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Description of key information

Acute oral toxicity: LD50 > 2000 mg/kg bw; Notox 1999, OECD Guideline Study
Acute dermal toxicity: LD50 > 2000 mg/kg bw; Notox 1999, OECD Guideline 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:
10.06. - 05.09.1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline study, GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted on 1996
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Remarks:
NOTOX B.V., Hambakenwetering 7, 5231 DD ‘s-Hertogenbosch, The Netherlands
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL Ltd., Basel, Switzerland.
- Age at study initiation: approx. 7 weeks old
- Fasting period before study: Food was withheld overnight (for a maximum of 20 hours) prior to dosing until approximately 3-4 hours after administration of the test substance.
- Housing: Group housing of 3 animals per sex per cage in labeled polycarbonate cages containing purified sawdust as bedding material (SAWI, Jelu Werk, Rosenberg, Germany).
- Diet: standard pelleted laboratory animal diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days before start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 50
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: gavage
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: The vehicle was selected based on a pretest performed at NOTOX.

DOSAGE PREPARATION:
The formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of vehicle.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 (two groups of 3, stepwise treatment)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Body weights: days 1 (pre-administration), 8 and 15
- Mortality: checked twice daily
- Clinical signs:
At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded.
At the end of the observation period, all animals were sacrificed by asphyxiation using an oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Lethargy was observed in all animals on the day of treatment. Uncoordinated movements were seen in all females and in one male also on day 1. All animals had recovered from the symptoms on day 2.
Body weight:
The body weight gain shown by the surviving 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.
Conclusions:
The oral LD50 value of the test article in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

In an oral toxicity study according to OECD guideline 423 (Acute Toxic Class Method), three male and three female Wistar rats were dosed once with the test article in propylene glycol by gastric intubation at a dose level of 2000 mg/kg body weight and observed for 14 days. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15). No mortalities were recorded. Lethargy was observed in all animals on the day of treatment. Uncoordinated movements was seen in all females and one male also on day 1. All animals had recovered from the symptoms on day 2. The 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 article in Wistar rats was established to exceed 2000 mg/kg body weight.

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

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:
10.06. - 04.09.1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline study, GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted on 1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes
Remarks:
NOTOX B.V., Hambakenwetering 7, 5231 DD ‘s-Hertogenbosch, The Netherlands
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Germany.
- Age at study initiation: approx. 8 weeks old
- Housing: Individually housed in labelled polycarbonate cages containing purified sawdust as bedding material (Woody SPF, supplied by B.M.I., Helmond, The Netherlands).
- Diet: standard pelleted laboratory animal diet, ad libitum
- Water: tap-water, ad libitum
- Acclimation period: at least 5 days before start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 50
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12

Type of coverage:
semiocclusive
Vehicle:
propylene glycol
Details on dermal exposure:
TEST SITE
- Area of exposure: 5x7 cm on the back
- % coverage: 10% of the total body surface, i.e. 25 cm² for males and 18 cm² for females.
- Type of wrap if used: The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch, successively covered with aluminum foil and Coban flexible bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
-24 hours, after which dressings were removed and the skin cleaned of residual test substance using water.

TEST MATERIAL
- Concentration (if solution): 2000 mg/kg bw
- Constant volume or concentration used: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw
Duration of exposure:
24 hrs
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: twice daily
- Necropsy of survivors performed: yes
- Other examinations performed:
clinical signs: At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales.


Statistics:
No statistical analysis was performed.
Preliminary study:
Not applicable.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Red staining of the nose, neck and head (considered an indicator of generalized stress and derived from chromodacryorrhea) was noted on day 2 in two females. The animals had recovered from the symptoms between days 3 and 7. Scales were seen in the treated skin-area of one female between days 3 and 7.
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.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Other findings:
Not applicable.
Conclusions:
The dermal LD50 value of the test article in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

The acute dermal toxicity of the test substance was assessed in a toxicity study following OECD guideline 402 and in compliance with GLP. The test article was administered to five Wistar rats of each sex by dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15). No mortality occurred. Red staining of the nose, neck and head (considered an indicator of generalized stress and derived from chromodacryorrhea) was noted on day 2 in two females. The animals had recovered from the symptoms between days 3 and 7. Scales were seen in the treated skin-area of one female between days 3 and 7. The mean body weight gain during the observation period was within the range expected for rats used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals. The dermal LD50 value of the test substance in Wistar rats was established to exceed 2000 mg/kg body weight

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

Additional information

Oral

In a GLP-compliant acute oral toxicity study (OECD 423, Notox 1999), the test substance in propylene glycol was administered by oral gavage to three Wistar rats of each sex at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15). Lethargy was observed in all animals on the day of treatment. Uncoordinated movements was seen in all females and one male also on day 1. All animals had recovered from the symptoms on day 2. The 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. Therefore, the oral LD value in Wistar rats was established to exceed 2000 mg/kg body weight.

Dermal

In a GLP-compliant acute dermal toxicity study (OECD 402, Notox 1999), the test article in propylene glycol was administered to five Wistar rats of each sex by dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15). No mortality occurred. Red staining of the nose, neck and head (considered an indicator of generalized stress and derived from chromodacryorrhea) was noted on day 2 in two females. The animals, had recovered from the symptoms between days 3 and 7. Scales were seen in the treated skin-area of one female between days 3 and 7. The mean body weight gain during the observation period was within the range expected for rats used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals. In conclusion, the dermal LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight.


Justification for selection of acute toxicity – oral endpoint
GLP compliant guideline study

Justification for selection of acute toxicity – dermal endpoint
GLP compliant guideline study

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available experimental test data is reliable and suitable for the purpose of classification under Directive 67/548/EEC. Based on the data, classification for acute toxicity is not warranted under Directive 67/548/EEC.

 

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the data, classification for acute toxicity is not warranted under Regulation (EC) No.1272/2008.