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Administrative data

Description of key information

In the key acute oral toxicity study in rats, following a method similar or equivalent to EU Method B.1 and OECD Guideline 401 (Acute toxicity oral), the oral LD50 for males was 5210 mg/kg bw and for females 4500 mg/kg bw. 
In the key acute inhalation toxicity study carried out according to OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class (ATC) Method) the LC50 for 4-hour exposure of Niacin obtained was greater than 3.8 mg/L air (chemically determined mean aerosol concentration), which was the highest achievable aerosol concentration.
In the key dermal toxicity study in rats according to OECD Guideline 403 (Acute dermal toxicity) the LD50 for males/females was > 2000 mg/kg bw.
In conclusion, the test item was considered practically non-toxic administered via the oral, inhalation or dermal route.

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:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP study.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
- Mean body weight: 104.1 +/- 1.9 g (males) and 95.8 +/- 1.1 g (females)
- Housed in groups of five in screen-bottomed stainless steel cages, in a well-ventilated room, maintained at 23 +/1 1 degree C
- Stock diet and tap water were provided.
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
as 33% suspension in 0.5% aqueous solution of carboxymethyl cellulose
Details on oral exposure:
- Formulation: 33 % (w/v) aqueous solution, by oral gavage
- Volumes: 10.0 mL/kg to 20.7 mL/kg.
Doses:
3.30, 3.96, 4.75, 5.71 and 6.83 g/kg body weight.
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
The test substance was given by gavage as a 33 % (w/v) suspension in a 0.5 % aqueous solution of carboxy methyl cellulose (CMC) to groups of ten males and ten females in single doses of 10.0, 12.0, 14.4, 17.3 or 20.7 ml/kg body weight. After treatment, the rats received stock diet and tap water ad libitum. They were observed for signs of intoxication during a 14-day period, after which autopsies were carried out on the survivors.
Statistics:
The LD50 values were calculated according to the method of Weil (Biometrics 8 (1952): 249-263) for males and females separately, both after 24 hours and after 14 days.
Sex:
male
Dose descriptor:
LD50
Effect level:
5 210 mg/kg bw
Based on:
test mat.
95% CL:
> 4 740 - < 5 730
Sex:
female
Dose descriptor:
LD50
Effect level:
4 500 mg/kg bw
Based on:
test mat.
95% CL:
> 4 170 - < 4 860
Mortality:
At 24 hours after dosing, 1 male and 2 females in the 2.88 g/kg group had expired, as did 4 each (male and female) in the 3.44 g/kg group, and 5 males and 7 females from the 4.16 g/kg dose group. After 14 days, no additional animals died in the 2.88 g/kg group. However, the total number of deaths at 14 days in the two higher groups were: 5 males and 4 females in the 3.44 g/kg group and 8 males and 8 females in the 4.16 g/kg group.
Clinical signs:
Within one hour after dosing, the rats showed sluggishness and signs of ataxia. Later on coma was frequently observed. Most of the deaths occurred between 1 and 20 hours after dosing. Three males and three females, however, succumbed between day 2 and 4 after treatment. Hereafter, the survivors recovered gradually and looked quite healthy again at the end of the observation period.
Gross pathology:
Macroscopic examination of the survivors at autopsy did not reveal any treatment—related gross alterations.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
An acute oral toxicity test, similar to OECD 401 guideline, was undertaken on nicotinic acid. Male and female Wistar rats were given solutions of the test substance suspended in CMC at concentrations ranging from 3.30-6.83 g/kg bw, and observed for 14 days. The LD50 was found to be 5.21 g/kg bw in males and 4.50 g/kg bw in females.
Executive summary:

A study similar or equivalent to OECD Guideline 401 (Acute toxicity oral) was carried out. Male and female Wistar rats were given solutions of the test substance suspended in CMC at concentrations ranging from 3.30-6.83 g/kg bw, and observed for 14 days. The LD50 was found to be 5210 mg/kg bw in males and 4500 mg/kg bw in females. The test item was considered to be practically non-toxic.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 500 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:
1 (reliable without restriction)
Qualifier:
according to
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Harlan Laboratories Ltd.
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: RccHanTM:WIST(SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation:
Males: 9 weeks (Groups 1 and 3), 10 weeks (Group 2)
Females: 9 weeks (Groups 1 and 3), 10 weeks (Group 2)
- Weight at study initiation:
Males: 271.4 to 309.0 g
Females: 174.8 to 198.2 g
The weight variation did not exceed ± 7 % of the mean weight of the corresponding sex.
- Fasting period before study: None
- Housing: Makrolon® type-IV cages with wire mesh tops and standard softwood bedding including paper enrichment
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: At least six days under optimal hygienic laboratory conditions. Only animals without any visible signs of illness were used for the study. A further observation of clinical signs was performed on the day of each exposure, before exposure start. The animals were accustomed to the restraining tubes for 30 minutes on the day of exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod: 12 hour fluorescent light / 12 hour dark cycle

IN-LIFE DATES
- From: 21-Dec-2011
- To: 08-Feb-2012
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Flow-past, nose-only exposure system
- Method of holding animals in test chamber: Restraining tubes
- Rate of air: 1.0 L/min
- System of generating aerosols: A dust aerosol was generated from the test item using a CR3020 rotating brush aerosol generator connected to a micronizing jet mill. The aerosol generated was then discharged into the exposure chamber through a 63Ni charge neutralizer. The concentration of the test item in the inhalation chamber was controlled by regulating the flow of the test item to the inhalation tower.
- Method of particle size determination: The particle size distribution of the test aerosol was determined three times during each exposure using a Mercer 7 stage cascade Impactor. The particle size distribution was measured by gravimetrically analyzing the test item deposited on each stage of the cascade impactor. Mass Median Aerodynamic Diameters (MMAD) and Geometric Standard Deviations (GSD) were calculated on the basis of the results from the impactor, using Microsoft Excel Software. The target range was 1 to 4 μm for the MMAD and between 1.5 and 3 for the GSD.
- Temperature, humidity, pressure in air chamber:
Relative Humidity / Temperature
The temperature and relative humidity of the test atmosphere was measured continuously during each exposure using a calibrated device. The results were recorded manually and are reported in 30 minute intervals from the start of exposure.
Oxygen Concentration
The oxygen concentration of the test atmosphere was measured continuously during each exposure using a calibrated device. The results were recorded manually and are reported at 30 minute intervals from the start of exposure. The oxygen concentration was maintained above 19 % during each exposure.
Airflow Rate
The actual airflow rate through the exposure chamber was recorded in approximately 30 minute intervals from the start of the inhalation exposure.

TEST ATMOSPHERE
- Brief description of analytical method used:
Determination of the Nominal Aerosol Concentration
The test item usage was measured by weighing the generator cylinders containing the test item before and after each exposure to determine the quantity of test item used. The weight used was then divided by the total air-flow volume to give the nominal concentration.
Gravimetric Determination of Aerosol Concentrations
Gravimetric determinations of aerosol concentration were performed eight times during exposure of group 1 and six times during exposure of groups 2 and 3. The samples were collected on a filter, Type HVLP loaded in a 47 mm in-line stainless steel filter sampling device. The filters were weighed before and immediately after sampling using a calibrated balance. The test aerosol concentration was calculated from the amount of test item present on the filter and the sample volume.
Chemical Determination of Aerosol Concentrations
Chemical determinations of aerosol concentration were performed eight times during exposure of group 1 and six times during exposure of groups 2 and 3 using the filters for gravimetric determinations.
The samples were collected on a HVLP filter loaded in a stainless steel filter device. The filters were transferred into appropriate labeled vials, forwarded at ambient conditions to the scientist responsible for formulation analysis and stored at room temperature until analysis. The samples were analyzed using a HPLC method supplied
- Samples taken from breathing zone: Yes

TEST ATMOSPHERE
The Mass Median Aerodynamic Diameters (MMAD) obtained from three gravimetric measurements of particle size distribution during the exposure for each group were similar (MMAD between 2.39 μm and 3.83 μm). This led to the conclusion that the particle size distribution of the generated aerosol was stable during the whole exposure period. The MMADs were midway through the target range of 1 to 4 μm, thus deposition of the particles can be
assumed to have occurred in both the upper and the lower respiratory tract. In addition, the Geometric Standard Deviations (GSD) were within the target range of 1.5 to 3, except for the first measurement for group 3 which was slightly above 3. In conclusion, the particle size distributions obtained were considered to be respirable to rats and appropriate for acute inhalation toxicity testing.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:
Group 1: The target concentration was chosen due to expected respiratory irritancy.
Group 2: The target concentration is the recommended concentration after exposure at 0.5 mg/L air.
Group 3: The target concentration of 2.5 mg/L air was the highest feasible aerosol concentration as determined in the technical trials.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
HPLC/UV
Duration of exposure:
4 h
Concentrations:
Nominal test concentrations:
Group 1: 0.5 mg/L air
Group 2: 1.0 mg/L air
Group 3: 2.5 mg/L air
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 and weighing: Each animal was examined three times during exposure, immediately and 1 h after exposure on test day 1 and once daily during the observation period. Observations were detailed and carefully recorded using explicitly defined scales as appropriate. Only grossly abnormal signs were detectable during exposure as the animals were restrained in the exposure tubes. The body weight of each animal was recorded on test days 1 (before exposure), 2, 4, 8 and 15 (before necropsy).
- Necropsy of survivors performed: Yes
Statistics:
No statistical analysis was performed.
Sex:
male/female
Dose descriptor:
LC0
Effect level:
3.8 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3.8 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
All animals survived the scheduled observation period.
Clinical signs:
other: Group 1 (0.54 mg/L air): Tachypnea was observed in all animals during exposure period. After exposure end tachypnea and ruffled fur were recorded until test day 3. There were no clinical sings from test day 4 onwards. Group 2 (1.1 mg/L air): Tachypnea was
Body weight:
Group 1 (0.54 mg/L air):
From test day 1 to test day 2, slight body weight loss was noted in all males and two females. Stagnation of body weight was observed from test day 4 to 8 in the remaining female. Thereafter normal body weight development was recorded in all animals.
Group 2 (1.1 mg/L air):
From test day 1 to test day 2, slight body weight loss was noted in one male and two females. Stagnation of body weight was observed in the remaining two males during this period. Slight body weight loss from test day 2 to 4 was seen in the remaining female. Thereafter normal body weight development was recorded in all animals.
Group 3 (3.8 mg/L air):
From test day 1 to test day 2, slight body weight loss was noted in two males and all females. Further body weight loss was observed in one female until test day 4. Slight body weight loss was seen in the remaining male from test day 2 to 4. Thereafter normal body weight development was recorded in all animals.
Gross pathology:
No macroscopic findings at any group were present at necropsy.
Other findings:
None.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Treatment of RccHanTM:WIST(SPF) rats with test item at a concentration of 0.54, 1.1 or 3.8 mg/L air for 4 hours resulted in effects on body weight and clinical signs, such as tachypnea, ruffled fur and / or salivation. The observation on body weights exceeded the marginal body weight loss or stagnation of the body weight gain which is usually observed in acute inhalation studies. Therefore this was considered to be mainly an effects of the test item, especially due to the persistence until test day 4 or 8 in single animals. However, the restraining of the animals in the tubes during the noseonly exposure procedure may have added to the observed effect. In conclusion, the LC50 for 4-hour exposure of the test item obtained in this study was greater than 3.8 mg/L air (chemically determined mean aerosol concentration), which was the highest achievable aerosol concentration. There was no indication of relevant sex-related differences in toxicity of the test item.
Executive summary:

An acute inhalation toxicity study was carried out according to OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class (ATC) Method). Groups of male and female rats were treated with test item at a concentration of 0.54, 1.1 or 3.8 mg/L air for 4 hours. The LC50 for 4-hour exposure obtained in this study was greater than 3.8 mg/L air (chemically determined mean aerosol concentration), which was the highest achievable aerosol concentration. There was no indication of relevant sex-related differences in toxicity of the test item.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
38 000 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
Reliability:
1 (reliable without restriction)
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
RCC AG
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: males: 7 week s; females: 9 weeks
- Weight at study initiation: males: 208 - 226 g; females: 170 - 191 g
- Fasting period before study: None.
- Housing:Macrolon cages Type 2, with wire mesh lids
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 1 week under test conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Humidity (%): 55 +/- 10
- Photoperiod: 12 hours/day

IN-LIFE DATES: From: 10 Aug. 1983 To: 24 Aug. 1983
Type of coverage:
occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
2 %
Details on dermal exposure:
TEST SITE
- Area of exposure: 20 cm2
- % coverage: 100
- Type of wrap if used: Occlusive dressing which was fixed by an adhesive elastic bandage wrapped around the trunk

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The skin was cleaned with lukewarm water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 ml
- Concentration (if solution): 2000 mg/kg bw
- Constant volume or concentration used: Yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 4 ml
Duration of exposure:
Single exposure of 24 h.
Doses:
2000 mg/kg bw (limit test)
No. of animals per sex per dose:
5 male/5 female
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality: Five times during the first day, and daily thereafter.
Body weights:Body weights were recorded at the day of administration and days 8 and 15 of test.
Symptoms: Five times at day 1, and daily for the nature, onset, severity and duration of all gross or visible toxic or pharmacologic effects and time of death.
- Necropsy of survivors performed: Yes
Statistics:
The LOGIT Model could not be applied to the observed rates of death. The LD50 was estimated without use of a statistical model.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality observed during the observation period.
Clinical signs:
No clinical signs observed during the observation period.
Body weight:
Males 2000 mg/kg bw
day1 - 218 g +/- 7
day 8 - 249 g +/- 9
day 15 - 275 g +/- 8
Females 2000 mg/kg bw
day1 - 182 g +/- 8
day 8 - 190 g +/- 13
day 15 - 204 g +/- 19

Gross pathology:
No treatment related effects observed.
Other findings:
None.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In an acute dermal toxicity study with rats (5 male/5 female Wistar) a single dose of 2000 mg/kg bw (occlusive) was administered. Following a 24 h exposure period and washing of exposed skin, animals were observed for 14 days. The LD0 obtained for males/females was 2000 mg/kg bw. The LD50 for males/females was > 2000 mg/kg bw. The test item was considered practically non-toxic.
Executive summary:

A study according to OECD Guideline 402 (Acute dermal toxicity) was carried out. Groups of rats (5 male/5 female Wistar) were administered a single dose of 2000 mg/kg bw (occlusive). Following a 24 h exposure period and washing of exposed skin, animals were observed for 14 days. The LD0 obtained for males/females was 2000 mg/kg bw. The LD50 for males/females was > 2000 mg/kg bw. The test item was considered practically non-toxic.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity

Several acute oral toxicity studies similar or equivalent to EU Method B.1 and OECD Guideline 401 (Acute toxicity oral) were carried out in rats and mice. The LD50 values in males and females ranged from > 5000 to11650 mg/kg bw and > 4500 to 8900 mg/kg bw. In the key study fasted young Wistar rats (5 male/5 female) were given a single oral dose (gavage) of the test substance suspended in CMC at concentrations ranging from 3300 - 6830 mg/kg bw, and observed for 14 days. The LD50 was determined to be 5210 mg/kg bw in males and 4500 mg/kg bw in females. The test item was considered practically non-toxic.

Acute inhalation toxicity

An acute inhalation toxicity study was carried out according to OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class (ATC) Method). Groups of male and female rats were treated with test item at a concentration of 0.54, 1.1 or 3.8 mg/L air for 4 hours. The LC50 for 4-hour exposure obtained in this study was greater than 3.8 mg/L air (chemically determined mean aerosol concentration), which was the highest achievable aerosol concentration. There was no indication of relevant sex-related differences in toxicity of the test item.

Acute dermal toxicity

An acute dermal toxicity study was carried out according to OECD Guideline 403 (Acute dermal toxicity). Groups of rats (5 male/5 female Wistar) were administered a single dose of 2000 mg/kg bw (occlusive). Following a 24 h exposure period animals were observed for 14 days. The LD0 obtained for males/females was 2000 mg/kg bw. The LD50 for males/females was > 2000 mg/kg bw. The test item was considered practically non-toxic.

Justification for classification or non-classification

Based on results obtained in acute toxicity testing the substance is not classified and labeled according to Regulation 1272/2008/EEC (CLP) and Directive 67/548/EEC (DSD).