Registration Dossier

Administrative data

Description of key information

Oral: The acute oral LD50 was determined to be > 2000 mg/kg bw in rats. 
Dermal: The acute dermal LD50 was determined to be > 2000 mg/kg bw in rabbits.
Inhal.: The LD50 in the inhalation risk test was determined to be > 9 mg/l.

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:
2007-01-06 to 2007-01-16
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study with minor deviations (details e.g. for housing conditions were not provided).
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted December 17, 2001.
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Boyertown, PA
- Age at study initiation: approx. 9 weeks
- Weight at study initiation: Body weight range in males was 238 - 274 grams and in females was 172 - 206 grams
- Fasting period before study: 16 - 20 h
- Housing:The animals were identified by cage notation and indelible body marks, and housed in suspended wire mesh cages; 1/cage. Bedding was placed beneath the cages and changed at least three times/week.
- Diet: Fresh PMI Rodent Chow (Diet #5021) was freely available
- Water: Ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Temperature was controlled
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 0.55 mL
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 male and 5 female rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed at 1, 2 and 4 hours postdose and once daily thereafter for 14 days for toxicity and pharmacological effects. All animals were observed twice daily for mortality. Body weights were recorded immediately pretest, weekly and at termination.
- Necropsy of survivors performed: All animals were examined for gross pathology.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All ten animals survived the 2000 mg/kg oral dose
Clinical signs:
Instances of chromorhinorrhea, lethargy, ataxia, hunched posture, few feces, bloated abdomen,
chromodacryorrhea, soiling of the anogenital area and/or emaciation ware noted in several rats
during the study. Three rats were normal throughout the entire observation period.
Body weight:
One female was noted to be emaciated on Days 13 and 14; otherwise, body weight changes were normal.
Gross pathology:
The following abnormalities were noted in one or two rats at necropsy: slight or scattered red areas on the thymus, red areas on the intestines that ranged from slight or scattered to moderate or few; and/or slight or scattered soiling of the anogenital area. Bifurcated spleen was noted in two rats, although this abnormality should not be considered to be a result of treatment with the test article.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
GLP and guideline study

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Old study without GLP. Only basic details given.
Species:
rat
Strain:
other: Albino
Sex:
not specified
Route of administration:
inhalation: vapour
Mortality:
Exposure of rats for 4 h to an essentially saturated atmosphere generated at room temperature did not result in deaths.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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:
2007-01-03 to 2007-01-17
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study with minor deviations (Housing and feeding conditions)
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
Temperature of the animal room was outside of the protocol specific range
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Millbrook Breeding Labs, Amherst, MA
- Age at study initiation: 10 weeks
- Weight at study initiation: 330 - 388 grams for males and 206 - 221 grams for females
- Fasting period before study: no data
- Housing: Animals were housed 1 per cage in suspended wire cages. Bedding was placed beneath the cages and changed at least three times/week.
- Diet: Fresh PMI Rodent Chow (Diet #5012) was provided daily
- Water: Ad libitum
- Acclimation period: One week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 -22 °C
- Humidity (%): 18 - 72 %
- Photoperiod: 12 hour light/dark
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorsal area of the trunk
- coverage: 10 %
- Type of wrap if used: Impervious cuff and plastic-lined elastic bandage and secured with adhesive tape.

REMOVAL OF TEST SUBSTANCE
- Washing: Test sites were wiped with paper towels saturated with tap water and blotted dry with paper towels
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: 0.41 to 0.44 cc for females, 0.66 to 0.78 cc for males
- Concentration: Undiluted
- Constant volume or concentration used: yes

Duration of exposure:
24 h
Doses:
2000 mg/ kg bw
No. of animals per sex per dose:
5 animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed 1,2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for mortality. Animals were observed daily for dermal observations. Body weights were recorded immediately pretest, weekly and at termination
- Necropsy of survivors performed: All animals were examined for gross pathology. The contents of the abdominal and thoracic cavities were examined in situ for gross pathology
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality. All animals survived the 2000 mg/kg bw dermal application.
Clinical signs:
Instances of chromorhinorrhea, chromodaeryorrhea and/or wetness of the anogenital area were observed in all animals during the study. These observations were most likely due to the fact that the animals wore Elizabethan-type collars and were therefore unable to groom themselves normally.
Seven animals were noted to have flaking skin during the observation period.
Body weight:
Body weight changes were normal.
Gross pathology:
Necropsy results were normal in 4/10 animals. Six animals were noted with scattered flaking of the treated skin area.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
GLP and guideline study

Additional information

Oral:

For the investigation of the acute oral toxicity of the test item, five males and five females Wistar rats received a single oral dose of the test material at a dose level of 2000 mg/kg bw (GLP guideline study; MB Research Laboratories, 2007). All ten animals survived the 2000 mg/kg oral dose. Instances of chromorhinorrhea, lethargy, ataxia, hunched posture, few feces, bloated abdomen, chromodacryorrhea, soiling of the anogenital area and/or emaciation ware noted in several rats during the study. The following abnormalities were noted in one or two rats at necropsy: slight or scattered red areas on the thymus, red areas on the intestines that ranged from slight or scattered to moderate or few; and/or slight or scattered soiling of the anogenital area. Bifurcated spleen was noted in two rats, although this abnormality should not be considered to be a result of treatment with the test article. Under the conditions of this study, the LD50 of the test item after oral application was found to be greater than 2000 mg/kg bw.

This value is confirmed by two supporting studies with less reliability showing LD50 values of 3.73 mL/kg bw (Smyth, 1962) and 2.57 mL/kg bw (Bingman, 2001).

Dermal:

For the determination of the acute dermal toxicity, the test material was applied undiluted at a dose level of 2000 mg/kg bw to the clipped epidermis (dorsal parts of the trunk) of five male and five female rats and covered by a occlusive dressing for 24 hours. Systemic signs of toxicity were not noted. Necropsy results were normal in 4/10 animals. Six animals were noted with scattered flaking of the treated skin area. No mortality occurred. Under the conditions of this study, the LD50 of the test item after dermal application was found to be greater than 2000 mg/kg bw.

This value is confirmed by a supporting study with less reliability showing an LD50 value of 14.1 mL/kg bw (Smyth, 1962).

Inhalation:

In accordance with column 2 of REACH Annex VIII, the test acute toxicity after inhalation (required in section 8.5) does not need to be conducted as acute toxicity studies for oral and dermal application are available. In addition a supporting study with minor reliability shows, that the test substance is not acute toxic by inhalation as a saturated atmosphere generated at room temperature did not result in deaths of albino rats (Smyth, 1962).


Justification for selection of acute toxicity – oral endpoint
The Key study was selected (GLP and Guideline study).

Justification for selection of acute toxicity – dermal endpoint
The Key study was selected (GLP and Guideline study).

Justification for classification or non-classification

Classification for acute toxicity is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008.