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Administrative data

Description of key information

Oral (OECD 423), rat: LD50 > 2000 mg/kg bw
Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw (limit test)

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:
18 Feb - 21 Mar 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Health Care Inspectorate, Ministry of Health, Welfare and Sport, Den Haag, The Netherlands
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Wistar strain Crl:WI (Han) (outbred, SPF-quality)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 8 - 9 weeks
- Weight at dosing: 144-187 g
- Fasting period before study: food was withdrawn overnight prior to dosing and until 3-4 hours after administration of the test substance
- Housing: group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm) containing sterilized sawdust as bedding material and paper as cage-enrichment
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF Spezialdiäten, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

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

IN-LIFE DATES: From: 18 Feb 2014 To: 21 March 2014
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 3% and 20%
- Amount of vehicle: 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

CLASS METHOD
- Rationale for the selection of the starting dose: according to Guideline
Doses:
step 1: 300 mg/kg bw
step 2 and 3: 2000 mg/kg bw
No. of animals per sex per dose:
3 females per step (in total 9 females)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality/Viability was checked twice daily. Clinical signs were observed at periodic intervals on the day of dosing (Day 1) and once daily thereafter until Day 15. Body weights were determined on Days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes
Statistics:
No statistical analysis was performed.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: According to OECD Guideline 423, Annex 2d, a cut-off value of 5000 mg/kg bw was derived based on a limit test with 2000 mg/kg bw, since no mortality occurred in any step.
Mortality:
No mortality occurred.
Clinical signs:
At 300 mg/kg bw hunched posture and piloerection were noted for all animals between Days 1 and 4.
At 2000 mg/kg bw hunched posture and piloerection were noted in 3/6 animals on Day 1.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
At 300 mg/kg bw macroscopic post mortem examination did not reveal any abnormalities.
At 2000 mg/kg bw abnormalities of the liver (several, beige, focus/foci) were found in two animals, at macroscopic examination. Macroscopic examination of the other animals did not reveal any abnormalities.
Interpretation of results:
other:
Remarks:
CLP/EU GHS criteria are not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02-16 Apr 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Deviations:
yes
Remarks:
occlusive dressing was used
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
Aug 1998
Deviations:
no
Qualifier:
according to
Guideline:
other: Food and Argricultural Materials Inspection Centre (FAMIC), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Health Care Inspectorate, Ministry of Health, Welfare and Sport, Den Haag, The Netherlands
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar strain Crl: WI (Han) (outbred, SPF-quality)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 10 weeks
- Weight at study initiation: 294-338 g (males); 206-215 g (females)
- Housing: individually in labeled Makrolon cages (MIII type, height 18 cm) containing sterilized sawdust as bedding material and paper as cage-enrichment
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

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

IN-LIFE DATES: From: 02 Apr 2014 To: 16 Apr 2014
Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: 25 cm² for males and 18 cm² for females on the back
- % coverage: 10
- Type of wrap if used: The formulation was in contact with the skin with a dressing, consisting of a surgical gauze patch, successively covered with aluminum foil and elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Washing: Skin was cleaned of residual test substance using tap water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 10 mL/kg bw
- Concentration: 20%
- Constant volume or concentration used: yes
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality/Viability was checked twice daily. Clinical signs were observed at periodic intervals on the day of dosing (Day 1) and once daily thereafter until Day 15. Body weights were determined on Days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Slight scales or slight chromodacryorrhoea were observed on the treated skin-area on Day 3 for one male and one female animal, respectively.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
other:
Remarks:
CLP/EU GHS criteria are not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

The acute oral toxicity of the test substance was assessed in a GLP compliant OECD Guideline 423 study (Tosoh Corporation, 2014a). Initially the test substance was administered by oral gavage to three female Wistar rats at 300 mg/kg bw. In a stepwise procedure two additional groups of three females were dosed at 2000 mg/kg bw. Animals were observed daily for clinical signs and body weight was determined weekly. Macroscopic examination was performed at the end of the 14-day observation period at terminal sacrifice. There were no mortalities during the observation period and body weight gain of all animals was considered to be normal. Hunched posture and piloerection were noted for all animals dosed at 300 mg/kg bw between Days 1 and 4 and in 3/6 animals dosed at 2000 mg/kg bw on Day 1. Macroscopic post mortem examination did not reveal any abnormalities in animals at 300 mg/kg bw. At 2000 mg/kg bw abnormalities of the liver (several, beige, focus/foci) were found in two animals. The other animals at 2000 mg/kg bw did not reveal any abnormalities at macroscopic examination. Based on the results of this study, the LD50 value was determined to be > 2000 mg/kg bw in rats. In accordance with OECD Guideline 423, Annex 2d, a cut-off value of 5000 mg/kg bw was derived, since no mortality occurred in any step at the limit dose of 2000 mg/kg bw.

Inhalation

Due to the low vapour pressure, exposure considerations and animal welfare considerations, further testing by the inhalation route does not need to be conducted in accordance with Annex VIII, Column 2, Section 8.5.2, of Regulation (EC) No 1907/2006.

Dermal 

The acute dermal toxicity of the test substance was assessed in a limit test performed in 5 male and 5 female Wistar rats according to OECD Guideline 402 and in compliance with GLP (Latour, 2014b). A single dose of 2000 mg/kg bw of the test substance in water was applied to the clipped skin of rats under occlusive conditions for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice on Day 15. There was no mortality and no effects on body weight during the 14-day observation period. Slight scales or chromodacryorrhoea were seen in the treated skin-area on Day 3 for one male and one female animal, respectively. No abnormalities were found at macroscopic post mortem examination of the animals. The LD50 value for systemic toxicity is considered to be > 2000 mg/kg bw.

Justification for classification or non-classification

The available data on acute oral and dermal toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.