Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: 
LD50 (male and female rat): ca. 280 mg/kg bw, non-GLP, comparable to OECD 401, Val 2 (BASF XX/36, 1970).
The test substance is highly toxic after single ingestion. Clinical signs included sedate behaviour; spasmodic convulsions; opisthotonus; flexor spasms; tremor; pain; dyspnea; lacrimation; salivation; exophthalmus; chromodakryorrhoe; crouching position; movement dislike; accelerated, irregular respiration; scrubby fur.
Acute inhalative toxicity:
LC50 (male and female rat, 4h): 2.42 mg/L, non-GLP, comparable to OECD 403, Val 2, (BASF 85/207, 1987).
IHT: 3/12 and 6/6 rats died after 3 and 10 min exposure to an atmosphere that had been saturated at 20 degrees centigrade with the volatile parts of the compound within 3 min and within 10 min, respectively, Val 2 (BASF XX/36, 1970).
The test substance is of pronounced toxicity after a single inhalative application. Clinical signs included restless behavior; gasping respiration; lid closure; anemic aspect; tremors and convulsions (saltatory spasms); sighing, jerky and irregular respiration; upright respiratory posture in some animals; salivation; lateral or abdominal position; reddish discharge from the noses; encrustations; ruffled fur.
Acute dermal toxicity:
LD50 (male and female rabbit): > 200 mg/kg bw (no mortality), non-GLP, comparable to OECD 402, Val 2 (BASF 77/515, 1980).
The test substance was of moderate toxicity after a single dermal application. Clinical signs included irritation and formation of not reversible necrosis. No mortality or systemic toxicity was observed.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (no data on test substance purity, reduced observation period, limited documentation).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted in 1981
Deviations:
yes
Remarks:
(observation period 7 days instead of 14 days, 10 animals per sex instead of 5, no data on test substance purity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeder, Gassner
- Weight at study initiation: males: 225 ± 22 g; females: 187 ± 13 g

ENVIRONMENTAL CONDITIONS
- No data
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The test substance was applied as 2, 4, 8 or 20% (v/v) aqueous emulsion with Traganth.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg
Doses:
200, 250, 320, 400, 800, 1600 µL/kg bw (corresponding to approx. 165.2, 206.5, 264.3, 330.4, 660.8, 1321.6 mg/kg bw; calculation based on density of 0.826 g/cm³)
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Body weight was determined before the beginning of the study for dose calculation. Observation of clinical signs was determined several times on the day of administration and once daily afterwards with the exception of weekends and on holidays.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 280 mg/kg bw
Based on:
test mat.
Remarks on result:
other: The original value ca. 340 µL/kg was converted to mg/kg body weight using the density of 0.826 g/cm³
Mortality:
Results are given as dead animals/total number of animals:
165.2 and 206.5 mg/kg bw: 0/10 males and 0/10 females
264.3 mg/kg bw: 2/10 males and 5/10 females within 3 hours (6 animals) and 24 hours (one animal)
330.4 mg/kg bw: 8/10 males and 10/10 females within 1.5 (17 animals) to 3 (1 animal) hours
660.8 mg/kg bw: 10/10 males and 10/10 females within 1.5 hours
1321.6 mg/kg bw: 10/10 males and 10/10 females within 0.5 hour
Clinical signs:
264.3 - 1321.6 mg/kg bw: immediately after gavage sedate behaviour; 3 to 10 min after application convulsions; opisthotonus; flexor spasms; tremor; pain; dyspnea; lacrimation; salivation; exophthalmus; abdominal position; chromodakryorrhoe in the highest dose group.
264.3 - 660.8 mg/kg bw: surviving animals showed 4 to 6 hours after treatment crouching position; movement dislike; accelerated, irregular respiration; scrubby fur; sedate behaviour. Beginning on day 5 up to day 7 no abnormalities detectable.
165.2 and 206.5 mg/kg bw: immediately after gavage sedate behaviour; accelerated respiration; dyspnea; spasmodic convulsions; lacrimation; salivation. During the following observation period up to day 5: sedate behaviour; accelerated respiration; scrubby fur. Beginning with day 5 no abnormalities were detectable.
Body weight:
No data on body weight gain.
Gross pathology:
Deceased animals:
no abnormalities detected.

Sacrificed animals:
no abnormalities detected.

Table 1 Acute oral toxicity.

 

Dose

[mg/kg bw]

Mortality

Clinical signs

 

N*

%

Time of death

N*

Duration

Males

 

 

 

 

 

165.2

0/10

0

-

10/10

day 5

206.5

0/10

0

-

10/10

day 5

264.3

2/10

20

1.5 hours

10/10

until death, day 5

330.4

8/10

80

1.5 hours

10/10

until death, day 5

660.8

10/10

100

1.5 hours

10/10

until death

1321.6

10/10

100

0.5 hours

10/10

until death

Females

 

 

 

 

 

165.2

0/10

0

-

10/10

day 5

206.5

0/10

0

-

10/10

day 5

264.3

5/10

50

1.5 hours

10/10

until death, day 5

330.4

10/10

100

1.5 hours

10/10

until death

660.8

10/10

100

1.5 hours

10/10

until death

1321.6

10/10

100

0.5 hours

10/10

until death

*N= Number of animals / number of animals used

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
280 mg/kg bw
Quality of whole database:
The study is comparable to OECD Guideline 401 (Acute Oral Toxicity) using a standardized test method, not GLP compliant and has Klimsch score 2.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study with acceptable restrictions (mostly due to limited documentation in times before GLP)
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Wistar/Chbb:THOM
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: 8 - 9 weeks
- Mean body weight at study initiation: males: 259 ± 11.03 g and females 174 ± 11.7 g.
- Housing: groups of five in wire cages, type DIII, of Becker
- Diet: KLIBA laboratory diet rat/mouse A 343 10-mm pellets, supplied by Klingentalmuehle AG, Kaiseraugst, Switzerland, ad libitum
- Water: drinking water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Whole-body inhalation system; groups of 2 animals were placed in wire cages which were located in a glass-steel inhalation chamber
- Exposure chamber volume: ca. 200 L
- Method of conditioning air: The supply air was conditioned via central air conditioning in such a way that there was a temperature of 19-25°C in the exposure apparatus. There were no deviations from these specifications which might have had any adverse effect on the results of the study.
- System of generating particulates/aerosols: A mixture of vapour and air was generated by means of a continuous infusion pump INFU 362 (INDIGEL/Switzerland) and a glass evaporator with thermostat (BASF). By means of a metering pump, the test substance was supplied to an evaporator heated to 50°C for each test group. The vapours that were formed were mixed with a flow of fresh air and passed into the inhalation chamber.
- Treatment of exhaust air: By means of an exhaust air system, the pressure ratios in the inhalation system were adjusted in such a way that there was a pressure slightly below the atmospheric pressure (negative pressure). This ensured that there was no contamination of the laboratory due to possible leakage from the inhalation chambers.
- Temperature, humidity, pressure in air chamber: 19-25°C

TEST ATMOSPHERE
- Brief description of analytical method used:
• The nominal concentration was determined from the consumption of test substance and the air flow.
- Sampling was performed using 2 absorption vessels connected in series and a downstream fritted glass flask. The fritted glass flask was used to check the sorption effectiveness for all samples of a test group and was analyzed separately. Thereby a sampling station with gas meter, impulse counter and automatic pump switch was used.
Sorption solvent: Dimethylformamide (DMF); Sampling velocity: 1.25 m/s; Sampling amount: 5L-10L; Sampling site: Immediately adjacent to the animal noses; Sampling probe diameter: 4 mm; Sampling frequency: 1 sample hourly per concentration group
• Analytical method of determination: A gas chromatographical method was used for the quantitative determination of the vapour concentration.
The samples were taken up in about 45 mL DMF (sorption solvent) and topped up to 50 mL after addition of 1 mL of internal standard solution.
- Gas chromatographical analysis: Equipment: GC HP 5840 A (Hewlett Packard);
- Calibration: A calibration curve was prepared with the test substance in the solvent specified. The curve was calculated with a Hewlett Packard Computer Program SD 03A (curve adjustment: linear regression).
- Calculation of the concentration: The concentrations in mg/L were calculated from the amounts determined analytically and the sample volumes of the inhalation atmosphere.


Analytical verification of test atmosphere concentrations:
yes
Remarks:
gas chromatographical method
Duration of exposure:
4 h
Concentrations:
Nominal concentration [mg/L]: Group 1: 8.24; group 2: 3.43; group 3: 2.64; group 4: 2.20
Analytical concentration [mg/L]: Group 1: 6.84; group 2: 2.82; group 3: 2.04; group 4: 1.88
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight of the animals was checked before the beginning of the test, after 7 days and at the end of the observation period. A check for mortalities was made daily.
- Necropsy of survivors performed: yes, at the end of the 14-day observation period, the surviving animals were sacrificed with CO2 and were subjected to a gross-pathological examination like all other animals which had died before.
- Other examinations performed: Clinical findings were generally recorded several times during exposure and at least once each workday during the post-exposure observation period.
Statistics:
The statistical evaluation of the concentration/effect relationship was carried out based on a probit analysis of D.J. Finney (Finney, D.J.: Probit Analysis 1971, pp 1-150. Published by the Syndics of the Cambridge University Press, Bentley House, 200 Euston Road, London N.W. 1).
Sex:
male/female
Dose descriptor:
LC50
Effect level:
2.42 mg/L air (analytical)
Based on:
test mat.
95% CL:
2.26 - 2.64
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
2.59 mg/L air (analytical)
Based on:
test mat.
95% CL:
2.33 - 3.03
Exp. duration:
4 h
Sex:
female
Dose descriptor:
LC50
Effect level:
2.26 mg/L air (analytical)
Based on:
test mat.
95% CL:
2.07 - 2.59
Exp. duration:
4 h
Mortality:
1.88 mg/L: no deaths occured;
2.04 mg/L: total at the end of the study: 5/20; 1/10 males and 4/10 females within 24 hours
2.82mg/L: total at the end of the study: 16/20; 7/10 males and 9/10 females within 24 hours
6.84 mg/L: total at the end of the study: 20/20; 10/10 males and 10/10 females within 24 hours
Clinical signs:
During exposure:
All test groups: restless behavior, lid closure, reddish discharge from the noses and anaemic aspect; in some animals tremors and convulsions.
Additionally, the animals of test groups (1) 6.84 mg/L, (2) 2.82 mg/L, and (3) 2.04 mg/L showed: wiping of the snouts; intermittent and irregular respiration; upright respiratory posture in some animals; salivation; lateral position in some cases.
The animals of test group 1 (6.84 mg/L) additionally showed: gasping; abdominal position; fur in the anogenital region reddish and smeared; tonus with stretching before death.

After exposure:
All test groups: margins of the noses reddish and encrusted (evidence of blood positive); slight tremor in some animals.
The animals of test group 2 (2.82 mg/L) additionally showed: slightly ruffled fur; anaemic aspect.
The animals of test group 3 (2.04 mg/L ) additionally showed: occasionally convulsions; ruffled fur; slight breathing sounds on day 3 after exposure.
The animals of test group 4 (1.88 mg/L) additionally showed: intermittent respiration in some animals.

No abnormalities were detectable in animals of the test group 2 (2.82 mg/L) from the 5th day of observation, in those of test group 3 (2.04 mg/L ) from the 7th day of observation and those of test group 4 (1.88 mg/L) from the 2nd day of the observation period.
Body weight:
Mean body weight:
Test Group (1): 6.84 mg/L: at study start: males: 259 g, females: 174 g
Test Group (2): 2.82 mg/L: at study start: males: 264 g, females: 185 g; after 7 days: males: 273 g, females: 192 g; after 14 days: males: 303 g, females: 202 g
Test Group (3): 2.04 mg/L: at study start: males: 254 g, females: 163 g; after 7 days: males: 281 g, females: 180 g; after 14 days: males: 306 g, females: 194 g
Test Group (4): 1.88 mg/L: at study start: males: 259 g, females: 175 g; after 7 days: males: 298 g, females: 192 g; after 14 days: males: 335 g, females: 201 g

The body weight gain of the males (test groups 2 and 3) and females (test group 2) was slightly retarded as compared with a historical control group during the first week of the observation period, but returned to normal body weight gain in the second week of the observation period.

The body weight gain of the males (test group 4) and females (test group 3) was not impaired as compared with a historical control group throughout the observation period.

The body weight gain of the females of test group 4 was slightly retarded as compared with a historical control group during the second week of the observation period; the biological relevance is questionable since there was no concentration-dependent effect as compared with the body weight gain of the females of test group 3.
Gross pathology:
Deceased animals (males and females): General passive hyperemia
Sacrificed animals (males and females): Organs: no abnormalities detected

Table1 Acute oral toxicity.

 

Concentration

[mg/L]

Mortality

Clinical signs

 

N*

%

Time of death

N*

Duration

Males

 

 

 

 

 

1.88

0/10

0

-

10/10

day 2

2.04

1/10

10

3 hours

10/10

until death, day 4

2.82

7/10

70

1.5 – 4 hours

10/10

until death, day 5

6.84

10/10

100

1 – 2.5 hours

10/10

until death

Females

 

 

 

 

 

1.88

0/10

0

-

10/10

day 2

2.04

4/10

40

3.5 hours

10/10

until death, day 4

2.82

9/10

90

3.5 – 4 hours

10/10

until death, day 5

6.84

10/10

100

1 – 2.5 hours

10/10

until death

*N= Number of animals/ number of animals used

 

Table 2 Body weight.

 

Concentration

[mg/L]

Body weight (mean ± SD)

 

initial

7 days

14 days

Males

 

 

 

1.88

259± 16.1 (10)

298± 14.3 (10)

335± 18.5 (10)

2.04

254± 8.8 (10)

281± 7.5 (9)

306± 10.8 (9)

2.82

264± 9.1 (10)

273± 8.6 (3)

303± 15.0 (3)

6.84

259± 6.9 (10)

-

-

Historical group

245

283

315

Females

 

 

 

1.88

175± 13.2 (10)

192± 11.35 (10)

201± 15.5 (10)

2.04

163± 7.7 (10)

180± 12.3 (6)

194± 11.9 (6)

2.82

185± 6.2 (10)

192(1)

202 (1)

6.84

173± 5.9 (10)

-

-

Historical group

176

196

211

 

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
2.42 mg/m³
Quality of whole database:
The study is comparable to OECD Guideline 403 (Acute Inhalation Toxicity), not GLP compliant and has Klimsch score 2.

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented report which meets basic scientific principles.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
(only one test concentration)
GLP compliance:
no
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: M. GAUKLER, Offenbach; Germany
- Mean weight at study initiation: males: 2.4 kg; females: 2.5 kg
- Diet: Ssniff K, Standard diet for rabbits and guinea pigs, INTERMAST GmbH, Soest, Germany, ad libitum
- Water: water, ad libitum

ENVIRONMENTAL CONDITIONS
- no data


Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: the clipped skin of the back and flanks; clipping of the dorsal and lateral parts of the trunk was performed ca 15 to 24 hours before treatment.
- Application area: approx. 50 cm²
- Type of wrap if used: inert foil, fixed with a adhesive tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with warm water or a water:lutrol mixture and dried with cellulose
- Time after start of exposure: 24 hrs

Duration of exposure:
24 h
Doses:
200 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 8 days
- Frequency of observations and weighing: Check for dead or moribund animals was performed within 1, 24 and 48 hours and within 8 days. Clinical signs of intoxication were recorded on working days.
- Necropsy of survivors performed: yes, animals were sacrificed with CO2
- Other examinations performed: clinical signs, local irritating skin findings
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality (0/10 animals died).
Mortality:
0/5 males and 0/5 females died.
Clinical signs:
No systemic toxicity observed.
24 hours after application all animals showed irritation and formation of necrosis, not reversible at the end of the observation period.
Gross pathology:
Sacrificed animals: no substance-related findings.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Quality of whole database:
The study is acceptable for assessment, well documented, meets basic scientific principles and has Klimisch score 2.

Additional information

There are valid in vivo data available for the assessment of the acute oral, inhalative and dermal toxicity of the test item.

Oral

In the key study, a non-GLP study performed comparable to OECD Guideline 401 (Acute Oral Toxicity) using a standardized test method, rats (10/sex/dose) were given a single oral dose (gavage) of the test item (analytical purity: no data) at the doses of 200, 250, 320, 400, 800 and 1600 µL/kg bw (corresponding to approx. 165, 207, 264, 330, 661 and 1322 mg/kg bw; calculation based on density of 0.826 g/cm³) (BASF XX/36, 1970). The test item was diluted in an aqueous emulsion with Traganth at a concentration of 2, 4, 8 or 20 % v/v and administered at a maximum volume dosage of 10 mL/kg. The animals were observed subsequently for a period of 7 days. All surviving animals were killed and together with animals that died during the study subjected to gross pathology.

All animals in the high dose group died within 0.5 hours. No animals died in the lowest dose group. Signs of systemic toxicity were sedate behaviour, spasmodic convulsions, opisthotonus, tremor, lacrimation, salivation, exophthalmus, chromodakryorrhoe, crouching position, movement dislike, accelerated, dyspnea and irregular respiration and scrubby fur. In the two low dose groups’ sedate behaviour, accelerated respiration, dyspnea, spasmodic convulsions, lacrimation, salivation were noted. From day 6 to 8 up to the end of the study nothing abnormal was detected in both treatment groups.

There were no data on body weight gain during the study. No abnormalities were noted at necropsy of deceased and sacrifized animals.

The acute oral toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for an oral toxicity test (OECD 401) in rats (no data on test substance purity, reduced observation period, limited documentation).

The acute oral LD 50 of the test item for male and female rats was estimated to ca. 280 mg/kg body weight.

Inhalative

In the key study, an acute inhalation non-GLP study, comparable to OECD 403, male and female Wistar/Chbb:THOM rats (10/dose/sex) were whole body exposed to the test substance (analytical purity: 99 %) as a vapour at analytical concentrations of 1.88, 2.04, 2.82 and 6.84 mg/L for 4 hours and observed for 14 days (BASF 85/207, 1987). Using an infusion pump the aerosol was pressed into a glass evaporator heated to 50°C. The vapours formed were mixed with fresh air and passed into the inhalation chamber with a temperature of 19 - 25°C.

Clinical signs, mortality, body weights, and gross pathological findings were evaluated.

All animals at the highest concentartion died within 24 hours. No animals died at the lowest concentration.

Clinical signs were observed at nearly all concentrations (restless behavior; gasping respiration; lid closure; anemic aspect; tremors and convulsions (saltatory spasms); sighing, jerky and irregular respiration; upright respiratory posture in some animals; salivation; lateral or abdominal position; reddish discharge from the noses; encrustations; ruffled fur).

Beginning with day 2 to 7 up to the end of the experiment no clinical signs were detectable at the low and the mid concentration groups.

Body weight gain was slightly retarded during the first week of the observation period, but returned to normal body weight gain in the second week as compared to a historical control group.

No substance related gross pathology abnormalities were observed. General passive hyperaemia were observed in deceased animals.

The acute inhalative toxicity study is acceptable (reliability 2), and does satisfy the guideline requirements for an inhalative toxicity test (OECD 403) in rats.

The acute inhalative LC50 of the test item for male and female rats after 4 h vapour exposure was determined to be 2.42 mg/L.

In an acute inhalation hazard non-GLP test comparable to OECD 403 (adopted on 1981, 12th May; inhalation hazard test), rats were whole body exposed to an atmosphere of saturated vapour-aerosol mixture of the test substance (analytical purity: not known) at 20 °C for 3 (6/dose/sex) or 10 (3/dose/sex) minutes at a mean nominal concentration of ca.130 mg/L and observed for 7 days (BASF XX/36, 1970). Mortality was observed with 3/12 rats within 3 min and 6/6 rats within 10 min after 3 and 10 min exposure, respectively.

Clinical signs were strong attempts to escape, gasping, strong mucosal irritation, tremor, convulsions and disturbances of equilibrium. There were no data about body weight of single animals. In deceased and sacrificed animals no gross pathological abnormalities were detected.

These studies show that exposure of highly saturated vapour-air mixtures represents a severe hazard and there is evidence that the test substance is irritating to the respiratory system. The study is acceptable (reliability 2), but does not satisfy the guideline requirements for an inhalative toxicity test (OECD 403) in rats (limited documentation, no analytical monitoring of test atmosphere concentration).

 

Dermal

In the key study, an acute dermal toxicity, non-guideline study conducted similar to OECD Guideline 402, a single dermal administration of the test substance (analytical purity: > 98 %) was performed under occlusive conditions by applying 200 mg/kg body weight of the undiluted test substance on a clipped area of almost 10 % of the estimated body surface of male and female Vienna White rabbits (5/sex) for 24 hours (BASF 77/515, 1980). At the end of the exposure period the residual test substance was rinsed. The observation period following administration was 8 days. Clinical signs, mortality, body weights, and gross pathological findings were evaluated.

No mortality occurred. No systemic toxicity was observed. 24 hours after application all animals showed irritation and formation of necrosis, not reversible at the end of the observation period. No substance-related gross pathological findings were observed in sacrificed animals. The acute dermal toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for a dermal toxicity test (OECD 403) in rats (only one test concentration).

The acute dermal LD50 of the test item for male and female rabbits was > 200 mg/kg body weight.

 

Supportingly, an acute dermal toxicity study of 1-methylpiperidine (CAS No. 626 -67 -5), a compound with similar structure was taken as read across.

In the acute dermal toxicity study conducted according to GLP and to EPA OTS 798.1100 (Acute Dermal Toxicity), a single dermal administration of the test substance (analytical purity: 99.6 %) was performed under occlusive conditions by applying doses of 100, 300, and 1000 mg/kg body weight of the undiluted test substance on an area of approximately 10 % of the body surface of New Zealand White rabbits (5/sex/dose) for 24 hours (PSL 1994). At the end of the exposure period test sites were gently wiped with water and a clean towel to remove any residual test substance. The observation period following administration was 14 days.

Clinical signs, mortality, body weights, and gross pathological findings were evaluated. No mortality occurred at 100, 300 and 1000 mg/kg bw. The clinical symptoms noted in three animals were laxation, ano-genital staining and soft feces. Apart from severe dermal irritation at the dose site, all other animals appeared active and healthy. Gross necropsy findings at terminal sacrifice were unremarkable, all tissues and organs appeared normal.

Originally, in a limit test (2000 mg/kg) the test substance was applied dermal to two animals (PSL 1994). Both rabbits were in severe distress and adverse clinical signs (lethargy, irregular respiration and pale skin) were noted within minutes of application. Both animals died within 21 hours of application. Gross necropsy revealed discoloration of the lungs and intestines with vascular injection and gaseous distention of the intestines in one animal. The study was terminated and lower dose levels were selected for testing.

The acute dermal toxicity study is acceptable (reliability 2), and does satisfy the guideline requirements for a dermal toxicity study (OECD 402) in rabbits.

The LD50 for dermal exposure was reported to be > 1000 to < 2000 mg/kg body weight for rabbits.

 

Conclusion

The test substance is of high toxicity after single oral uptake, of pronounced toxic after single inhalation and of moderate toxicity after short-term skin contact.

 


Justification for selection of acute toxicity – oral endpoint
Only one study available.

Justification for selection of acute toxicity – inhalation endpoint
Highest quality study.

Justification for selection of acute toxicity – dermal endpoint
Only one study available.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available experimental test data for oral, dermal and inhalative toxicity are reliable and suitable for the purpose of classification under Directive 67/548/EEC. As a result the substance is considered to be classified for acute inhalative toxicity (Xn, R20), acute dermal toxicity (Xn, R21) and acute oral toxicity (Xn, R22) under Directive 67/548/EEC.

 

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

The available experimental test data for oral, inhalative and dermal toxicity are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. As a result the substance is considered to be classified for acute oral toxicity (Cat 3, H301, Toxic if swallowed), acute inhalative toxicity (Cat 3, H331, Toxic if inhaled) and for acute dermal toxicity (Cat 4, H312: Harmful in contact with skin), under Regulation (EC) No.1272/2008.