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Description of key information

The LD50 value for acute oral toxicity was >5000 mg/kg bw in rats.

The LC50 value for acute inhalation toxicity was >0.416 mg/L air in rats.

The LD50 value for acute dermal toxicity was >2000 mg/kg bw in rats.

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:
15 Nov 1985 to 29 Nov 1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
other: Toxic Substances Control Act Health Effects Guidelines; Office of Toxic Substances; Office of Pesticides and Toxic Substances; United States Environmental Protection Agency, August 1982; Acute Exposure, Oral Toxicity.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of the test item (as cited in study report): Nickel dibutyldithiocarbamate
- Batch No.: 0131100 NF
- Appearance: Dark green, powder
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Manston Road, Margate, Kent, England
- Age at study initiation: 4-6 weeks
- Weight at study initiation: 291-300 g (males) and 246-250 g (females)
- Fasting period before study: overnight prior to dosing
- Housing: individually, in metal cages with wire mesh floors
- Diet: Labsure LAD 1, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENT
- Temperature (°C): 20 - 22
- Humidity (%): 63
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50% (w/v)
- Amount of vehicle (if gavage): 10 mL/kg
Doses:
5.0 g/kg bodyweight
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 and weighing: Animals were observed soon after dosing; then at frequent intervals for the remainder of Day 1. On subsequent days the animals were observed at least twice per day. Body weights were recorded on Days 1, 2, 3, 5, 8, 11, and 15.
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no mortalities following a single oral dose of the test substance at 5.0 mg/kg bodyweight.
Clinical signs:
Pilo-erection was seen shortly after dosing in all rats. This had resolved by Day 3. No other signs of reaction to treatment were observed.
Body weight:
Bodyweight losses were recorded for three male and three female rats on Day 3 and for one female rat on Day 11. Bodyweight gains were recorded on all other occasions.
Gross pathology:
Terminal autopsy findings were normal.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
5 000 mg/kg bw

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:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Principles of method if other than guideline:
The acute inhalation toxicity of the test substance was assessed by exposing groups each of 10 rats, for a period of 4 hours, to two concentrations of an aerosol of the test substance.
GLP compliance:
yes
Test type:
traditional method
Limit test:
no
Specific details on test material used for the study:
- Name of the test item (as cited in study report): Nickel dibutyldithiocarbamate
- Batch No.: C 0131100 NF
- Appearance: Dark green, powder
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Manston Road, Margate, Kent, England, obtained on 1 November 1985 and 20 November 1985
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 143-211 g
- Housing: before exposure animals were housed in polypropylene cage (size 38 x 56 cm x 18 cm height) per 10 rats (5 males and 5 females) before exposure; following exposure animals were housed in stainless steel mesh cage (30.5 x 19 x 20 cm height) per rat
- Diet: Labsure LAD 1, ad libitum
- Water: tap water, ad libitum

ENVIRONMENT
- Temperature: 19.2 - 21.3 °C
- Humidity: 42-51%
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
<= 5.5 µm
Details on inhalation exposure:
DUST GENERATOR
A Wright dust generator was used to produce a test atmosphere containing the dust of the test substance. The generator was designed to produce and maintain test atmospheres containing dust by suspending material scraped from the surface of a compressed powder in a stream of dry air. The concentration of dust in the air may be altered by changing the gear ratio of the mechanism.

EXPOSURE CHAMBERS
The whole-body exposure chambers used were the square section an were fitted with pyramidal tops. The chambers were made of perspex and had an internal volume of approximately 0.13 m3. For exposure the animals were held in cages of stainless steel mesh partitioned to provide 10 individual animal compartments.
The test atmosphere entered the chamber through a port in the top for Group 2 (Test 1) or in the base centre for Group 3 (Test 2) and passed out through small holes in the lower edge of the square section. The neutraliser was not used for Groups 3 (Test 2) as it was found that higher concentration was achieved by introducing the material directly into the chamber.

AEROSOL CONDITIONING
The test atmoshere produced by the generator for Group 2 (Test 1) only was passed through a Thermo Systemc Inc., Model 3054, aerosol neutraliser to attempt to minimise electrostatic charge effects.

PROCEDURE
A sample of the test substance was packed into the container of the Wright dust generator using a hydraulic bench press to assist packing. Even density of the powder was achieved by packing the container in stages and applying a force of 0.5 tons weight. The packed container was weighed.
For Group 2 (Test 1) the dust generator was positioned on a stand at the side of the exposure chamber and the output connected to an inlet port in the top centre of the chamber by the aerosol neutraliser.
For Group 3 (Test 2) the dust generator was positioned on a stand below the chamber and was connected to the inlet port of the chamber. The gear ratio of the generator mechanism was set to give the highest possible concentration of dust (1).
A supply of clean dried compressed air was connected to the dust generator and the supply pressure was adjusted to give a flow rate of 25 litres per minute measured at the generator outlet nozzle. The total chamber air supply was derived from the air flow through the dust generator.
The rats were placed into separate compartments of the exposure chamber.
The powder container of the Wright dust generator was advanced manually until a trace of suspended dust was in the chamber. The gearing on the generator was then engaged and the generator motor switched on to start the exposure. After a 12-minute equilibration period (2), the exposure was timed for 4 hours (2). The generator was then switched off and the chamber allowed to clear before the rats were removed for examination.
The rats were placed into individual cages and returned to the holding room for the remainder of the observation period. The rack containing the cages was placed in a ventilated cabinet drawing its air supply from the holding room.
The control group was treated similarly but received clean air only for 4 hours.

(1) The performance of the dust generators was assessed prior to scheduling the animal exposures. The gear ratio of 8:1 (increased speed) used in this study was the highest consistent with reliable operation of the dust feed with this material.
(2) 12 minutes is the theoretical time for the chamber concentration to reach 90% of the final concentration under the conditions described.
(3) Operation of the dust generator was interrupted briefly to change the canister on 1 occasion.

CHAMBER ATMOSPHERE ANALYSES
Eight air samples were taken from a sampling port in the chamber during exposure and weighed to determine the concentration of the test substance in the chamber air. A further 4 samples were taken from'a second sampling port in a different wall of the chamber to check the spatial distribution of the test material.
The samples were drawn through a weighed Whatman GF/A glass fibre filter, mounted in an open face filter holder, at a rate of 4 litres per minute. The volume of the air sample was measured with a wet type gas meter.
Four further air samples were taken using an Andersen mini sampler (Andersen 2000 Inc.) and the collected material was weighed to determine the particle size distribution of the test substance.
At a sampling rate of 1.4 litres per minute the collection characteristics of the Andersen sampler are:
Stage 1 - Particles larger than 5.5 µm aerodynamic diameter (a.d.)
Stage 2 - Particles between 3.5 µm and 5.5 µm a.d.
Stage 3 - Particles between 2.0 µm and 3.5 µm a.d.
Stage 4 - Particles between 0.3 µm and 2.0 µm a.d.
Filter - Particles smaller than 0.3 µm a.d.

CHAMBER AIR TEMPERATURE
The air temperature in the exposure chamber was measured with a mercury-in-glass thermometer and recorded at the start of the exposure and then at 60-minute intervals during the 4-hour exposure.

RELATIVE HUMIDITY
The concentration of water vapour in the chamber air was monitored using an Analytical Development Co. Ltd., water vapour analyser, model 225, and recorded at the start of exposure and then at 60-minute intervals.
The relative humidity was calculated from the recorded data for the water vapour content and temperature of the chamber air.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Group 2 (Test 1): 0.090 mg/L (37% respirable)
Group 3 (Test 2) 0.416 mg/L (14% respirable)
0.416 mg/L was the highest concentration that could be generated.
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days post exposure
- Frequency of observations and weighing: The rats were observed continuously during exposure and twice daily throughout the observation period. All rats were weighed on Days 1 (before exposure), 2, 3, 5, 8, 11 and 15.
- Necropsy of survivors performed: Yes. The lungs were infused with, and preserved in, buffered 10% formalin together with samples of the liver and kidneys for possible future microscopic examination.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.416 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
There were no deaths during the study.
Clinical signs:
other: During exposure: closing or partial closing of the eyes, abnormal breathing and abnormal body posture were observed in all rats exposed to the test substance in group 3. The signs were considered to be consistent with a non-specific response to dust expos
Body weight:
In group 2 (Test 1) body weight gain was not affected by exposure to the test substance.
In group 3 (Test 2) there were slight reductions or reductions in the rate of gain overnight following exposure but subsequently weight gain was similar to that of the control rats.
Gross pathology:
There were no treatment-related macroscopic abnormalitites.

Nominal concentration

The nominal concentrations determined by dividing the total test substance used by the total airflow were 9.84 and 10.32 mg/L for Groups 2 and 3 respectively.

Particle size distribution

The, results show that, on average, 37% for Group 2 and 14% for Group 3 by weight, of the test substance in the chamber air was 5.5 µm or less in aerodynamic diameter and therefore of respirable size. The lower respirable fraction for Group 3 than for Group 2 was due to the equipment configuration. For Group 2 a greater proportion of nonrespirable particles would be lost in the aerosol neutraliser which would also act as an elutriation column.

Chamber air

The chamber mean air temperatures were between 23.1 and 23.3 °C.

Relative humidity

The mean relative humidity of the chamber air was between 35 and 47%.

Interpretation of results:
study cannot be used for classification
Conclusions:
The study determined a LC50 of > 0.416 mg/L, which was the highest concentration that could be generated. In order to achieve applicability of animal experiments to human exposure, the mean mass aerodynamic diameter (MMAD) should be low enough to ensure that the test substance will deposit in all regions of the rats respiratory tract of the appropriate test animal. According to OECD TG 403, the primary goal should be to achieve a MMAD of 1 - 4 µm when testing aerosols. In the study, particle size distribution analysis showed that the majority of the test substance exceeds a particle size of 5.5 µm during exposure. Because of the low efficiency of generation (measured concentration was only 0.9 - 4% of the nominal concentration) and the relative large particle size, data cannot be used for classification of acute inhalation toxicity. As sufficient data are available on the other two routes of exposure, the study is not warranted.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
416 mg/m³

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:
14 Nov 1985 to 28 Nov 1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
equivalent or similar to guideline
Guideline:
other: Toxic Substances Control Act Health Effects Test Guidelines; Office of Toxic Substances; Office of Pesticides and Toxic Substances; United States Environmental Protection Agency, August 1982; Acute Exposure, Dermal Toxicity.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of the test item (as cited in study report): Nickel dibutyldithiocarbamate
- Batch No.: 0131100 NF
- Appearance: Dark green, powder
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Froxfield Rabbits, Petersfield, Hampshire, England
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 2.3-2.7 kg
- Housing: The rabbits were housed individually in metal cages with perforated floors.
- Diet: SQC Standard Rabbit Diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: minimum of 6 days

ENVIRONMENT
- Temperature (°C): 20-21
- Humidity (%): 45 ± 10
- Air changes (per hr): 19
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
24 hours prior to treatment hair was clipped from the dorso-lumbar region of each rabbit exposing an area approximately 10% of the total body surface area. The test substance was applied by spreading evenly over the clipped treatment site in as uniform a manner as possible moistened with 2.0 mL/kg bodyweight saline. Treatment in this manner was performed on Day 1 of the study only.

After the exposure period of 24 hours the dressing was removed an the treatment site gently washed with water to remove any residual test substance. Collars were fitted on each rabbit and were worn for approximately 23 hours to prevent ingestion of any residual test substance.
Duration of exposure:
24 hours
Doses:
2.0 g/kg bodyweight
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 and weighing: ANimals were observed soon after dosing and then at frequent intervals for the remainder of Day 1. On subsequent days the animals were observed once in the morning and once at the end of the experimental day. Body weights were recorded on Days 1, 2, 3, 5, 8, 11 and 15.
- Local dermal reactions (erythema/oedema) at the treatment site were assessed daily.
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no mortalities.
Clinical signs:
Two male rabbits were observed to have consumed little food on Days 4 and 5. Diarrhoea, was observed on Day 3 in one of these rabbits. There were no signs of systemic toxicity in the remaining 3 male or five female rabbit.
Body weight:
A bodyweight loss was recorded for two male and three female rabbits on Day 2, for four males and three female rabbits on Day 3, for one male rabbit on Day 8 and for one female rabbit on Day 11. A poor weight gain was recorded on Days 3 and 8 for one male rabbit and on Day 15 for one other male rabbit. An unchanged weight was recorded for one male rabbit on Day 2 only.
Gross pathology:
Terminal autopsy findings were normal.
Other findings:
There were no dermal reactions at the site of application in any of the rabbits, however some staining of the skin and adjacent fur, by the test substance was observed.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity

In a pre-GLP acute toxicity study similar to OECD 401, 5 rats per sex were orally exposed to 5000 mg/kg bw test substance. Animals were observed for 14 days and clinical signs and body weight were reported. After 14-days, all animals were necropsied and abnormal macroscopic appearance of organs was recorded. No mortality was observed. Pilo-erection was observed shortly after dosing in all rats and lasted until Day 3. Body weight losses were recorded for three male and three female rats on Day 3 and for one female rat on Day 11. Body weight gains were recorded on all other occassions. Terminal autopsy findings were normal. The LD50 was determined to be greater than 5.0 g/kg bodyweight.

In a pre-GLP acute toxicity study similar to OECD 401, 10 rats per sex/dose were orally exposed to 1000, 2500 and 5000 mg/kg bodyweight in one single dose. Animals were observed for 14 days for signs of intoxication. Autopsies were carried out on the survivors after 14 days. No mortality nor toxic symptoms were observed. Terminal autopsy findings were normal. The LD50 was determined to be greater than 5.0 g/kg bodyweight.

In a pre-GLP acute toxicity study similar to OECD 401, 5 rats per sex were orally exposed to 5000 mg/kg bodyweight in one single dose. The test substance was given by gavage as a 25% (w/v) suspension in DMSO (20 mL). Animals were observed for 14 days for signs of intoxication. Autopsies were carried out on the survivors after 14 days. No mortality was observed. A few hours after exposure, rats showed sluggishness and signs of ataxia, which disappeared after 24 hours. Terminal autopsy findings were normal. The LD50 was determined to be greater than 5.0 g/kg bodyweight.


Acute inhalation toxicity

In a GLP acute toxicity study similar to OECD 403, 5 rats per sex/dose were continuously exposed (whole body) for 4 hours to the highest possible generated atmosphere concentrations of an aerosol of the test substance (0.091 mg/l; 37% respirable, and 0.416 mg/l; 14% respirable) using a Wright dust generator. A control group received clean air only for 4 hours. Animals were observed for 14 days and clinical signs and body weights were reported. No mortality was observed. In the 0.416 mg/l group during exposure, abnormal body posture and abnormal breathing were observed in all rats. the effect was considered a non-specific response to dust exposure. In the 0.090 mg/l group, abnormal respiratory pattern was for up to seven days after exposure. Bodyweight gain was not affected by exposure to the test substance. Terminal autopsy findings were normal. The LC50 was determined to be greater than 0.416 mg/l.


Acute dermal toxicity

In a pre-GLP acute toxicity study similar to OECD 402, 5 rabbits per sex were dermally exposed for 24 hours to 2000 mg/kg bw test substance (occlusive). Animals were observed for 14 days and clinical signs, dermal irritation and body weight were reported. After 14-days, all animals were necropsied and abnormal macroscopic appearance of organs was recorded. No mortality was observed. Diarrhoea was observed in one of these animals on Day 3. A bodyweight loss was recorded for two male and three female rabbits on Day 2, for four males and three female rabbits on Day 3, for one male rabbit on Day 8 and for one female rabbit on Day 11. A poor weight gain was recorded on Days 3 and 8 for one male rabbit and on Day 15 for one other male rabbit. An unchanged weight was recorded for one male rabbit on Day 2 only. Terminal autopsy findings were normal. The LD50 was determined to be greater than 2.0 g/kg bodyweight.

Justification for classification or non-classification

The available data for acute oral and dermal toxicity are reliable and suitable for classification purposes under Regulation 1272/2008. Based on the result of the available studies, classification for acute oral and dermal toxicity is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008.

The acute inhalation toxicity study determined a LC50 of > 0.416 mg/L, which was the highest concentration that could be generated. In order to achieve applicability of animal experiments to human exposure, the mean mass aerodynamic diameter (MMAD) should be low enough to ensure that the test substance will deposit in all regions of the rats respiratory tract of the appropriate test animal. According to OECD TG 403, the primary goal should be to achieve a MMAD of 1 - 4 µm when testing aerosols. In the study, particle size distribution analysis showed that the majority of the test substance exceeds a particle size of 5.5 µm during exposure. Because of the low efficiency of generation (measured concentration was only 0.9 - 4% of the nominal concentration) and the relative large particle size, data cannot be used for classification of acute inhalation toxicity. As sufficient data are available on the other two routes of exposure, the study is not warranted.