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Description of key information

Oral: LD50 (female rat) = 300 mg/kg bw; range of mortality (male/female) = 200 - 2000 mg/kg bw.

Inhalation: LC50 > 5.18 mg/L.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2011-05-31 to 2011-07-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
up-and-down procedure
Limit test:
no
Specific details on test material used for the study:
Batch No.: 1176335
Purity: 99.8%
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, B.V.
- Age at study initiation: 10 – 12 weeks
- Weight at study initiation: 169.2 – 193.5 g
- Fasting period before study: overnight prior to treatment and approximately 3 - 4 hours post dose
- Housing: In groups of five in Makrolon type-4 cages with wire mesh tops and standard softwood bedding including paper enrichment
- Diet (e.g. ad libitum): Pelleted Teklad Rat-Mouse Diet 2914C, ad libitum
- Water (e.g. ad libitum): Community tap-water, ad libitum
- Acclimation Period: Five to sixteen days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour fluorescent light / 12-hour dark cycle, Music was played during the daytime light period.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 9.5, 30 or 95 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight.
- Justification for choice of vehicle: A 20%:80% (weight:weight) mixture of the test item with polyethylene glycol 300 formed a beige, viscous liquid suitable for
oral gavage application.
- Lot/batch no. (if required): STBB2046019

MAXIMUM DOSE VOLUME APPLIED:

DOSAGE PREPARATION (if unusual):
The dose formulations were prepared on the day of application, shortly before each treatment. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle was added (weight:volume). The formulations were homogenized using a spatula and a magnetic stirrer.
Homogeneity of the test item in the vehicle was maintained using a magnetic stirrer until administration.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Potential dose levels for the test were 3, 9.5, 30, 95, 300, 950 and 2000 mg/kg body weight. The starting dose was 300 mg/kg body weight. Depending on survival or death of the treated animals, the dose levels were increased or decreased.
Doses:
95, 300, 950 mg/kg body weight
No. of animals per sex per dose:
2, 3, 1 animal each for 95, 300, 950 mg/kg body weight dose level
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Viability / Mortality: Daily during acclimatization; prior to treatment, within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on test day 1 (with the clinical signs); twice daily during test days 2-15.
- Clinical Signs: Daily during acclimatization; prior to treatment, within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on test day 1; once daily during test days 2-15.
- Body Weights: On the last day of acclimatization (prior to removal of food), on test day 1 (prior to treatment), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: All animals surviving to the end of the observation period and all moribund animals were sacrificed by carbon dioxide asphyxiation. An external examination and opening of the abdominal and thoracic cavities for examination of major organs was performed. All macroscopic abnormalities were recorded. Thereafter, the animals were discarded. No organs or tissues were retained. Animals that died spontaneously during the observation period were
examined as soon as they are found dead. All animals killed in extremis for animal welfare reasons were considered in the same way as animals that die on the test.
Statistics:
The statistical program AOT425StatPgm was used for the selection of dose levels and calculation of the LD50 value.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
300 mg/kg bw
Based on:
test mat.
95% CL:
> 50.13 - < 1 220
Mortality:
All animals treated with 95 mg/kg survived until the end of the observation period. One animal treated with 300 mg/kg survived until the end of the observation period, while two animals treated with 300 mg/kg were killed in extremis on test day 1. One animal treated with 950 mg/kg was killed in extremis on test day 1.
Clinical signs:
other: No clinical signs were observed throughout acclimatization. In animals which survived treatment (animals treated with 95 or 300 mg/kg, respectively), mild clinical signs, such as slightly increased activity, slightly ruffled fur and slight tachypnea were
Gross pathology:
No macroscopic findings were recorded at necropsy of the animals that survived the scheduled observation period (animals treated with 95 or 300 mg/kg).
The stomach of all animals which were killed in extremis on test day 1 contained fluid (animals treated with 300 or 950 mg/kg). Additionally, the animal treated with 950 mg/kg was noted with light brown discolored kidneys.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The estimated median lethal dose of test item after single oral administration to female rats, observed over a period of 14 days, is:
LD50 (female rat) = 300 mg/kg body weight (the one dose with partial response), 95% PL confidence interval is 50.13 to 1220 mg/kg body weight
Executive summary:

The acute toxicity of the test item when administered by a single oral gavage to rats was assessed based on OECD 425.

Six female RccHan:WIST (SPF) rats were treated sequentially with test item by single oral gavage administration at dose levels of 95, 300 or 950 mg/kg body weight. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. Body weights were recorded on test day 1 (prior to administration) and on test days 8 and 15. All animals were necropsied and macroscopically examined.

All animals treated with 95 mg/kg survived until the end of the observation period. One animal treated with 300 mg/kg survived until the end of the observation period, while two animals treated with 300 mg/kg were killed in extremis on test day 1. One animal treated with 950 mg/kg was killed in extremis on test day 1.

No clinical signs were observed throughout acclimatization. In animals which survived treatment, mild clinical signs, such as slightly increased activity, slightly ruffled fur and slight tachypnea were observed after treatment on test day 1 and up to test day 3. No clinical signs were observed in these animals from test day 4 until the end of the observation period.

In animals which were killed in extremis after treatment on test day 1 marked clinical signs such as collapse, dragging of fore and hind limbs, moderately to markedly decreased activity, slightly to moderately ruffled fur, ptosis and/or clear lacrimation of both eyes, slight to marked tachypnea, prostration, hunched posture and moderately reduced body temperature were observed prior to sacrifice.

The body weight of the animals was within the range commonly recorded for this strain and age. Body weight development of the surviving animals was not affected by treatment with the test item.

There were no macroscopic findings at the necropsy of the animals that survived the scheduled observation period. The stomach of all animals which were killed in extremis on test day 1 contained fluid. Additionally, the animal treated with 950 mg/kg was noted with light brown discolored kidneys.

The estimated median lethal dose of test item after single oral administration to female rats, observed over a period of 14 days, is:

LD50 (female rat) = 300 mg/kg body weight (the one dose with partial response), 95% PL confidence interval is 50.13 to 1220 mg/kg body weight

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
From 1994-01-26 to 1994-02-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
1992
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
Batch No.: 9
Purity: not specified
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
-Animals and animal hoshandry
Animal species: rat/ wistar/chbb: thom(spf)
Age of the animals: young adult animals
Animal weights at start of the study: animals of comparable weight; (150g - 300g)
Animal identification: individual identification using cage cards and group identification by tail marking
Room temperature/ relative humidity: the animals were housed in fully air-conditioned rooms. Central air-conditioning guaranteed a range of 20 - 24 degrees celsius for temperature and of 30 - 70 % for relative humidity.
There were no deviations from these ranges which influenced the results of the study.
Day/night rhythm: 12 h/12 h (6.00 a.m. - 6 .00 p.m. / 6.00 p.m. - 6.00 a.m.)
Type of cage: stainless steel wire mesh cages
No. of animals per cage: single housing.
Bedding: no bedding in the cages; sawdust in the waste trays.
Drinking water: tap water ad libitum per day.
Diet: kliba-labordiaet 393, klingentalmuehle ag kaiseraugst, switzerland, ad libitum. Analysis of drinking water: the drinking water is regularly assayed for chemical contaminants by the municipal authorities of frankenthal and the technical services of BASF aktiengesellschaft as well as for the presence of germs by a contract laboratory.
Analysis of feed: the feed used in the study was assayed for chemical and microbiological contaminants.
Route of administration:
oral: gavage
Details on oral exposure:
Route of administration: single oral administration by gavage
Test substance formulation with: 0 .5% tylose CB 30 .000 (cleaned natriumcarboxymethylcellulose from hoechst ag) in aqua bidest.
Reason for the vehicle: aqueous formulation corresponds to the physiological medium.
Form of administration: suspension
Amounts administered: dose (kg/mg) concentration (g/100ml) administration volume (ml/kg)
Dose no 1 200 2.000 10.00
Dose no 2 2000 20.000 10.00

Time of day of administration: in the morning.
Observation period: dose 1: 14 days; dose 2: 1 day
Body weight determination: individual body weights shortly before application (day 0), weekly thereafter and at the end of the study (before fasting period).
Signs and symptoms: recording of signs and symptoms several times on the day of administration, at least once each workday for the individual.
General observations and mortality: check was made twice each workday and once on sundays and on public holidays for general observations and for any dead or moribund animals.
Pathology: necropsy at the last day of the observation period. Withdrawal of food at least 16 hours before killing with CO2; then necropsy with grosspathology examination. Wecropsy of all animals that died before as early as possible.
Doses:
200 and 2000 mg/kg body weight
No. of animals per sex per dose:
6 (3 males and 3 females)
Control animals:
not specified
Details on study design:
Observation period: dose 1: 14 days; dose 2: 1 day
Body weight determination: individual body weights shortly before application (day 0), weekly thereafter and at the end of the study (before fasting period).
Signs and symptoms: recording of signs and symptoms several times on the day of administration, at least once each workday for the individual.
General observations and mortality: check was made twice each workday and once on sundays and on public holidays for general observations and for any dead or moribund animals.
Ppathology: necropsy at the last day of the observation period. Withdrawal of food at least 16 hours before killing with CO2; then necropsy with grosspathology examination. Necropsy of all animals that died before as early as possible.
Key result
Sex:
male/female
Dose descriptor:
other: range of mortality
Effect level:
> 200 - <= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals of the 2000 mg/kg dose group died 3 hours or 1 day after application.
Clinical signs:
other: The surviving animals, which showed symptoms appeared normal 1 day after application.
Gross pathology:
Necropsy finding of the animals that died was agonal congestion. No abnormalities were noted at necropsy of animals sacrificed at the end of the study.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the conditions of this study the range of mortality following a single oral administration was found to be greater than 200 and less or equal 2000 mg/kg body weight.
Executive summary:

The study procedure for this investigation was based on European Economic Eommunity (EEC), EEC directive 92/69, methods for the determination of toxicity, Publication No. L 383A, B .1: Acute toxicity - oral, December 29, 1992.

The study was performed to assess the range of mortality following oral administration of the test material to Wistar rats.

A group of 3 fasted animals (males) was given a single oral dose of test material preparation in 0 .5 % solution of tylose CB 30 .000 in aqua bidest. At a dose level of 2000 mg/kg body weight. Another group of 6 fasted animals (3 males and 3 females) was treated in the same way with a dose of 200 mg/kg body weight.

Signs of toxicity noted in the 2000 and 200 mg/kg dose group comprised impaired or poor general state, dyspnoea, apathy, abdominal or lateral position, staggering, atonia, paresis, erythema and salivation.

The surviving animals, which showed symptoms appeared normal 1 day after application.

The expected body weight gain has generally been observed in the course of the study.

All animals of the 2000 mg/kg dose group died 3 hours or 1 day after application. Necropsy finding of the animals that died was agonal congestion.

No abnormalities were noted at necropsy of animals sacrificed at the end of the study.

Under the conditions of this study the range of mortality after oral application was found to be greater than 200 mg/kg and less or equal 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 mg/kg bw
Quality of whole database:
Guideline study, GLP

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:
From 2018-01-29 to 2018-04-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
2009
Deviations:
no
GLP compliance:
yes
Test type:
fixed concentration procedure
Limit test:
yes
Specific details on test material used for the study:
Batch No.: 20170707
Purity: 99.13%
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Received from SAGE labs
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8-10 weeks
- Weight at study initiation: males 283-338 g; females 190-203 g
- Fasting period before study:
- Housing: Housed in suspended stainless steel cages
- Diet (e.g. ad libitum): Envigo Teklad Global 16% Protein Rodent Diet, ad libitum
- Water (e.g. ad libitum): Filtered tap water, ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 43-59
- Air changes (per hr): 12 changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
3.25 µm
Geometric standard deviation (GSD):
2.35
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Nose-only inhalation chamber
- Exposure chamber volume: 6.7 L
- Method of holding animals in test chamber: Animals were individually housed in polycarbonate holding tubes which seal to the chamber with an "O" ring during exposure.
- Source and rate of air: Filtered generator air was supplied to the spray atomization nozzle by an air compressor.
- Method of conditioning air:
- System of generating particulates/aerosols: The test substance was aerosolized using a modified Wtight Dust Generator. The test substance was packed into the dust container and compressed 3000 lbs/in2 using a lab press. The container was then fitted with a cutting head. Compressed generator and mixing air were supplied to the dust generator. The aerosolized dust was then fed directly into the chamber through the dust outlet assembly.
- Method of particle size determination: An eight-stage 1 ACFM Andersen Ambient Particle Sizing Sampler was used to assess the particle size distribution of the test atmosphere.

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric samples were withdrawn at 6 intervals from the breathing zone of the animals. Samples were collected using 37 mm glass fiber filters in a filter holder attached by 1/4 inch Tygon tubing to a vacuum pump. Filter papers were weighed before and after collection to determine the mass collected. This value was divided by the total volume of air sampled to determine the chamber concentration. Sample airflows were measured using a Mass Flow Controller.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5.18 mg/L
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights of the animals were recorded prior to test substance exposure (initial) and again on Days 1, 3, 7, and 14 (terminal). All animals were observed for mortality during the exposure period. The animals were examined for signs of gross toxicity, and behavioral changes upon removal from the exposure tube and at least one daily thereafter for 14 days. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma.
- Necropsy of survivors performed: All rats were euthanized via CO2 inhalation at the end of the 14-day observation period. Gross necropsies were performed on all animals. Tissues and organs of the thoracic and abdominal cavities were examined.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:
Statistics:
Statistical analytis was limited to the calculation of the mean and standard deviation.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.18 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
All animals survived exposure to the test atmosphere.
Clinical signs:
other: All rats were hypoactive and exhibited irregular respiration. Two males and three females were noted as having ano-genital staining. However, all animals recovered by day 3 and appeared active and healthy for the remainder of the 14-day observation period
Body weight:
All animals gained body weight during the study.
Gross pathology:
No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the single exposure acute inhalation LC50 of the substance is greater than 5.18 mg/L in male and females rats.
Executive summary:

An acute inhalation toxicity test was conducted with rats to determine the potential for the substance to produce toxicity from a single exposure via the inhalation route (nose-only exposure) based on OECD 403.

The single exposure acute inhalation LC50 of the substance is greater than 5.18 mg/L in male and females rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 180 mg/m³ air
Quality of whole database:
Guideline study, GLP

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because skin contact in production and/or use is not likely
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral:

Two GLP studies are available.

In one study acute toxicity of the test item when administered by a single oral gavage to rats was assessed based on OECD 425. The estimated median lethal dose of test item after single oral administration to female rats, observed over a period of 14 days, is LD50 = 300 mg/kg bw.

Another study was conducted according to EEC method B.1, the range of mortality following a single oral administration was found to be greater than 200 and less or equal 2000 mg/kg body weight.

Inhalation:

An acute inhalation toxicity test was conducted with rats to determine the potential for the substance to produce toxicity from a single exposure via the inhalation route (nose-only exposure) based on OECD 403.

The single exposure acute inhalation LC50 of the substance is greater than 5.18 mg/L in male and females rats.

Justification for classification or non-classification

Oral: LD50 (female rat) = 300 mg/kg bw; range of mortality (male/female) = 200 - 2000 mg/kg bw.

Inhalation: LC50 > 5.18 mg/L.

Therefore in accordance with Regulation (EC) No. 1272/2008 (amended by 286/2011) Table 3.1.1, this substance should be classified as Category 4.

Specific target organ toxicity-single exposure:

No macroscopic findings in acute toxicity studies, therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.8.1 and 3.8.2, this substance should not be classified for this endpoint.