3-methoxy-N,N-dimethylpropionamide

Endpoint summary

Description of key information

Acute oral (OECD423): LD50 >2000 mg/kg bw

Acute inhalation (OECD403): LC50 >5 mg/L

Acute dermal (OECD402): LD50 >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:

18 October 2006 - 16 November 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

17 December 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Crl: CD® (SD) IGS BR

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Eight to twelve weeks
- Weight at study initiation: 198 - 223g
- Fasting period before study: Overnight before dosing until three to four hours after dosing.
- Housing: Group housing of 3 animals per cage in suspended solid-floor polypropylene cages.
- Diet: Free access to Certified Rat and Mouse diet.
- Water: Free access to mains water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS set to maintain:
- Temperature (°C): 19 – 25
- Humidity (%): 30 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on oral exposure:

GAVAGE METHOD: metal cannula attached to a graduated syringe.

Frequency: single dosage, on Day 1.

MAXIMUM DOSE VOLUME APPLIED:
300 mg/kg (10 mL/kg) body weight.
2000 mg/kg (Dose volume calculated as dose level (g/kg) / specific gravity)

DOSAGE PREPARATION: For the purpose of the 300 mg/kg dose level the test material was freshly prepared, as required, as a solution at the appropriate concentration in distilled water. For the purpose of the 2000 mg/kg dose level the test material was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Using available information on the toxicity of the test material, 300 mg/kg was chosen as the starting dose.

Doses:

300 and 2000 mg/kg body weight

No. of animals per sex per dose:

2000 mg/kg: 6 (2 groups of three females in a stepwise manner)
300 mg/kg: 3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/overt signs of toxicity: 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
Body weights: Prior to dosing and seven and fourteen days after treatment.
- Necropsy of survivors performed: At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross pathological examination.
- Other examinations performed: none.

Statistics:

No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: There were no signs of systemic toxicity noted in animals treated at a dose level of 300 mg/kg bw. In the 2000 mg/kg bw dose group, hunched posture and ataxia were noted in all animals during the day of dosing with hunched posture noted in all animals one

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

other: Not classified

Remarks:

According to Regulation (EC) No. 1272/2008.

Conclusions:

In an acute oral toxicity study with female rats, performed according to OECD 423 test guideline and GLP principles, an LD50 >2000 mg/kg bw was determined.

Executive summary:

3-methoxy-N,N-dimethylpropanamide was tested at 300 and 2000 mg/kg bw in an acute oral toxicity study with female rats, performed according to OECD 423 test guideline and GLP principles.

No mortality occurred. There were no signs of systemic toxicity noted in animals treated at a dose level of 300 mg/kg bw. In the 2000 mg/kg bw dose group, hunched posture and ataxia were noted in all animals during the day of dosing with hunched posture noted in all animals one day after dosing and in three animals two days after dosing. Animals in this dose group appeared normal two or three days after dosing.

All animals showed expected gains in bodyweight over the study period and no abnormalities were noted at necropsy.

Based on the results, an LD50 >2000 mg/kg bw was determined and 3-methoxy-N,N-dimethylpropanamide does not have to be classified for acute oral toxicity according to Regulation (EC) No. 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The acute oral toxicity result is of sufficient quality and adequate for this dossier.

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:

07 October 2011 - 25 October 2011

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:

07 September 2009

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2008

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Crl: WI (from SPF colony)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Model and Services, Germany GmbH (Sandhofer Weg 7, D-97633, Sulzfeld).
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 311-328 g (males); 212-234 g (females)
- Fasting period before study: no
- Housing: group housing of 5 animals/sex in Polycarbonate solid floor cages
- Diet: free access to Autoclavable Complete Feed for Rats and Mice- Breeding and Maintenance (SM R/M-Z+H from SNIFF Spezialdiäten GmbH, D-59494 Soest, Germany)
- Water: free access to tap water from the municipal supply
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 - 24.9
- Humidity (%): 35 - 64
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

3.48 µm

Geometric standard deviation (GSD):

1.97

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: TSE Rodent Exposure System (TSE Systems GmbH, Bad Homburg, Germany). This system comprises of two concentric anodised aluminium chambers and a computer control system incorporating pressure detectors and mass flow controllers.
- Exposure chamber volume: No data.
- Method of holding animals in test chamber: Each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber.
- Source and rate of air: Flow of compressed air was at least 0.5 L/min.
- Method of conditioning air: Compressed air was supplied by means of an oil-free compressor passed through a suitable filter system prior to introduction to the nebulizer.
- System of generating particulates/aerosols: Stainless steel concentric jet nebulizer (TSE Systems GmbH, Bad Homburg, Germany)
- Method of particle size determination: The particle size of the test atmosphere was determined three times during the exposure period using a 7-stage Mercer style impactor (TSE Systems GmbH, Bad Homburg, Germany). Such devices employ an inertial separation technique to isolate patticles in the discrete aerodynamic size ranges. Samples were taken from an unoccupied exposure port (representing the animal's breathing zone). The collection substrates and the backup filter were analyzed using a validated HPLC-UV method after the sampling and the amount of test item collected at each stage was calculated. The total amount collected for each stage was used to determine the cumulative amount below each cut-off point size. In this way, the proportion (%) of aerosol less than< 0.550, 0.550, 0.960, 1.550, 2.1 05, 3.555, 6.655 and 10.550 µm was calculated. From these data, using the software supplied with the impactor (TSE Systems GmbH, Bad Homburg, Germany), the Mass Median Aerodynamic Diameter (MMAD), and Geometric Standard Deviation (GSD) were calculated. In addition, the proportion (%) of aerosol less than 4µm (considered to be the inhalable portion) was determined.
- Treatment of exhaust air: No data.
- Temperature, humidity, pressure in air chamber: The chamber temperatures were recorded manually and hourly using a calibrated min-max thermometer. The relative humidity values in the inhalation chamber were not registered due to the malfunction of the built-in humidity sensor. Chamber airflow rates, test atmosphere carbon dioxide concentrations and oxygen concentrations were monitored continuously and recorded every minute during each exposure period.

TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere was sampled at regular intervals during the exposure period. Samples were taken from an unoccupied exposure port (representing the animal's breathing zone) by pulling a suitable, known volume of test atmosphere through GF10 glass fiber filters (Type GF10, Whatman, Germany) and then the filters were analyzed using a validated HPLC-UV method. The amount of the depositions on the filters expressed in original test item, divided by the volume of atmosphere sampled, was equal to the actual achieved test atmosphere concentration. The nominal concentration was calculated by dividing the mass of test material disseminated into the chamber by the total volume of air that through the chamber during the same period.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- Particle size distribution: Analysis of the particle size distribution of the aerosol at the animals' breathing zone demonstrated, that during both parts of the study (sighting exposure and main study) the test atmosphere was respirable to the animals.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The mean values of the particle size distribution parameters calculated from three samples of each exposure was 3.48 / 1.97.

SIGHTING EXPOSURES
The sighting study was performed in order to estimate the test substance inhalation toxicity, identity sex differences in susceptibility and assist in selecting exposure concentration levels for the main study.
One group of animals (1 male and 1 female) was exposed to a concentration of 5.25 mg/L. As no lethality occurred, therefore 5 mg/L target concentration was selected for the main study exposure.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5 mg/L

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:
Morbidity/mortality: Animals were checked hourly during exposure, 1 hour after exposure and twice daily (early and late in the working day) during the 14-day observation period.
Clinical signs: All animals were observed for clinical signs at hourly intervals during exposure whilst the animals were still restrained. Following exposure, clinical observations were performed twice on the day of exposure (following removal from the restrainer and approximately one hour after completion of the exposure) and subsequently once daily for 14 days.
Body weight: Individual body weights were recorded prior to treatment on the day of exposure (before the exposure on Day 0) and on Days 1, 3, 7 and 14.
- Necropsy of survivors performed: Yes, at the end of the 14-day observation period, the surviving animals were sacrificed by exsanguination under anaesthesia and gross macroscopic examination was performed.

Statistics:

No statistical analysis was performed (the method used was not intended to calculate a LC50 value).

Preliminary study:

One group of animals (using a single male and female rat) was exposed to a concentration of 5.25 mg/L (MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 3.33 / 1.91. As no lethality occurred, therefore 5 mg/L target concentration was selected for the main study exposure.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No animals died during the study.

Clinical signs:

other: Slight laboured respiration was observed in all animals during the exposure and shortly thereafter when removed from the restraint tubes. Slight weak body condition was seen in a single male and a single female rat on Day 1-2. From Day 4 all animals were

Body weight:

Slight bodyweight loss (1-6%) or a reduction in bodyweight gain was recorded in all animals on Day 1. Both males and females gained back their initial bodyweight by Day 3 with exception of a single female where by Day 7.

Gross pathology:

No external or internal finding was recorded at necropsy.

Other findings:

Additionally, wet fur was generally recorded in all animals of the study on the day of exposure and red-brown staining was noted in a single male on Day1-3. These observations were considered to be related to the restraint and exposure procedures and were considered not to be of toxicological relevance.

Interpretation of results:

other: Not classified.

Remarks:

According to Regulation (EC) No. 1272/2008.

Conclusions:

In an acute inhalation toxicity study with male and female rats, performed according OECD 403 test guideline and GLP principles, an LC50 >5 mg/L was determined for 3-methoxy-N,N-dimethylpropanamide.

Executive summary:

An acute inhalation toxicity study with nose-only exposure was performed according OECD 403 test guideline and GLP principles. Five male and five females per group were exposed for 4 hours to an aerosol concentration of 5.07 mg/L.

No animals died during the study. Slight laboured respiration was observed in all animals during the exposure and shortly thereafter when removed from the restraint tubes. Slight weak body condition was seen in a single male and a single female rat on Day 1-2. From Day 4 all animals were symptom-free. Slight bodyweight loss (1-6%) or a reduction in bodyweight gain was recorded in all animals on Day 1. Both males and females gained back their initial bodyweight by Day 3 with exception of a single female where by Day 7. No external or internal finding was recorded at necropsy.

Based on this result, an inhalation LC50 >5 mg/L was established for 3-methoxy-N,N-dimethylpropanamide, which implies that the test substance does not have to be classified for acute dermal toxicity according to Regulation (EC) No. 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 000 mg/m³ air

Quality of whole database:

The acute inhalation toxicity result is of sufficient quality and adequate for this dossier.

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:

27 July 2011 - 10 August 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

24 February 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

30 may 2008

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

August 1998

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar strain, RjHAN:(WI)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: JANVIER S.A.S.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adult animals
- Weight at study initiation: 224 - 245g
- Housing: Individual housed in type II polypropylene/polycarbonate cages
- Diet: Free access to autoclavable complete feed for rats and mice - breeding and maintenance (SM R/M-Z+H from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water from the municipal supply.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS set to maintain
- Temperature (°C): 22.0 – 24.8
- Humidity (%): 47 - 70
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Approximately 24 hours before exposure (Day -1) the back of each animal was shaved (approx. 10% of the total body surface).

The formulation was applied as a single dose as supplied to the shaved skin and remained in contact with the skin for the 24 hour exposure period. For that purpose, the appropriate amount of the test item was moistened with water and distributed as uniformly as possible. Sterile gauze pads were placed on the skin of the rats to cover the test item. These gauze pads were kept in contact with the skin by a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was then wrapped with semi occlusive plastic wrap for 24 hours.

At the end of the exposure period, the area of skin treated with the test item was washed with water of body temperature.

Duration of exposure:

24 hours.

Doses:

2000 mg/kg

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:
Mortality/Viability: no data
Body weights: On Day 0 (before test item administration) and on Days 7 and 14.
Clinical signs: On the day of dosing at 1 and 5 hours after application of the test item and once each day for 14 days thereafter.
- Necropsy of survivors performed: Yes
- Other examinations performed: none.

Statistics:

None.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: No clinical signs were observed after treatment with the test item or during the 14-day observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

No local effects were observed after treatment with the test item or during the 14-day observation period.

Interpretation of results:

other: Not classified.

Remarks:

According to Regulation (EC) No. 1272/2008.

Conclusions:

In an acute dermal toxicity study with male and female rats, performed according to OECD 402 test guideline and GLP principles, an LD50 >2000 mg/kg bw was determined.

Executive summary:

3-methoxy-N,N-dimethylpropanamide was tested at 2000 mg/kg bw in an acute dermal toxicity study with male and female rats, performed according to OECD 402 test guideline and GLP principles.

No mortality occurred. No clinical signs and no local effects were observed after treatment with the test item or during the 14-day observation period. The body weight and body weight gain did not show any test item-related effect. No abnormalities were noted at necropsy.

Based on the results, an LD50 >2000 mg/kg bw was determined and 3-methoxy-N,Ndimethylpropanamide does not have to be classified for acute dermal toxicity according to Regulation (EC) No. 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The acute dermal toxicity result is of sufficient quality and adequate for this dossier.

Additional information

Acute oral:

3-methoxy-N,N-dimethylpropanamide was tested at 300 and 2000 mg/kg bw in an acute oral toxicity study with female rats, performed according to OECD 423 test guideline and GLP principles.

No mortality occurred. There were no signs of systemic toxicity noted in animals treated at a dose level of 300 mg/kg bw. In the 2000 mg/kg bw dose group, hunched posture and ataxia were noted in all animals during the day of dosing with hunched posture noted in all animals one day after dosing and in three animals two days after dosing. Animals in this dose group appeared normal two or three days after dosing.

All animals showed expected gains in bodyweight over the study period and no abnormalities were noted at necropsy.

Based on the results, an LD50 >2000 mg/kg bw was determined.

Acute inhalation:

An acute inhalation toxicity study with nose-only exposure was performed according OECD 403 test guideline and GLP principles. Five male and five females per group were exposed for 4 hours to an aerosol concentration of 5.07 mg/L.

No animals died during the study. Slight laboured respiration was observed in all animals during the exposure and shortly thereafter when removed from the restraint tubes. Slight weak body condition was seen in a single male and a single female rat on Day 1-2. From Day 4 all animals were symptom-free. Slight bodyweight loss (1-6%) or a reduction in bodyweight gain was recorded in all animals on Day 1. Both males and females gained back their initial bodyweight by Day 3 with exception of a single female where by Day 7, no external or internal finding was recorded at necropsy.

Based on this result, an inhalation LC50 >5 mg/L was established for 3-methoxy-N,N-dimethylpropanamide.

Acute dermal:

3-methoxy-N,N-dimethylpropanamide was tested at 2000 mg/kg bw in an acute dermal toxicity study with male and female rats, performed according to OECD 402 test guideline and GLP principles.

No mortality occurred. No clinical signs and no local effects were observed after treatment with the test item or during the 14-day observation period. The body weight and body weight gain did not show any test item-related effect. No abnormalities were noted at necropsy.

Based on the results, an LD50 >2000 mg/kg bw was determined.

Justification for classification or non-classification

Based on the results, 3-methoxy-N,N-dimethylpropanamide does not have to be classified for acute oral, acute inhalation and acute dermal toxicity according to Regulation (EC) No. 1272/2008.