-day post-treatment period.

Body weight:
The mean body weight of animals treated with 2000 mg/kg bw dose corresponded to their species and age throughout the study.
Gross pathology:
All animals treated with 2000 mg/kg bw dose survived until the scheduled necropsy on Day 15.
Slight hydrometra was found ione animal and severe hydrometra was detected in two two other animals. Hydrometra is physiological finding and connected to the estrous cycle of the animal. No pathological changes were found related to the treatment with the test item during the macroscopic examination of animals treated with 2000 mg/kg bw dose.
Interpretation of results:
GHS criteria not met
Conclusions:
In an acute oral toxicity study (acute taxic class method, ATC) according to OECD guideline 423, an LD50 of above 2000 mg/kg bw was determined.
Executive summary:

The acute oral toxicity of the test item was assessed in an acute oral toxicity study (ATC) according to OECD guideline 423. A single oral administration - followed by a fourteen-day observation period - was performed by gavage in young adult female Wistar rats. The day before treatment the animals were fasted. The food but not water was withheld overnight. Animals were weighed before the application and the food was given back 3 hours after the treatment.

The acute toxic class method was carried out involving a stepwise procedure with the use of 2000 mg/kg bw as the starting dose in three female rats. The dose refers to the dye content (88 %, correction factor of 1.14) and corresponds to 2280 mg product/kg bw. No animal died in the first step at 2000 mg/kg bw dose level, so treatment with 2000 mg test item/kg bw was repeated on further three female rats. No animal died in the second step, too. The stopping criteria of Annex 2d of OECD Guideline No. 423 was met, consequently, the test was finished. No clinical signs were observed. The treatment had no effect on the body weight development of the animals. No pathological changes were found related to the treatment with the test item during the macroscopic examination of animals treated with 2000 mg/kg bw dose.

The method used, was not intended for calculation of a precise LD50 value. However an LD50 of above 2000 mg/kg bw was determined.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
Guideline and GLP conform study.

Additional information

Acute oral toxicity

The acute oral toxicity of the test item was assessed in an acute oral toxicity study (ATC) according to OECD guideline 423. A single oral administration - followed by a fourteen-day observation period - was performed by gavage in young adult female Wistar rats. The day before treatment the animals were fasted. The food but not water was withheld overnight. Animals were weighed before the application and the food was given back 3 hours after the treatment.

The acute toxic class method was carried out involving a stepwise procedure with the use of 2000 mg/kg bw as the starting dose in three female rats. The dose refers to the dye content (88 %, correction factor of 1.14) and corresponds to 2280 mg product/kg bw. No animal died in the first step at 2000 mg/kg bw dose level, so treatment with 2000 mg test item/kg bw was repeated on further three female rats. No animal died in the second step, too. The stopping criteria of Annex 2d of OECD Guideline No. 423 was met, consequently, the test was finished. No clinical signs were observed. The treatment had no effect on the body weight development of the animals. No pathological changes were found related to the treatment with the test item during the macroscopic examination of animals treated with 2000 mg/kg bw dose.

The method used, was not intended for calculation of a precise LD50 value. However an LD50 of above 2000 mg/kg bw was determined.

Acute inhalation toxicity:

The study does not need to be conducted as exposure of humans via inhalation is not a likely route of exposure. Furthermore, physicochemical and toxicological properties do not suggest a potential for a significant rate of respiratory absorption.

Acute dermal toxicity:

According to REACH Annex VIII point 8.5.3 the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation). Acute dermal toxicity can be excluded since dermal absorption is assumed to be negligible on the basis of the high molecular weight and the low water solubility of the test substance.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on acute oral toxicity, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the twelfth time in Regulation (EU) No 2019/521.