Registration Dossier

Administrative data

Description of key information

The tests were performed according to the following methods:

Method B.1 tris: Acute Oral Toxicity - Acute Toxic Class Method, Council Regulation (EC) No.440/2008, published in O.J. L 142, 2008.

OECD Guidelines for Testing of Chemicals (1981) No. 403 “Acute Inhalation Toxicity” referenced as Method B2 (Inhalation) of Council Regulation (EC) No. 440/2008.

Both: GLP study

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:
27.7.-11.8.2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2008
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeding farm VELAZ s.r.o., Koleč u Kladna, Czech Republic, RČH CZ 21760152
- Age at study initiation: 8-10 weeks at the time application
- Weight at study initiation: 134.67-164.12 g
- Fasting period before study: About twenty hours before oral administration the animals were not fed, water was given ad libitum.
- Housing:animal room with monitoring conditions – 3 animals of one sex in one plastic breeding cage Velaz T4
- Bedding: sterilized shavings of soft wood
- Diet: ST 1 BERGMAN – standard pelleted diet ad libitum (producer: Ing.Mrkvička Miroslav - Výroba krmných směsí, Mlýn Kocanda, 252 42 Jesenice u Prahy).
- Water: drinking tap water ad libitum (quality corresponding to Regulation No. 252/2004 Czech Coll. of Law)
- Acclimation period: 5 days
- Randomisation: according to the internal rule, at the start of the study the weight variation of animals was minimal and did not exceed + 20 % of the mean weight for each sex
- Identification of animals: colour marks 1 - 3 on tail of animals, each cage was marked with the number of study, sex and dose of the test substance
- Health condition: certificate of good health condition – from breeding farm; no signs of diseases were observed at clinical check-in, during the acclimatisation period and before the start of study.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature 22 +/- 3°C, permanently monitored
- Humidity (%): relative humidity 30 – 70 %, permanently monitored
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): light period 12-hour light/12 hour dark


STUDY TIME SCHEDULE
- Animal supply: 22. 7. 2009
- Experimental part of study: 27. 7. - 11. 8. 2009
- Evaluation of results and final report elaboration: 7. 7. - 13. 8. 2009
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle: It is not toxic. It is possible to prepared homogenous suspension with test substance.
- Batch No.: L803142
- Expiration.: 09/2009
- Producer: Dr. Kulich Pharma Hradec Králové


MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw


DOSAGE PREPARATION (if unusual):Immediately before application the test substance was weighed, mixed in vehicle (olive oil) and resulting suspension was administered to the stomach by tube. The single volume of administered suspension was 1ml/100 g of animal body weight.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: according to the methodology
Testing schedule (according to EU Method B.1 tris Annex 1D)
START: 2000 mg/kg – 3 females (Step No.1): no deaths ► 2000 mg/kg – 3 females (Step No. 2): no deaths ► END of study
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 females (Step No. 1: 3 females, Step No. 2: 3 females)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were weighed before application, on the 8th day of study and at day 15, before euthanasia of animals. Average body weight in a group was calculated from individual body weights.
- Clinical examination: After application the animals were observed individually:
The first day: twice (30 minutes and 3 hours after application)
The second day: twice (in the morning and in the afternoon) and daily thereafter for 14 days.
Observations included changes in skin and fur, eyes, visible mucous membranes, behaviour of animals, somatomotor activity, reactions to stimuli, and presence of lacrimation, salivation and discharge from nostrils, function of respiratory, digestive and urogenital system.
- Pathological examination
All test animals survived to the end of study were sacrificed on the 15th day by prolonged ether narcosis and gross necropsy was carried out. Nutritious status, body surface, body foramina, thoracic, abdominal and cranial cavity were evaluated. All gross macroscopic changes of organs and tissues were recorded on special data sheets.
- Body weight increments were calculated from body weight at the start of the study, during the first week and at the end of the study.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No animals died during the study.
Clinical signs:
No clinical signs of intoxication were detected after application in all animals (see tables No. 2 and No. 3).
Clinical signs of intoxication (piloerection) were observed in all six animals at the 3 hours after application only.
Body weight:
Body weight was recorded and weight increments were calculated in all surviving animals at the end of study (see table No. 1).
Weight increments were adequate to species, sex and age of animals in experiment.
Gross pathology:
The test substance caused no pathological changes in all animals from both groups (see tables No. 4 and No. 5).

Table No. 1: Individual body weight (g) – 2000 mg/kg (Steps No. 1 and No. 2)

Dose   (mg/kg) 

(Step No.)

Animal

No.

Body weight (g)

Body weight gain (g)

Before
application

8 days
p.a.

15 days
p.a.

Death

0-8 days
p.a.

8-15 days
p.a.

2000

(1)

1

151.50

181.27

198.26

-

29.77

16.99

2

137.85

157.03

168.09

-

19.18

11.06

3

164.12

195.88

212.38

-

31.76

16.50

mean

151.16

178.06

192.91

-

26.90

14.85

SD

13.14

19.62

22.62

-

5.52

2.69

2000

(2)

4

137.86

155.80

170.35

-

17.94

14.55

5

134.67

153.78

167.96

-

19.11

14.18

6

148.06

176.03

191.70

-

27.97

15.67

mean

140.2

161.87

176.67

-

21.67

14.80

SD

6.99

12.30

13.07

-

4.48

0.63

Table No. 2: Clinical observation – 2000 mg/kg (Step No. 1)

Animal

No.

Death after

application

Observed changes

1

No

30 minutes: no clinical signs of intoxication

3 hours: piloerection

2nd– 14thday: no clinical signs of intoxication.

2

No

30 minutes: no clinical signs of intoxication

3 hours: piloerection

2nd– 14thday: no clinical signs of intoxication..

3

No

30 minutes: no clinical signs of intoxication

3 hours: piloerection

2nd– 14thday: no clinical signs of intoxication..

Table No. 3: Clinical observation – 2000 mg/kg (Step No. 2)

Animal No.

Death after

application

Observed changes

4

No

30 minutes: no clinical signs of intoxication

3 hours: piloerection

2nd– 14thday: no clinical signs of intoxication..

5

No

30 minutes: no clinical signs of intoxication

3 hours:piloerection

2nd– 14thday: no clinical signs of intoxication.

6

No

30 minutes: no clinical signs of intoxication

3 hours: piloerection

2nd– 14thday: no clinical signs of intoxication.

Table No. 4: Pathological examination – 2000 mg/kg (Step No. 2)

Animal No.

Necropsy findings

1

Without pathologic changes

2

Without pathologic changes

3

Without pathologic changes

Table No. 5: Pathological examination – 2000 mg/kg (Step No. 2)

Animal No.

Necropsy findings

4

Without pathologic changes

5

Without pathologic changes

6

Without pathologic changes

Interpretation of results:
GHS criteria not met
Conclusions:
The test substance toxicity was evaluated on the basis of mortality, clinical signs of intoxication, body weight increments during the observation period and necropsy findings at the end of study.
The test substance administered at the dose of 2000 mg/kg caused no death of animals. Clinical signs of intoxication (piloerection) were observed in all six animals at the 3 hours after application only. No pathologic macroscopic changes were diagnosed during pathological examination in all animals.
Executive summary:

The aim of the study was to investigate acute toxic effects of the test substance, Semi Dry Absorption (SDA) Product, after a single oral administration to Wistar rats.

The testing was performed according to the Method B.1 tris: Acute Oral Toxicity - Acute Toxic Class Method, Council Regulation (EC) No.440/2008, published in O.J. L 142, 2008.

The test substance was administered in a single dose as solution in vehicle (olive oil), given orally via gavage to two groups of three female Wistar rats.

The dosing was performed sequentially in two groups of three females: group No. 1 - first step using the starting dose of 2000 mg/kg of body weight and group No.2 - second step using the same dose.

The test substance administered at the dose of 2000 mg/kg caused no death of animals. Clinical signs of intoxication (piloerection) were observed in all six animals at the 3 hours after application only.

No pathologic macroscopic changes were diagnosed during pathological examination in all animals

According to the study results the value of LD50 of the test substance for female rats is higher than 2000 mg/kg of body weight.

The classification of the test substance toxicity was performed according to the Directive 67/548/EEC, Annex VI. part 3.1.5. and 3.2..

Based on the test results and according to the EC criteria for classification and labelling requirements for dangerous substances and preparations the test substance Semi Dry Absorption (SDA) Product, did not fall into any of quoted categories of toxicity and has no obligatory labelling requirement in this respect.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
20.01.- 30.03.2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
yes
Remarks:
(see Results part)
GLP compliance:
yes
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air

Results

Due to its nature, it proved impossible to generate consistent, controllable and reliable atmospheres of the test material in its normal or ground state. It was, therefore, not possible to continue this study so as to expose animals to an atmosphere of the material suitable for an acute inhalation study.

Interpretation of results:
other: not to be possible to generate a suitable test atmosphere from the test material
Conclusions:
The dust generation properties of Semi Dry Absorption (SDA) Product were shown to be low and mechanical systems designed to produce dust aerosols were unsuccessful in producing a dust atmosphere. It was, therefore, considered not to be possible to generate a suitable test atmosphere from the test material, for use in an inhalation study.
In view of the physical nature of the test material, its apparent low volatility and its apparent hygroscopic nature, it is considered unlikely to represent a significant hazard by the inhalation route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity study

The test substance toxicity was evaluated on the basis of mortality, clinical signs of intoxication, body weight increments during the observation period and necropsy findings at the end of study.
The test substance administered at the dose of 2000 mg/kg caused no death of animals. Clinical signs of intoxication (piloerection) were observed in all six animals at the 3 hours after application only. No pathologic macroscopic changes were diagnosed during pathological examination in all animals.

Acute inhalation toxicity study

Due to test material nature, it proved impossible to generate consistent, controllable and reliable atmospheres of the test material in its normal or ground state. It was, therefore, not possible to continue this study so as to expose animals to an atmosphere of the material suitable for an acute inhalation study.

Justification for classification or non-classification

Acute oral toxicity study

From the results of acute oral toxicity study follows that the substance is not classified as hazard substance (LD50 > 2000 mg/kg bw).

Acute inhalation toxicity study

The dust generation properties of Semi Dry Absorption (SDA) Product were shown to be low and mechanical systems designed to produce dust aerosols were unsuccessful in producing a dust atmosphere. It was, therefore, considered not to be possible to generate a suitable test atmosphere from the test material, for use in an inhalation study.

In view of the physical nature of the test material, its apparent low volatility and its apparent hygroscopic nature, it is considered unlikely to represent a significant hazard by the inhalation route.