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Description of key information

The oral and dermal LD50 of the test substance was determined to be > 2,000 mg/kg bw.

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:
From September 27, 2011 to October 14, 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
Specific Gravity / Density: 1.14 g/cm3; pH: (1% in water, indicative range) 5.5 – 5.5 (determined at NOTOX); Stability at higher temperatures: yes, maximum temperature 40°C.
Species:
rat
Strain:
Wistar
Remarks:
strain Crl:WI (Han) (outbred, SPF-Quality).
Sex:
female
Details on test animals or test system and environmental conditions:
Age and body weight: young adult animals (approx. 9 weeks old) were selected. Body weight: variation did not exceed +/- 20% of the sex mean. Identification: earmark. Health inspection: a health inspection was performed prior to commencement of treatment, to ensure that the animals were in a good state of health.
Conditions: animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0ºC (actual range: 19.3 – 21.2ºC), a relative humidity of 40-70% (actual range: 44 - 76%) and 12 hours artificial fluorescent light and 12 hours darkness per day. Accommodation: group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom). Acclimatization period was at least 5 days before start of treatment under laboratory conditions. Diet Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany). Water: free access to tap water.
Results of analysis for diet (nutrients and contaminants), sawdust, paper and water were assessed and did not reveal any findings that were considered to have affected the study integrity. All certificates and results of analysis are retained in the NOTOX archives.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
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 test substance and vehicle. In consultation with the sponsor, in order to obtain homogeneity, the test substance and test substance formulations were heated in a water bath. The test substance was heated at a maximum temperature of 40ºC for a maximum of 1 hour and 55 minutes. The test substance formulations were heated at a maximum temperature of 55.8ºC for a maximum of 18 minutes. The test substance formulations were allowed to cool down to a temperature of maximally 38ºC prior to dosing.
Doses:
2000 mg/kg
No. of animals per sex per dose:
Each dose group consisted of 3 animals.
Control animals:
yes
Details on study design:
The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture was noted for all animals on Day 1. In addition, one animal showed piloerection 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:
No abnormalities were found at macroscopic post mortem examination of the animals.
Other findings:
-

The results were evaluated according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations and Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures.

Interpretation of results:
other: CLP criteria not met
Conclusions:
Under the study conditions, the acute oral toxicity of the test substance was > 2000 mg/kg bw.
Executive summary:

A study was conducted to determine the acute oral toxicity of the test substance according to OECD Guideline 423, EU Method B.1 and EPA OPPTS 870.1100. The substance (dissolved in polyethylene glycol) was administered by oral gavage to two subsequent groups of three female Wistar rats at 2000 mg/kg bw. Animals were subject to daily observations and weekly determinations of body weight. Microscopic examination was performed at terminal sacrifice (Day 15). No mortality occurred. Hunched posture was noted for all rats on Day 1. In addition, one animal showed piloerection on Day 1. Body weight gain over the study period was similar to that expected of untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination. Under the study conditions, the acute oral toxicity of the test substance to rats was > 2000 mg/kg bw (Stitzinger, 2011).

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:
From October 12, 2011 to October 26, 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Principles of method if other than guideline:
The study also followed this guideline: "Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions".
GLP compliance:
yes
Specific details on test material used for the study:
Specific Gravity / Density: 1.14 g/cm3; pH: (1% in water, indicative range) 5.5 – 5.5 (determined at NOTOX); Stability at higher temperatures: yes, maximum temperature 40°C.
Species:
rat
Strain:
Wistar
Remarks:
strain, Crl:WI (Han) (outbred, SPF-Quality).
Sex:
male/female
Details on test animals or test system and environmental conditions:
Source: Charles River Deutschland, Sulzfeld, Germany. Number of animals 5 males and 5 females (females were nulliparous and non-pregnant). Age and body weight: young adult animals (approx. 11 weeks old) were selected. Body weight: variation did not exceed +/- 20% of the sex mean. Identification: earmark. Health inspection: a health inspection was performed prior to commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from any abnormality.
Conditions: Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0ºC (actual range: 19.3 – 21.2ºC), a relative humidity of 40-70% (actual range: 46 - 73%) and 12 hours artificial fluorescent light and 12 hours darkness per day. Accommodation: individually housed in labeled Makrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom). Acclimatization period was at least 5 days before start of treatment under laboratory conditions. During the acclimatization period the animals were group housed in Makrolon cages (MIV type, height 18 cm). Diet: free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany). Water: free access to tap water. Results of analysis for diet (nutrients and contaminants), sawdust, paper and water were assessed and did not reveal any findings that were considered to have affected the study integrity. All certificates and results of analysis are retained in the NOTOX archives.
Type of coverage:
semiocclusive
Vehicle:
polyethylene glycol
Details on dermal exposure:
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 test substance and vehicle. In consultation with the sponsor, in order to obtain homogeneity, the test substance and test substance formulations were heated in a water bath with a maximum temperature of 55.8ºC for 21 minutes. The test substance formulations were allowed to cool down to a temperature of maximally 25.3ºC prior to dosing.
Duration of exposure:
24h, after which dressings were removed and the skin cleaned of residual test substance using tap water.
Doses:
2000 mg/kg (10 mL/kg) body weight
No. of animals per sex per dose:
5 males and 5 females
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Chromodacryorrhoea was noted in two males and one female on Day 1 only. Yellow discolouration of the back, scabs on the treated skin and/or scales on the back and/or treated skin were observed among the animals. No clinical signs were noted for one male and four females.
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 toxicologically relevant abnormalities were found at macroscopic post mortem examination of the animals.
Other findings:
One male showed diaphragmatic hernia of the median lob of the liver. This is occasionally noted among rats of this age and strain and was considered not toxicologically significant.

A dermal LD50 value was derived. The results were evaluated according to: Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007), and Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures.

Interpretation of results:
other: CLP criteria not met
Conclusions:
Under the study conditions, the acute dermal toxicity of the test substance was > 2000 mg/kg bw.
Executive summary:

A study was conducted to determine the acute dermal toxicity of the test substance according to OECD Guideline 402, EU Method B.3 and EPA OPPTS 870.1200. The substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg bw for 24 h. Animals were subject to daily observations and weekly determinations of body weight. Microscopic examination was performed at terminal sacrifice (Day 15). No mortality occurred. Chromodacryorrhoea was noted in two males and one female on Day 1 only. Yellow discolouration of the back, scabs on the treated skin and/or scales on the back and/or treated skin were observed. No clinical signs were noted for one male and four females. The mean body weight gain during the observation period was within the range expected for rats used in this type of study. Finally, no toxicologically relevant abnormalities were found at macroscopic post mortem examination. Under the study conditions, the acute dermal toxicity of the test substance was > 2000 mg/kg bw (Stitzinger, 2011).

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

Additional information

Oral toxicity

A study was conducted to determine the acute oral toxicity of the test substance according to OECD Guideline 423, EU Method B.1 and EPA OPPTS 870.1100.The substance (dissolved in polyethylene glycol) was administered by oral gavage to two subsequent groups of three female Wistar rats at 2000 mg/kg bw. Animals were subject to daily observations and weekly determinations of body weight. Microscopic examination was performed at terminal sacrifice (Day 15).No mortality occurred. Hunched posture was noted for all rats on Day 1. In addition, one animal showed piloerection on Day 1. Body weight gain over the study period was similar to that expected of untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination. Under the study conditions, the acute oral toxicity of the test substance to rats was > 2000 mg/kg bw (Stitzinger, 2011).

 

Dermal toxicity

A study was conducted to determine the acute dermal toxicity of the test substance according to OECD Guideline 402, EU Method B.3 and EPA OPPTS 870.1200. The substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg bw for 24 h. Animals were subject to daily observations and weekly determinations of body weight. Microscopic examination was performed at terminal sacrifice (Day 15). No mortality occurred. Chromodacryorrhoea was noted in two males and one female on Day 1 only. Yellow discolouration of the back, scabs on the treated skin and/or scales on the back and/or treated skin were observed. No clinical signs were noted for one male and four females. The mean body weight gain during the observation period was within the range expected for rats used in this type of study. Finally, no toxicologically relevant abnormalities were found at macroscopic post mortem examination. Under the study conditions, the acute dermal toxicity of the test substance was > 2000 mg/kg bw (Stitzinger, 2011).

Justification for classification or non-classification

The acute oral and dermal LD50 values of the substance in rats are both > 2000 mg/kg bw. No classification is therefore required for these endpoints according to CLP (1272/2008) criteria.