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Description of key information

LD50 = >2000 mg/kg bw; OECD 420; Anon, 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:
06 Feb - 27 Feb 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study conducted in accordance with international guidelines and in accordance with GLP. All guideline criteria were met.
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Oxon, UK
- Females (if applicable) nulliparous and non-pregnant: Yes and yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 159-193g. Body weight variation did not exceed ±20% of the mean body weight at the start of treatment.
- Fasting period before study: Overnight fasting before dosing
- Housing: up to four test animals in suspended solid-floor polypropylene cages furnished with wood flakes
- Diet (e.g. ad libitum): ad libitum except for overnight before dosing and approx 3-4 hours after dosing during which time rats were fasted.
- Water (e.g. ad libitum): ad libitum except for approx 3-4 hours after dosing during which time rats were fasted.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70%
- Air changes (per hr): at least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours continuous light / 12 hours darkness

IN-LIFE DATES: From: 06-Feb-2017 To: 27-Feb-2017
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Remarks:
For the purpose of the 300 mg/kg dose level the test item was freshly prepared, as required, as a solution in arachis oil BP, because the test item did not dissolve/suspend in distilled water.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: For the purpose of the 300 mg/kg dose level (sighting test): 30 mg/mL
- Amount of vehicle (if gavage): For the purpose of the 300 mg/kg dose level (sighting test): Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.
- Justification for choice of vehicle: Arachis oil BP (for the 300 mg/kg dose level) was used because the test item did not dissolve/suspend in distilled water.
- Lot/batch no. (if required): 461/16
- Purity: 98.9%

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg

DOSAGE PREPARATION (if unusual): For the purpose of the 300 mg/kg dose level the test item was freshly prepared, as required, as a solution in arachis oil BP. Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose. In the absence of mortality at a dose level of 300 mg/kg bw, an additional animal was dosed with 2000 mg/kg bw. In the absence of mortality at a dose level of 2000 mg/kg bw, an additional 4 animals were dosed with 2000mg/kg bw.

Doses:
All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose group to confirm the survival of the previously dosed animals.
A total of 6 females were treated. A single female was treated with 300mg/kg bw. An additional female was treated with 2000mg/kg bw. In the absence of mortality, a further 4 females were treated with 2000mg/kg bw.
No. of animals per sex per dose:
1 female in the first sighting test (300 mg/kg bw)
1 female in second sighting test (2000 mg/kg bw)
4 females in the main test (2000 mg/kg bw)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made 30 minutes, 1,2 and 4 hours after dosing and then daily for 14 days. Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Morbidity and mortality checks were made twice daily, early and late during normal working days, and once daily at weekends and public holidays. Clinical observations were performed. (Necropsy: External examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded).

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:
There was no mortality.
Clinical signs:
Hunched posture was noted 1, 2 and 4 hours after dosing. No other signs of systemic toxicity were noted.
Body weight:
All animals showed expected gains in body weight.
Gross pathology:
No abnormalities were noted at necropsy.

Table 1 presents the clinical observations of the treated animals. In the initial sighting study (dose of 300mg/kg bw), hunched posture was noted 1, 2 and 4 hours after dosing. No other signs of systemic toxicity were noted. For the initial singular animal treated with a dose level of 2000 mg/kg bw, hunched posture was noted 1, 2 and 4 hours after dosing in the initial treated animal. No other signs of systemic toxicity were noted in this animal. No signs of systemic toxicity were noted in the additional four treated animals during the observation period. No abnormalities were noted in necropsies of all animals. Table 2 demonstrates the weight changes throughout the study in the individual test animals. Table 3 demonstrates the necropsy findings of individual test animals.

Table 1. Individual Clinical Observations and Mortality Data

DOSE LEVEL mg/kg

ANIMAL NUMBER AND SEX

EFFECTS NOTED AFTER DOSING
(Hours)

EFFECTS NOTED DURING PERIOD AFTER DOSING
(Days)

EFFECTS NOTED DURING PERIOD AFTER DOSING
(Days)

1/2

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

300

1-0 Female

0

H

H

H

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2000

2-0 Female

0

H

H

H

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-0 Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-1 Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-2 Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-3 Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0 = no signs of systemic toxicity

H = hunched posture

Table 2. Individual body weights and body weight changes

DOSE LEVEL mg/kg

ANIMAL NUMBER & SEX

BODY WEIGHT (g) AT DAY

BODY WEIGHT GAIN (g) DURING WEEK

0

7

14

1

2

300

1-0 Female

183

198

219

15

21

2000

2-0 Female

159

170

191

11

21

3-0 Female

193

214

221

21

7

3-1 Female

193

212

224

19

12

3-2 Female

170

190

230

20

40

3-3 Female

179

191

228

12

37

Table 3. Individual necropsy findings

DOSE LEVEL mg/kg

ANIMAL NUMBER AND SEX

TIME OF DEATH

MACROSCOPIC OBSERVATIONS

300

1-0 Female

Killed day 14

No abnormalities detected

2000

2-0 Female

Killed day 14

No abnormalities detected

3-0 Female

Killed day 14

No abnormalities detected

3-1 Female

Killed day 14

No abnormalities detected

3-2 Female

Killed day 14

No abnormalities detected

3-3 Female

Killed day 14

No abnormalities detected

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight.
Executive summary:

The acute oral toxicity of the test substance was measured using the fixed dose method (OECD 420 and EU Method B. 1) on the Wistar rat strain. One rat was given a dose of 300mg/kg bw (sighting test), followed by one rat given a dose of 2000mg/kg bw, followed by four further rats given a dose of 2000mg/kg bw. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Under the condition of this study, the acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight.

Based on these results, the test item does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
A single key study was submitted which meets the REACH data requirements.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Annex VIII, Section 8.5.1, Column 2, and ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7a, If no systemic effects are observed during acute oral testing, the requirement to conduct inhalation testing should be considered on a case-by-case basis. In the absence of any signs of systemic toxicity in acute and subacute studies conducted for this substance, acute inhalation testing was not considered to be appropriate. No acute hazard via inhalation is concluded for the substance.
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
The oral LD50 of >2,000 mg/kg bw (not classified) and no signs of toxicity were observed in the in vivo skin sensitisation study, no further justification should be necessary.
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a single key study, the acute oral toxicity of the test substance was measured using the fixed dose method (OECD 420 and EU Method B. 1) on the Wistar rat strain. One rat was given a dose of 300mg/kg bw (sighting test), followed by one rat given a dose of 2000mg/kg bw, followed by four further rats given a dose of 2000mg/kg bw. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Under the condition of this study, the acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight.

Justification for classification or non-classification

The test item does not meet the classificaiton criteria in accordance with Regulation (EC) No 1272/2008 (CLP).

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