Registration Dossier

Administrative data

Description of key information

LD50, rat, oral: > 1000 < 2000 mg/kg (67/548/EEC: R22; CLP 1272/2008: Acute oral Cat. 4)
LC50 inhalation: no mortality in an inhalation hazard test with saturated vapour of the test substance.
LD50 dermal: > 2000 mg/kg.

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:
31. May 2005 - 21. Sep 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (OECD)
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd Laboratory Animal Services, Wölferstrasse 4, CH-4414 Füllinsdorf, Switzerland.
- Age at study initiation: Young adult animals (female animals approx. 8- 12 weeks).
- Weight at study initiation: 179 g (mean)
- Fasting period before study: Feed was withdrawn from the animals at least 16 hours before administration, but water was available ad libitum.
- Housing: steel wire mesh cages, type DK-III (Becker & Co., Castrop-Rauxel, FRG).
- Diet: Kliba-Labordiät (Maus / Ratte Haltung "GLP"), Provimi Kliba SA, Kaiseraugst, Basel, Switzerland, ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12 / 12 (6.00 a .m. - 6 .00 p.m. / 6 .00 p.m. - 6.00 a .m.)
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 1.93 ml/kg

Doses:
1000 and 2000 mg/kg bw
No. of animals per sex per dose:
6 females per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights shortly before administration (day 0), weekly thereafter and at the end of the study . Additionally, at day of death in animals that died or were sacrificed moribund starting with study day 1. Recording of signs and symptoms several times on the day of administration, at least once each workday for the individual animals. A check for any dead or moribund animal was made twice each workday and once on Saturdays, Sundays and on public holidays.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.
Sex:
female
Dose descriptor:
LD50
Effect level:
1 000 - 2 000 mg/kg bw
Mortality:
Four animals of the 2000 mg/kg administration groups and one animal of the 1000 mg/kg administration groups were found dead on study days 1 and 2, respectively.
Clinical signs:
Clinical observation in the 2000 mg/kg administration groups revealed impaired and poor general state, dyspnoea, lateral position, staggering, piloerection, salivation and lacrimation and were observed from hour 0 until including study day 6 after administration.
Clinical observation in the 1,000 mg/kg administration groups revealed impaired general state, dyspnoea, staggering, piloerection, salivation and lacrimation and were observed from hour 0 until including study day 5 after administration.

Body weight:
The mean body weights of the surviving animals of the administration groups increased throughout the study period .
Gross pathology:
The following macroscopic pathologic findings were observed in the animals that died:
- Few (2-5) or several (6-10), black erosions/ulcers in the glandular stomach, diameter 1 mm or up to 4 mm (2,000 mg/kg: 4 females).
- Slight red or red discoloration of contents of the small intestine (2,000 mg/kg: 2 females).
- Many (>10), black erosions/ulcers in the glandular stomach, diameter 1 mm; dark red discoloration of contents of the large intestine; red discoloration of the small intestine; beige discoloration of the liver (1,000 mg/kg: 1 female).

No macroscopic pathologic abnormalities were noted in the animals examined at termination of the study (2,000 mg/kg: 2 females; 1,000 mg/kg: 5 females).

Mortality:

Dose (mg/kg bw)

1000

2000

Administration

1

2

1

2

No. of animals

3

3

3

3

 

after

 

 

 

 

day 1

0

0

0

2

day 2

0

1

1

3

day 14

0

1

1

 

Mortality

1 / 6

4 / 6

 

Maximum incidence (and maximum duration) of clinical findings:

Dose (mg/kg bw)

1000

2000

Administration

1

2

1

2

No. of animals

3

3

3

3

 

Impaired general state

3

(h0-d1)

3

(h0-d5)

3

(h0-d6)

3

(h0-h4)

Poor general state

-

 

-

 

-

 

1

(d1)

Dyspnoea

3

(h0-d1)

3

(h0-d5)

3

(h0-d6)

3

(h0-d1)

Lateral position

-

 

-

 

-

 

1

(d1)

Staggering

3

(h2-d1)

2

(h3-d1)

1

(h1-d1)

3

(h0-h4)

Piloerection

3

(d1)

1

(d1-d2)

3

(d1-d6)

-

Salivation

3

(h1-h3)

2

(h0-h2)

3

(h0-h4)

3

(h0-d1)

Lacrimation

2

(h1-h2)

3

(h1-d1)

3

(h0-h3)

3

(h0-d1)

 

Individual body weights:

Dose 1000 mg/kg bw, Administration 1

Weightday

0

7

14

at death

Animal 994

181

196

211

 

Animal 995

183

191

205

 

Animal 996

179

182

217

 

 

Dose 1000 mg/kg bw, Administration 2

Weightday

0

7

14

at death

Animal 118

180

 

 

169 (d2)

Animal 119

182

193

215

 

Animal 120

183

204

217

 

 

Dose 2000 mg/kg bw, Administration 1

Weightday

0

7

14

at death

Animal 010

174

 

 

163 (d2)

Animal 011

170

175

194

 

Animal 012

171

187

201

 

 

Dose 2000 mg/kg bw, Administration 2

Weightday

0

7

14

at death

Animal 043

180

 

 

175 (d2)

Animal 044

179

 

 

177 (d1)

Animal 045

181

 

 

168 (d1)

 

 

 

 

 

 

Interpretation of results:
harmful
Remarks:
Migrated information criteria for interpretation: EU/GHS
Conclusions:
Under the conditions of this study the median lethal dose of the test substance after oral administration was found to be greater than 1000 mg/kg bw and less than 2000 mg/kg bw in rats.
Executive summary:

The study is reliable without restriction (GLP-study according to OECD guideline 423).

Single doses of 2000 and 1000 mg/kg bw of the unchanged test material were given to four administration groups of three fasted female Wistar rats, each, by gavage in a sequential manner. After administration a 14 -day observation period followed.

Four animals of the 2000 mg/kg administration groups and one animal of the 1000 mg/kg administration groups were found dead from study day 1 until including study day 2.

Clinical observation in the 2000 mg/kg administration groups revealed impaired and poor general state, dyspnoea, lateral position, staggering, piloerection, salivation and lacrimation. Findings were observed from hour 0 until including study day 6 after administration. Clinical observation in the 1000 mg/kg administration groups revealed impaired general state, dyspnoea, staggering, piloerection, salivation and lacrimation. Findings were observed from hour 0 until including study day 5 after administration.

The mean body weights of the surviving animals of the administration groups increased throughout the study period.

During necropsy findings in the animals that died in the 2000 mg/kg and 1000 mg/kg administration groups comprised few, several or many black erosions/ulcers in the glandular stomach and red or slight red discoloration of contents of the small intestine. In addition one animal of the 1000 mg/kg administration group that died showed dark red discoloration of contents of the large intestine and beige discoloration of the liver. No macroscopic pathologic abnormalities were noted in the surviving animals of the 2000 mg/kg and 1000 mg/kg administration groups examined at the end of the observation period.

Conclusion: Under the conditions of this study the median lethal dose of the test substance after oral administration was found to be greater than 1000 mg/kg bw and less than 2000 mg/kg bw in rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Aug. 21, 1981 to Sept. 7, 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable with the inhalation hazard test described in the Annex of OECD Guideline 403 with acceptable restrictions (non-GLP, low number of rats).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
Annex: Inhalation Hazard Test
Deviations:
yes
Remarks:
only 6 animals instead of 10
GLP compliance:
no
Test type:
other: Inhalation Hazard Test
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Wiga, Sulzfeld, Germany
- Age at study initiation: 7-10 weeks
- Weight at study initiation: 180-250 g
- Housing: Wire mesh cage (Becker, D III), 3 animals/cage
- Diet: Herilan MRH of EGGERSMANN KG, Rinteln, Germany, in the form of pellets ad libitum
- Water: About 250 ml/cage tap water daily
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 5%
- Photoperiod (hrs dark / hrs light): 12 / 12 (6 .00 - 18 .00 h light, 18 .00 - 6 .00 h dark)
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other:
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The test substance was filled to a height of 5 cm in a glass bottle (fritted glass flask, pore-size 90 - 150 µm, diameter 30 mm), and the net weight was determined. A stream of 200 l/h compressed air was supplied to the fritted glass flask containing the product, which had been placed in a water bath maintained at 20 +/- 1°C by a thermostat. The mixture of air and test substance generated in this way was passed through a glass distributor to 6 glass tubes in which 3 male and 3 female animals had been placed. The emerging mixtures of test substance and air were exhausted. After 30 min, the fritted glass flask was replaced by a new one filled with fresh test substance as described above. This generator was then used for the whole remaining time of the test.

TEST ATMOSPHERE
- Samples taken from breathing zone: no
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
7 h
Concentrations:
Saturated vapour (The test substance consumed was determined by reweighing the fritted glass flasks).
No. of animals per sex per dose:
3 males and 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Clinical signs of the animals were recorded daily.
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
other: Inhalation Hazard Test
Effect level:
other: saturated vapor
Exp. duration:
7 h
Remarks on result:
other: no mortality observed
Sex:
male/female
Dose descriptor:
LC0
Effect level:
ca. 380 mg/m³ air
Exp. duration:
7 h
Remarks on result:
other: calculated using MW 71.08 and vapour pressure 0.13 hPa
Mortality:
No mortality observed
Clinical signs:
During exposure: attempts to escape, wiping of snouts
After exposure: normal
Body weight:
Not determined
Gross pathology:
Nothing abnormal detected in the organs
Interpretation of results:
practically nontoxic
Remarks:
Migrated information
Conclusions:
No mortality occurred in rats exposed for 7 h to a saturated vapour of the test substance.
Executive summary:

The study is comparable to the inhalation hazard test described in the Annex of OECD Guideline 403 with acceptable restrictions (non-GLP, low number of rats).

Three male and 3 female rats were exposed for 7 h to a saturated vapour of the test substance. Clinical signs during exposure were attempts to escape and wiping of snouts. After exposure no clinical signs were observed. No mortalities occurred during the 14 days of post-exposure observation period. Nothing abnormal was detected in the organs at necropsy.

Conclusion: No mortality occurred in rats exposed for 7 h to a saturated vapour of the test substance.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline 402
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
low animal number
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
Vienna White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Gaukler, Offenbach/Main, Germany
- Age at study initiation: young adult animals
- Weight at study initiation: animals of comparable weight (2.0-3.0 kg)
- Housing: Single housing in cages made of stainless steel with wire mesh walk floors; floor area 40 x 51 cm; no bedding in the cages; sawdust in the waste trays
- Diet: Kliba Labordiaet 341, 4 mm (Klingentalmuehle AG, Kaiseraugst, Switzerland), about 130 g per animal per day
- Water: about 250 ml tap water per animal per day
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 / 12 (18.00 - 6.00 h dark / 6.00 - 18.00 h light)
Type of coverage:
semiocclusive
Vehicle:
other: undiluted
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped epidermis (dorsal and dorsolateral parts of the trunk)
- % coverage: at least 10% of the body surface (about 200 cm²)
- Type of wrap if used: four layers absorbent gauze (Ph. Eur. Lohmann GmbH&Co. KG) and Fixomull stretch (Adhesive fleece; Beiersdorf AG)

REMOVAL OF TEST SUBSTANCE
- Washing: rinsing of the application site with warm water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 1.98 ml/kg bw
- Concentration: undiluted
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3 males and 3 females per dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Recording of signs and symptoms several times on the day of administration, at least once each workday for the individual animals. A check was made twice each workday and once on saturdays, sundays and on public holidays for general observations and for any dead or moribund animals. Individual reedings for the scoring of skin findings (according to Draize JH, 1959: Appraisal of the safety of chemicals in foods, drugs and cosmetics. The association of food and drug officials of the United States, Austin, Texas) were performed 30-60 min after removal of the semiocclusive dressing (day 1), weekly thereafter and at the end of the study (last day of observation period). Individual body weights were determined shortly before application (day 0), weekly thereafter and at the end of the study (before fasting period).
- Necropsy of survivors performed: yes (withdrawal of food at least 16 h before killing with CO2; then necropsy with gross pathology examination)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
1 male after day 1
Clinical signs:
no abnormalities
Body weight:
Normal body weight gains. For details see table below.
Gross pathology:
Animal that died (1 male): general congestion; heart: dilation, right ventricle
Sacrificed animals (2 males, 3 females): no pathologic findings
Other findings:
Scaling of local effects at the readings of days 7 and 14 (males) and day 7 (females).
day 0 day 7 day 13
Males 2.7 2.81 2.93
Females 2.66 2.83 2.94
Interpretation of results:
practically nontoxic
Remarks:
Migrated information criteria for interpretation: EU
Conclusions:
The acute dermal LD50 of the test material is >2000 mg/kg bw for male and female rabbits.
Executive summary:

The study was a GLP-study according to OECD guideline 402 without restrictions.

The acute dermal toxicity of the test substance was investigated in a group of 3 male and 3 female Vienna White rabbits. The test material was applied undiluted to the clipped epidermis (dorsal and dorsolateral parts of the trunk) of each animal at a dose level of 2000 mg/kg bw, and was covered by a semiocclusive dressing for 24 h.

There were no signs of systemic toxicity. After the removal of the dressing no skin reactions could be observed. All animals exhibited scaling of skin findings 7 days after application. This skin reaction persisted in the male animals until study termination (day 14). The expected body weight gain was observed. One male animal died one day after application (no further mortality). Necropsy of the animal that died revealed general congestion and dilation of the right ventricle of the heart. No abnormalities were observed at the end of the study in the surviving animals.

Conclusions: The acute dermal LD50 of the test material is >2000 mg/kg bw for male and female rabbits.

Endpoint conclusion
Dose descriptor:
LD50

Additional information

Oral exposure route:

In the key study conducted by BASF AG (2005) single doses of 2000 and 1000 mg/kg bw of the unchanged test material were given to four administration groups of three fasted female Wistar rats, each, by gavage in a sequential manner. After administration a 14 -day observation period followed. The LD50 was found to be greater than 1000 mg/kg bw and less than 2000 mg/kg bw. Clinical symptoms were an impaired and poor general state, dyspnoea, lateral position, staggering, piloerection, salivation and lacrimation. At necropsy, findings in the animals that died comprised few, several or many black erosions/ulcers in the glandular stomach and red or slight red discoloration of contents of the small intestine. In addition, one animal of the 1000 mg/kg administration group that died showed dark red discoloration of contents of the large intestine and beige discoloration of the liver. No macroscopic pathologic abnormalities were noted in the surviving animals examined at the end of the observation period.

Two other acute oral LD50s in rats ranged between 1150 and 1444 mg/kg bw (BASF AG 1981, Air Products and Chemicals, Inc. 1991). These studies do not provide additional information on the acute oral toxicity of the test substance.

Inhalation exposure route:

No mortality occured in an acute vapour inhalation study comparable to the inhalation hazard test described in the Annex of OECD Guideline 403 with acceptable restrictions (non-GLP, low number of animals). In this study 3 male and 3 female Sprague-Dawley rats were exposed for 7 hours to a saturated vapour of the test substance. Clinical signs during exposure were attempts to escape and wiping of snouts. After exposure no clinical signs were observed. No mortality occurred during the 14 days of post-exposure observation period. Nothing abnormal was detected in the organs at necropsy (BASF AG 1981).

Dermal exposure route:

The dermal LD50 in a group of 3 male and 3 female Vienna White rabbits was found to be greater than 2000 mg/kg bw (BASF AG 1992). In this study according to OECD Guideline 402 no signs of systemic toxicity could be observed. One male animal died one day after application (no further mortality). Necropsy of the animals that died revealed general congestion and dilation of the right ventricle of the heart. No abnormalities were observed at the end of the study in the surviving animals.

Other exposure routes:

A LD50 of approx. 100 mg/kg was determined after intraperitoneal injection of the test substance in groups of five male and five female mice per dose (BASF AG, 1982).

Justification for classification or non-classification

GHS classification according to Annex I 1272/2008 CLP (EU GHS):

- Oral route: Acute Category 4

- Dermal route: no classification required

- Inhalation route (vapour): no classification required