Registration Dossier

Administrative data

Description of key information

Oral: LD50 > 2000 mg/kg bw, female rate, OECD 423, 2017

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:
30 Jan - 08 Mar 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study was conducted in acordance with international guidelines and in accordance with GLP. All guideline validity criteria were met.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF Guidelines (2000)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Wistar Han
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Approx. 8 weeks old
- Weight at study initiation: 143 - 171 g
- Fasting period before study: 20 h prior to dosing and 3-4 after dosing.
- Housing: Up to 5 animals (of the same sex and dose group) housed together in polycarbonate cages (Makrolon Miv type; height 18 cm) containing sterlised sawdust bedding (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany).
- Diet (e.g. ad libitum): ad libitum (except during designated procedures)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24 ºC
- Humidity (%): 40 - 70 %
- Air changes (per hr): 10 or greater
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 01 Feb 2017 To: 08 Mar 2017
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle:
- Amount of vehicle (if gavage): 10 mL/kg b.w.
- 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.
- Lot/batch no. (if required): Not reported
- Purity: Not reported

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

DOSAGE PREPARATION (if unusual): N/A

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The starting dose level should be the one that is likely to produce mortality in at least some of the animals and was selected based on available toxicity data of the test item.
Doses:
Test substance was administered by oral gavage to three female Wistar rats at 300 mg/kg body weight. In a stepwise procedure two additional groups of three females were dosed at 2000 mg/kg body weight.
No. of animals per sex per dose:
3 females at 300 mg/kg bw and 6 females at 2000 mg/kg bw.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing (time after dosing): 0, 2, 4 h and twice daily thereafter (clinical signs). Day 1, 8 and 15 (weight).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Statistics:
Not required.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
None
Clinical signs:
At 300 mg/kg, piloerection was noted for all animals on Day 1 only.

At 2000 mg/kg, piloerection, uncoordinated movements, abnormal gait, quick breathing, shallow respiration, hunched posture and/or ptosis were noted for all animals on Day 1 only.
Body weight:
The mean 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.
Other findings:
- Organ weights: N/A
- Histopathology: No abnormalities in any of the animals.
- Potential target organs: N/A
- Other observations: N/A

Table 1:      Mortality Data


TEST DAY
HOURS AFTER TREATMENT
 

 
1
0
 

 
1
2
 

 
1
4
 

 
2

 

 
3

 

 
4

 

 
5

 

 
6

 

 
7

 

 
8

 

 
9

 

 
10

 

 
11

 

 
12

 

 
13

 

 
14

 

 
15

 

FEMALES 300 MG/KG

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

FEMALES 2000 MG/KG

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

FEMALES 2000 MG/KG

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Table 2:       Clinical Signs

 
TEST DAY
HOURS AFTER TREATMENT
 



MAX
GRADE


1
0


1
2


1
4


2




3




4




5




6




7




8




9




10




11




12




13




14




15




FEMALES 300 MG/KG

ANIMAL 1

Skin / fur

 Piloerection

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 2

Skin / fur

 Piloerection

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 3

Skin / fur

 Piloerection

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-


FEMALES 2000 MG/KG

ANIMAL 4

Gait / motility

 Uncoordinated movements

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 Abnormal gait

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Breathing

 Quick breathing

(1)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 Shallow respiration

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin / fur

 Piloerection

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 5

Gait / motility

 Uncoordinated movements

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 Abnormal gait

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Breathing

 Quick breathing

(1)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 Shallow respiration

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin / fur

 Piloerection

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 6

Gait / motility

 Uncoordinated movements

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 Abnormal gait

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Breathing

 Quick breathing

(1)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 Shallow respiration

(3)

-

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Skin / fur

 Piloerection

(1)

1

1

1

-

-

-

-

-

-

-

-

-

-

-

-

-

-

ANIMAL 7

Posture

Hunched posture

(1)

1

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

Breathing

Quick breathing

(1)

 -

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

Skin / fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Piloerection

(1)

1

1

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

Various

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ptosis

(3)

 -

1

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

ANIMAL 8

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

(1)

 -

1

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Quick breathing

(1)

 -

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

Skin / fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Piloerection

(1)

1

1

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

ANIMAL 9

Posture

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

(1)

1

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

Breathing

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Quick breathing

(1)

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

Skin / fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Piloerection

(1)

1

1

1

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

 -

Table 3:       Body weights (g)

 
SEX/DOSE LEVEL


ANIMAL


DAY 1


DAY 8


DAY 15


FEMALES 300MG/KG

 

1

161

194

205

2

143

175

195

3

169

208

220

 

MEAN

158

192

207

ST.DEV.

13

17

13

N

3

3

3


FEMALES 2000 MG/KG

 

4

156

188

210

5

159

195

206

6

149

186

190

 

MEAN

155

190

202

ST.DEV.

5

5

11

N

3

3

3


FEMALES 2000 MG/KG

 

7

147

185

201

8

171

187

215

9

143

182

198

 

MEAN

154

185

205

ST.DEV.

15

3

9

N

3

3

3

 

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of the test substance in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results, the test substance ndoes not have to be classified for acute oral toxicity according to GHS.
Executive summary:

The potential toxicity of the test item, when given by oral gavage at a single dose to rats of a single sex at one or more defined doses, was evaluated in accordance with OECD Guideline 423 and GLP.

Initially, the test item was administered by oral gavage to three female Wistar rats at 300 mg/kg body weight. In a stepwise procedure two additional groups of three females were dosed at 2000 mg/kg bw. All animals were subjected to daily observations and weekly determination of bodyweight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred.

At 300 mg/kg, piloerection was noted for all animals on Day 1 only. At 2000 mg/kg, piloerection, uncoordinated movements, abnormal gait, quick breathing, shallow respiration, hunched posture and/or ptosis were noted for all animals on Day 1 only.

The mean body weight gain shown by the animals over the study period was considered to be normal.

No abnormalities were found at macroscopic post mortem examination of the animals.

 

The oral LD50 value of the test item in Wistar rats was established to exceed 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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

OECD 423, 2017 - The potential toxicity of the test item, when given by oral gavage at a single dose to rats of a single sex at one or more defined doses, was evaluated in accordance with OECD Guideline 423 and GLP.

Initially, The test item was administered by oral gavage to three female Wistar rats at 300 mg/kg body weight. In a stepwise procedure two additional groups of three females were dosed at 2000 mg/kg bw. All animals were subjected to daily observations and weekly determination of bodyweight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred.

At 300 mg/kg, piloerection was noted for all animals on Day 1 only. At 2000 mg/kg, piloerection, uncoordinated movements, abnormal gait, quick breathing, shallow respiration, hunched posture and/or ptosis were noted for all animals on Day 1 only.

The mean body weight gain shown by the animals over the study period was considered to be normal.

No abnormalities were found at macroscopic post mortem examination of the animals.

 

The oral LD50 value of the test item in Wistar rats was established to exceed 2000 mg/kg body weight.

Further, there was no evidence to suggest that GHS category 5 woulc be relevant for protection of vulnerable populations.  Testing to 5000 mg/kg is discouraged unless there is strong evidence that the results of such testing would have direct relevance to to the protection of human health.

Justification for classification or non-classification

The substance does not meet calssification criteria under Regulation (EC) No 1272/2008 for acute toxicity.