Propanamide, 2-hydroxy-N,N-dimethyl-

Endpoint summary

Description of key information

Acute Oral: The LD50 (female rat) of the test substance after single oral administration observed over a period of 14 days is greater than 2000 mg/kg body weight. 
Acute Inhalation: The median lethal concentration (LC50) of the test substance for rats exposed by the inhalation route for 4 hours and observed over 15 days was estimated to be greater than 5.004 mg/L air.
Acute Dermal: The LD50 (rat) of the test substance after single dermal administration to rats of both sexes was greater than 2000 mg/kg bw.

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:

2006-11-22 to 2006-12-15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline compliant study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

(2001)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Version / remarks:

(2004)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: HanRcc:WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: 11 weeks
- Weight at treatment day: 175-190 g
- Fasting period before study: 18-19 hours (access to water was permitted)
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, ad libitum
- Water: Community tap water from Füllinsdorf ad libitum.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity: 30-70 %
- Air changes: 10-15 air changes per hour
- Photoperiod: Automatically controlled light cycle of 12 hours light and 12 hours dark

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

Total 6 females

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Weighing: On test days 1 (prior to administration), 8 and 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: Mortality/viability, clinical signs

Statistics:

No statistical analysis was used.

Sex:

female

Dose descriptor:

discriminating dose

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: No clinical signs were observed during the course of the study.

Gross pathology:

No macroscopic findings were recorded at necropsy.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

GLP and guideline compliant study.

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:

2007-02-09 to 2007-02-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline compliant study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

(1992)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

(1992)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

(1998)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), Guidelines for Preparation of Study Results, Acute Inhalation Toxicity Studies Guideline 2-1-3. Notification 12 NohSan No. 8147 (2005)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HanRcc:WIST(SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf, Switzerland
- Age at study initiation: Males: 9 weeks; Females: 10 weeks
- Weight at study initiation: Males: 237.6 g - 255.2 g; Females: 204.9 g - 211.4 g
- Fasting period before study: No data
- Housing: Group of five in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding
- Diet: Pelleted standard Kliba-Nafag 3433, rat maintenance diet, ad libitum
- Water: Tap-water from Füllinsdorf, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 ± 1°C
- Humidity: 30 to 70%
- Air changes: 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light / 12 hours darkness

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 exposure chamber
- Exposure chamber volume: 12.0 L/min
- Method of holding animals in test chamber: Confined separately in restraint tubes, using a system similar to that originally described by Sachsse et al. (1973, 1976)
- Source and rate of air: The exposure airflow rate was recorded nine times during the inhalation exposure period, i.e. at 30 minute intervals from the start to the end of the inhalation exposure. The total airflow was maintained at 12.0 L/min.
- Method of conditioning air: No extra diluent air was added. The airflow rate of the aerosol as it arrived at the animal ports was 0.92 L/min/animal port.
- System of generating particulates/aerosols: Test aerosol was generated in ambient conditions using a nebuliser connected to a syringe pump.
- Method of particle size determination: Mercer 7 stage cascade impactor
- Treatment of exhaust air: The exhaled air is extracted through the gap near each feed tube leaving the exposure chamber via its outer cylinder followed by the extraction tube.
- Temperature, humidity: Temp: ~21°C; Hum: ~2.1%

TEST ATMOSPHERE

Test concentration:
Samples from the test aerosol were collected four times during exposure on pairs of Whatman GF/C glass fiber filters. For aerosol sampling each filter was loaded in a 47 mm in-line stainless steel filter sampling device. For gravimetric determination of aerosol concentration the filters were carefully weighed before and after sampling using a Mettler MX5 analytical balance.
For chemical analysis the filters were put into an appropriate, umber coloured glass vial and covered with 10 mL of chloroform to minimise possible loss of test item by evaporation from the filter.
The filter samples were analysed by gas chromatography (GC) with flame ionisation detection (FID).

Temperature/Relative humidity
The temperature and relative humidity were continuously monitored and recorded for the duration of the exposure period using a calibrated VAISALA HMI 32 humidity and temperature indicator (Kuenzli Elektronik, CH-8006 Zürich, Switzerland), connected to an analogue chart recorder. The results are reported at 30 minute intervals from the start to the end of the inhalation exposure.

Oxygen concentration
The oxygen concentration was continuously monitored and recorded for the duration of the exposure period using a calibrated Oxopac RD device (Dräger AG, CH-8305 Dietlikon, Switzerland) connected to an analogue chart recorder. The results are reported at 30 minute intervals from the start to the end of the inhalation exposure.

- Samples taken from breathing zone: Yes

- Particle size distribution: The particle size distribution was determined twice during the exposure using a Mercer 7 stage cascade impactor, flow rate of 1.0 L/min and the particles deposited according to their aerodynamic size onto stainless steel slips and the final filter stage on each stage of the impactor. To obtain the mass deposited on each stage of the impactor, the steel slips and the final filter stage were carefully weighed before and after sampling.
The total mass (μg) deposited in the impactor was then calculated by adding together the mass deposited on each of the stainless steel slips and the final filter stage. As the Effective Cut-off Diameters (ECD) represent the lower size limit of the particles collected on each stage, the percentages less than the indicated size were tabulated as a function of the ECD.

- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Cumulative percent values were used to calculate the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) using Microsoft Excel software. The target range for the mass median aerodynamic diameter was 1 to 4 μm.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

The nominal aerosol concentration attained over the entire 30 minute pre-exposure aerosol generation and 4 hour exposure period amounted to 5.383 mg/L air.

No. of animals per sex per dose:

5 males and 5 females

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Prior to exposure on test day 1, and during the observation period on test days 4, 8 and 15.
- Necropsy of survivors performed: Yes on day 15, all animals were sacrificed and necropsied.
- Other examinations performed: Clinical signs, macroscopic pathology

Sex:

female

Dose descriptor:

LC50

Effect level:

5.004 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: (chemically determined mean aerosol concentration equivalent to a gravimetrically determined mean aerosol concentration of 5.226 mg/L air).

Mortality:

No spontaneous deaths occurred in this study.

Clinical signs:

other: Examination of each animal during and after exposure did not reveal any clinical signs during the 15-day observation period.

Body weight:

Body weight loss, marginal in degree, or retardation in body weight gain was evident in four of five male animals (nos. 1, 3, 4 & 5, mean weight change in the affected males –0.2%) and body weight loss, moderate to marked in degree, in all of five female animals (nos. 6 to 10, mean weight loss in the females –6.7%) over the first three days following the inhalation exposure (test days 1 to 4). During the remainder of the 15-day observation period all animals gained body weight normally.
A relationship of these, transient effects on body weight to the treatment with the test item could not be entirely discounted, although there were no clinical signs or other indications of toxicity during this study and slight physical stress, e.g. during restraint in the exposure tubes, may have contributed to these effects.

Gross pathology:

Examination of each animal on the scheduled day of necropsy (test day 15) did not reveal any macroscopic findings.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5.004 mg/m³ air

Quality of whole database:

GLP and guideline compliant study.

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:

2006-11-22 to 2006-12-13

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline compliant study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

(Feb, 1987)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

(July 1992)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HanRcc:WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: Males: 8 weeks, Females: 11 weeks
- Weight at treatment day: 196-256 g
- Fasting period before study: No
- Housing: In groups of five per sex
- Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, ad libitum.
- Water: Community tap water from Füllinsdorf, ad libitum
- Acclimation period: 7 days

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

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: Backs of the animals
- % coverage: Approximately 10 % of the total body surface
- Type of wrap if used: Elastic adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing: Lukewarm tap water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL
- Concentration: 2000 mg/kg
- Constant volume or concentration used: Yes
- For solids, paste formed: Yes

Duration of exposure:

24 hours

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

5 males and 5 females

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Weighing: On test days 1 (prior to administration), 8 and 15
- Necropsy of survivors performed: Yes
- Other examinations performed: Mortality/viability, clinical signs, body weight, local signs

Statistics:

No statistical analysis was used.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: No systemic signs of toxicity were observed during the study period. Local signs of irritation were noted at the application site of all animals except one female. A slight erythema was noted in the five males and four females. In addition, all males and

Gross pathology:

No macroscopic findings were observed at necropsy.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

GLP and guideline compliant study.

Additional information

Acute oral toxicity

The acute oral toxicity test was GLP compliant and was conducted according to the OECD guideline 423.

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with the test substance by oral gavage administration at a dosage of 2000 mg/kg body weight. The test substance was diluted in vehicle (purified water) at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. No clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

The LD50 (female rat) of the test substance after single oral administration observed over a period of 14 days is greater than 2000 mg/kg body weight.

Acute dermal toxicity

The acute dermal toxicity test was GLP compliant and was conducted according to the OECD guideline 402.

The Five male and five female HanRcc:WIST (SPF) rats were treated with the test substance at 2000 mg/kg by dermal application. The test substance was diluted in vehicle (purified water) at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The application period was 24 hours.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

No deaths occurred during the study. No clinical signs of systemic toxicity were observed during the course of the study. Local findings were noted at the application site of all animals except one female. These comprised slight erythema, slight scaling and slight to moderate scab formation. At the end of the two-week observation period, local findings were still present in one male and four female animals. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy.

The LD50 (rat) of the test substance after single dermal administration to rats of both sexes was greater than 2000 mg/kg bw.

Acute inhalation toxicity

The acute inhalation toxicity test was GLP compliant and was conducted according to the OECD guideline 403. A group of five male and five female albino rats [HanRcc:WIST(SPF)] was exposed by noseonly, flow-past inhalation to the test item at a chemically determined mean concentration of 5.004 mg/L air (s.d. ± 0.107 mg/L air, n = 3), equivalent to a gravimetrically determined mean concentration of 5.226 mg/L air (s.d. ± 0.113 mg/L air, n = 4). Two gravimetric measurements of particle size distribution during the exposure produced mass median aerodynamic diameters (MMADs) and geometric standard deviations (GSD) of 2.52 μm (GSD 1.93) and 2.32 μm (GSD 2.15). All animals were observed for clinical signs and mortality during and following the inhalation exposure, i.e. over a 15-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 4, 8 and 15. On day 15, all animals were sacrificed and necropsied. The ranges of temperature, relative humidity, oxygen content, particle size and airflow measured during the exposure were considered to be satisfactory for a study of this type. There were no deaths, no clinical signs and no macroscopic pathology findings. Retardation in body weight gain or marginal body weight loss were evident in four of five male animals (mean weight change in the affected males –0.2%) and moderate to marked body weight loss in all female animals (mean weight loss in the females –6.7%) over the first three days following the inhalation exposure (test days 1 to 4). The effects on body weight were only transient and were followed by normal body weight gain in all animals. A relationship of the transient effects on body weight to the treatment with the test substance could not be entirely discounted, although slight physical stress, e.g. during restraint in the exposure tubes, may have contributed to these effects.

In conclusion, the LC50 of the test substance obtained in this study was estimated to be greater than 5.004 mg/L air (chemically determined mean aerosol concentration equivalent to a gravimetrically determined mean concentration of 5.226 mg/L air).

Justification for selection of acute toxicity – oral endpoint
GLP and guideline compliant study.

Justification for selection of acute toxicity – inhalation endpoint
GLP and guideline compliant study.

Justification for selection of acute toxicity – dermal endpoint
GLP and guideline compliant study.

Justification for classification or non-classification

Based on the test results of the acute oral toxicity study (oral discriminating dose > 2000 mg/kg bw) to the test substance, classification is not warranted with regard to acute oral toxicity according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).

Based on the test results of the acute inhalation toxicity study (LC50 > 5.004 mg/L air ) to the test substance, classification is not warranted with regard to acute inhalation toxicity (dust/mist) according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).

Based on the test results of the acute dermal toxicity study (dermal discriminating dose > 2000 mg/kg bw) to the test substance, classification is not warranted with regard to acute dermal toxicity according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).