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Administrative data

Description of key information

Acute Toxicity: oral, rat: LD50 > 2000 mg:kg bw (OECD 423, GLP, K, rel.1)

Acute Toxicity: dermal, rat LD50 > 2000 mg:kg bw (OECD 402, GLP, K, rel.1)

Acute Toxicity: inhalation: waiver

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 January 11 to February 1, 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline No. 423 without deviation.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
inspected on September 22, 1999 / signed on January 18, 2000
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, 69210 L’Arbresle, France
- Age at study initiation: ca. 6 weeks
- Weight at study initiation (mean): Males - 175 ± 10 g; females - 142 ± 1 g
- Fasting period before study: Animals were fasted for an overnight period of approximately 18 hours before dosing, but had free access to water. Food was given back approximately 4 hours after administration of the test substance.
- Housing: The animals were housed in polycarbonate cages (48 cm x 27 cm x 20 cm). Each cage contained one to seven animals of the same sex during the acclimatization period and three rats of the same sex during the treatment period.
- Diet: A04 C pelleted diet (UAR, 91360 Villemoisson-sur-Orge, France), ad libitum
- Water: Drinking water filtered by a FG Millipore membrane (0.22 micron), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2 °C
- Humidity (%): 30-70%
- Air changes (per hr): Approximately 12 cycles/hour of filtered, non-recycled air.
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: January 11, 2000 To: February 1, 2000
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20 and 200 mg/mL
- Amount of vehicle: 10 mL/kg bw.
- Lot/batch no.: 107H1649

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw; The volume administered to each animal was adjusted according to body weight determined on the day of treatment.

DOSAGE PREPARATION: On the day of treatment, the test substance was ground to a fine powder using a mortar and pestle, then was prepared at the chosen concentrations in the vehicle.
Doses:
200 mg/kg bw (males only) and 2000 mg/kg bw (males and females)
No. of animals per sex per dose:
3 males (200 mg/kg bw)
3 males and 3 females (2000 mg/kg bw)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations: Animals were observed frequently during the hours following administration of the test substance, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day until day 15.
- Frequency of weighing: Animals were weighed individually just before administration of the test substance on day 1 and then on days 8 and 15.
- Necropsy of survivors performed: Yes; On day 15, all surviving animals were killed by carbon dioxide asphyxiation and a macroscopic examination was performed. The animal found dead during the study was subjected to a macroscopic examination as soon as possible.
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: One male was found dead on day 2 at the dose level of 2000 mg/kg bw.
Mortality:
No deaths were observed in the three males given 200 mg/kg bw. One male was found dead on day 2 at the dose level of 2000 mg/kg bw.
Clinical signs:
- No clinical signs were observed in the three males given 200 mg/kg bw.
- At the 2000 mg/kg bw dose-level, hypoactivity or sedation and piloerection were noted in all animals on day 1; dyspnea was observed in a few animals and coma was recorded in two males. On day 2, one male was found dead; hypoactivity, dyspnea and piloerection persisted in the surviving males. No clinical signs were observed in any females. From day 4 until the end of the observation period, no clinical signs were noted in the surviving animals.
Body weight:
The body weight gain of the males given 200 mg/kg bw was lower than that of laboratory historical control animals between day 1 and day 8. The body weight gain of the surviving animals given 2000 mg/kg bw was not affected by treatment with the test substance.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities in the animal found dead during the study and in the surviving animals killed at the end of the study.
Other findings:
None

None

Interpretation of results:
not classified
Conclusions:
Oral LD50 Combined > 2000 mg/kg bw. Under the test conditions, the test material is not classified for acute oral toxicity according to the annex I of the Regulation EC No. 1272/2008 (CLP) and of the GHS.
Executive summary:

In an acute oral toxicity study performed according to OECD Guideline No. 423/EU Method B.1 tris and in compliance with GLP, test substance was administered by oral route (gavage) to Sprague-Dawley rats at doses of 200 mg/kg bw (3 males) or 2000 mg/kg bw (3 males + 3 females), under a volume of 10 mL/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

 

No clinical signs and no deaths were observed in the three males given 200 mg/kg bw. At the 2000 mg/kg bw dose-level, hypoactivity or sedation and piloerection were noted in all animals on day 1; dyspnea was observed in a few animals and coma was recorded in two males. On day 2, one male was found dead; hypoactivity, dyspnea and piloerection persisted in the surviving males. No clinical signs were observed in any females. From day 4 until the end of the observation period, no clinical signs were noted in the surviving animals. The body weight gain of the males given 200 mg/kg bw was lower than that of historical control animals between day 1 and day 8. The body weight gain of the surviving animals given 2000 mg/kg bw was not affected by treatment with the test substance. No apparent abnormalities were observed at necropsy in the animal found dead during the study and in the surviving animals killed at the end of the study.

                                        

Oral LD50 Combined > 2000 mg/kg bw.

 

Under the test conditions, the test material is not classified for acute oral toxicity according to the annex I of the Regulation EC No. 1272/2008 (CLP) and of the GHS.

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The available study is GLP-compliant and of high quality (Klimisch score =1).

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure In the present case, inhalation exposure will be less than dermal exposure because the substance has a low vapour pressure (0.098 Pa at 25°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 2.94, water solubility = 609 mg/L).
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 June 6 to 21, 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline No. 402 without deviation.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on March 07, 2005/ signed on June 09, 2005)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Ltd, Margate, Kent, England
- Age at study initiation: ca. 8–20 weeks
- Weight at study initiation: 210–354 g
- Fasting period before study: None
- Housing: The rats were housed individually from Day -1 in metal cages until Day 5 when they were returned to group housing.
- Diet: Standard laboratory rodent diet (Special Diet Services RM1(E) SQC expanded pellet), ad libitum
- Water: Drinking water, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2 °C
- Humidity (%): 40-70%
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: June 6, 2005 To: June 21, 2005
Type of coverage:
occlusive
Vehicle:
corn oil
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorso-lumbar region (One day prior to treatment, hair was removed with electric clippers)
- % coverage: ca. 50 mm x 50 mm (approximately 10% of total body surface area)
- Type of wrap: Treatment area was covered with porous gauze held in place with a non-irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the animal.

REMOVAL OF TEST SUBSTANCE
- Washing: Treatment area was washed with warm water (30-40 °C) to remove any residual test substance
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount applied: 3 mL/kg bw
- Concentration: 666.7 mg/mL
- Dose: 2000 mg/kg bw
- Constant volume or concentration used: Yes
Duration of exposure:
24 hours
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:
Mortality: Cages of rats were checked at least twice daily for mortalities.
Clinical signs: Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only).
- Frequency of weighing: Bodyweight of each rat was recorded on Days 1 (prior to dosing), 8 and 15.
- Necropsy of survivors performed: Yes; all animals were killed on Day 15 by carbon dioxide asphyxiation and a macroscopic examination was performed.
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Mortality:
There were no deaths related to treatment in any animal.
Clinical signs:
There were no systemic responses to treatment in any animal.
Body weight:
All animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.
Other findings:
None

There were no dermal reactions observed in any animal during the study.

Interpretation of results:
not classified
Conclusions:
Dermal LD50 Combined > 2000 mg/kg bw. Under the test conditions, the test material is not classified according to the annex I of the Regulation EC No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In an acute dermal toxicity study (limit study) performed according to the OECD guideline No. 402 and in compliance with GLP, a group of ten rats (five males and five females) received a single topical application of the test substance, formulated in corn oil at a dose level of 2000 mg/kg bw, for a duration of 24 hours. The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations.

There were no deaths and no systemic response to treatment in any animal throughout the study. No dermal reactions were observed in any animal during the study. All animals were considered to have achieved satisfactory bodyweight gains throughout the study. No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15. 

 

Dermal LD50 Combined > 2000 mg/kg bw.

 

Under the test conditions, the test material is not classified according to the annex I of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The available study is GLP-compliant and of high quality (Klimisch score =1).

Additional information

Acute toxicity oral:

A key study was identified (CIT, 2000). This acute oral toxicity study was performed according to OECD Guideline No. 423/EU Method B.1 tris and in compliance with GLP.

No clinical signs and no deaths were observed in the three males given 200 mg/kg bw. At the 2000 mg/kg bw dose-level, hypoactivity or sedation and piloerection were noted in all animals on day 1; dyspnea was observed in a few animals and coma was recorded in two males. On day 2, one male was found dead; hypoactivity, dyspnea and piloerection persisted in the surviving males. No clinical signs were observed in any females. From day 4 until the end of the observation period, no clinical signs were noted in the surviving animals. The body weight gain of the males given 200 mg/kg bw was lower than that of historical control animals between day 1 and day 8. The body weight gain of the surviving animals given 2000 mg/kg bw was not affected by treatment with the test substance. No apparent abnormalities were observed at necropsy in the animal found dead during the study and in the surviving animals killed at the end of the study.                                    

Oral LD50 Combined > 2000 mg/kg bw.

 

Acute toxicity: dermal:

A key study was identified (Huntington, 2005). This acute dermal toxicity study (limit study) was performed according to the OECD guideline No. 402 and in compliance with GLP.

There were no deaths and no systemic response to treatment in any animal throughout the study. No dermal reactions were observed in any animal during the study. All animals were considered to have achieved satisfactory bodyweight gains throughout the study. No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15. 

Dermal LD50 Combined > 2000 mg/kg bw.

Acute toxicity: inhalation:

In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure In the present case, inhalation exposure will be less than dermal exposure because the substance has a low vapour pressure (0.098 Pa at 25°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 2.94, water solubility = 609 mg/L).

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self-classification:

Acute toxicity (Oral):

Based on the available data, the substance is:

- not classified according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- classified in Category 5 according to the GHS since there is reliable evidence that indicates the LD50 to be in the range of Category 5 values (one mortality observed at 2000 mg/kg bw).

Acute toxicity (Dermal):

Based on the available data, the substance is:

- not classified according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) as the dermal LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

Acute toxicity (Inhalation):

This information is not available.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Annex I of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification (C ≤ 300 mg/kg bw) and at the guidance value, oral for a Category 2 classification (2000 mg/kg bw ≥ C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to the Regulation (EC) No. 1272/2008 and to the GHS are met since narcotic effects were observed in the acute oral toxicity study (hypoactivity, sedation, piloerection, dyspnea, and coma).

Specific target organ toxicity: single exposure (Dermal):

The classification criteria according to the Annex I of the Regulation (EC) No 1272/2008 as specific target organ toxicant (STOT) – single exposure, dermal are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, dermal for a Category 1 classification (C ≤ 1000 mg/kg bw) and at the guidance value, dermal for a Category 2 classification (2000 mg/kg bw ≥ C > 1000 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to the Regulation (EC) No. 1272/2008 and to the GHS are not met since narcotic effects were not observed in the acute dermal toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

This information is not available.