N'-[3-(dimethylamino)propyl]-N,N-dimethylpropane-1,3-diamine

Endpoint summary

Description of key information

Acute oral toxicity: The oral LD50 in male/female Sprague-Dawley rats was estimated to be 1250 mg/kg bw based on the results of an key study conducted according to OECD Guideline 401 and EPA OTS 798.1175 (Mallory, 2000) and a supporting study according to OECD Guideline 401 (American Cyanamid Company, 1964).

Acute inhalation toxicity: Two K2 studies were performed according to a method similar to OECD Guideline 403. The studies are used in a weight of evidence approach. None of the animals died during the study (Jipina, 1978 and American Cyanamid Company, 1964).

Acute dermal toxicity: In a study conducted similar to OECD Guideline 402, the acute dermal LD50 was determined to be 370 mg/kg bw in male/female New Zealand White rabbits (American Cyanamid Company, 1964)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1999-09-20 - 1999-11-11

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): JCZR50B (JEFFCAT ZR-50B)
- Substance type: Colorless liquid
- Physical state: Liquid
- Lot/batch No.: 160-0497
- Storage condition of test material: Room temperature

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan
- Age at study initiation: Males: 8 weeks, females: 10 weeks
- Weight at study initiation: 180 - 194 grams (dose range); 179 - 287 grams (assay)
- Fasting period before study: animals were fasted over the night before dose administration.
- Housing: Rats were group-housed prior to treatment initiation. During the study, animals were housed individually in stainless steel cages in compliance with USDA guidelines.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days prior to treatment initiation

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

Test article formulation:
The test article was prepared on a weight to volume basis with distilled water

Doses:

500 mg/kg, 1000 mg/kg, 1250 mg/kg, 1600 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:
Clinical observations:
Recorded 1 and 4 hours (± 15 minutes) after dosing and once daily through Day 15. Signs of toxicity were recorded at least once daily as they were observed, including time of onset, degree and duration.
Weighing: Body weight: Recorded on day 1 (fasted) and on days 8 and 15 (at terminal sacrifice)
- Necropsy of survivors performed: yes: all rats were sacrificed on day 15 by CO2 asphyxiation and gross necropsies were performed, which included examination of the external body surfaces, all orifices and the thoracic, abdominal and pelvic cavities and their contents.

Statistics:

Evaluations were made of clinical signs and body weight data. Body weights were summarized using descriptive statistics (mean and standard deviation).

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 250 - < 1 600 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed at 500 and 1000 mg/kg. Three of ten and ten of ten were found dead at 1250 and 1600 mg/kg, respectively.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

All surviving animals gained weight over the course of the study.

Gross pathology:

No visible lesions were observed at 500 and 1000 mg/kg or in the surviving animals at 1250 mg/kg. At 1250 mg/kg necropsy observations included stomach-distended and/or fluid-filled red; abdominal cavity - fluid-filled; intestines -fluid-filled (red) and distended; and liver - mottled and/or soft. At 1600 mg/kg necropsy observations included stomach - fluid-filled red; distended, red lesions; and intestines fluid-filled red.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based upon the results of this study, the estimated LD50 for the test article, was between 1250 and 1600 mg/kg.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1964

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Non GLP study performed according to a method similar to OECD Guideline 401.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): bis-dimethyl aminopropylamine; 3,3'-bis (dimethylamino) dipropylamine; bis (N,N'-dimethylaminopropoyl) amine
- Other: density: 0.84 g/L

Species:

rat

Strain:

other: CF Nelson

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 105 g (525 mg/kg group), 98 g (1050 mg/kg group), 92 g (2100 mg/kg group), 113 g (4200 mg/kg group)

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

No data

Doses:

525, 1050, 2100 and 4200 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
- Other examinations performed: clinical signs, body weight, gross autopsy

Statistics:

No data

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

2 250 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 604 - <= 3 158

Mortality:

5/5 animals died at 4200 mg/kg (1 between 0 and 6 hours and 4 between 6 and 24 hours)
2/5 animals died at 2100 mg/kg (1 between 6 and 24 hours and one at day 5
No animals died at the other dose levels

Clinical signs:

other: Clinical signs observed at dose levels 1050, 2100 and 4200 mg/kg were depression, hematuria. Recovery was observed at day 5 of the recovery period for dose groups 1050 and 2100 mg/kg

Body weight:

other body weight observations

Remarks:

Mean body weight at termination: 165 g (525 mg/kg group), 147 g (1050 mg/kg group), 128 g (2100 mg/kg group)

Gross pathology:

survivors at 2100 mg/kg: adhesions of stomach to liver
other survivors: normal

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 in rats observed in this study was 2250 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 250 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1964

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Study was performed, comparable with OECD Guideline 403. However, documentation of information was very limited.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Specific details on test material used for the study:

- Name of test material (as cited in study report): bis-dimethyl aminopropylamine; 3,3'-bis (dimethylamino) dipropylamine; bis (N,N'-dimethylaminopropoyl) amine
- Other: density: 0.84 g/L

Species:

rat

Strain:

other: CF Nelson

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 160 g

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

not specified

Details on inhalation exposure:

Animals were exposed to near-saturated vapor

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

7.25 h

Concentrations:

No data

No. of animals per sex per dose:

6

Control animals:

not specified

Details on study design:

No data

Statistics:

No data

Key result

Sex:

male/female

Dose descriptor:

LC50

Remarks on result:

other: Since no animal died

Remarks:

the LC50 was not derived

Mortality:

0/6 animals died

Clinical signs:

other: No signs of intoxication observed

Body weight:

Mean body weight at termination: 212 g

Gross pathology:

Normal

Since no animals have died, no LC50 was derived.

Interpretation of results:

GHS criteria not met

Conclusions:

In this study, no animals died, no signs of intoxication were observed and gross autopsy was normal after exposure to near-saturated vapor for 7 1/4 hours at 23°C.

Reference 3

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1978-01-06 - 1978-01-23

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

The study was performed similar to OECD Guideline 403, however, documentation of study details are limited.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): imino-bis (N, N'-dimethylaminoproylamine)
- Substance type: clear, dark amber liquid
- Physical state: liquid
- Lot/batch No.: #81-582-CJ

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200-283 grams

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23.8 to 24.8 °C

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

The test material was placed in a 250 mL gas-washing bottle. Clean air was bubbled through the test material at a minimal rate of 4 liters per minute. The resulting saturated vapors were directed into a 26.5 liter glass exposure chamber. The exposure chamber atmospheric temperature was maintained at about 23.8 to 24.8 °C. The gas-washing bottle containing the test material (and delivery tubing) was weighed before and after the test material exposure to determine the nominal exposure concentration.

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

1 h

Concentrations:

During the exposure period, a total of 0.63 grams of test material was delivered, yielding a nominal exposure concentration of 2.63 milligrams per liter.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Animals were observed for signs of toxicity at 15 minute intervals during exposure, upon removal from the exposure chamber, hourly post-exposure for four hours, and daily thereafter for 17 days. Individual body weights were recorded on days 0 (prior to exposure), 1, 2, 4, 7, 14 and 17. On day 17 all animals were sacificed (ethyl ether) and gross necropsy examinations performed.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.63 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

1 h

Mortality:

None

Clinical signs:

other: see section 'Any other information on results'

Body weight:

Transient decrease in body weight in 8 of 10 rats.

Gross pathology:

Lung discoloration in 4 of 10 rats.

Other findings:

No abnormal signs were observed in any animal during the exposure period.

Clinical signs: Dry rales and a low incidence (three of ten rats) of yellow staining of the ano-genital fur were noted. During the four hourly post-exposure observations, a single observation of clear oral discharge was noted at one and dry rales was observed once in each of five animals and twice in a sixth animal during the remaining post-exposure observations. During the 14-day observation period, signs observed were dry rales (seven of ten rats), mucoid nasal discharge (three of ten rats), red nasal discharge and gasping (one of ten rats, each).

Interpretation of results:

GHS criteria not met

Conclusions:

Exposure to saturated vapor at a concentration of 2.63 mg/L air-vapor mixture produced minimal signs of toxicity and no deaths. No LC50 value was determined and the study cannot be used to classify the test substance according to criteria laid down in the CLP Regulation (EC) 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 2.63 mg/L air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1964

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Study performed according to a method equivalent to OECD Guideline 402. Some details are missing on test conditions, however enough animals and doses were tested.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): bis-dimethyl aminopropylamine; 3,3'-bis (dimethylamino) dipropylamine; bis (N,N'-dimethylaminopropoyl) amine
- Other: density: 0.84 g/L

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.70 kg (132 mg/kg group), 2.71 kg (263 mg/kg group), 2.95 kg (525 mg/kg group), 2.58 kg (1050 mg/kg group)

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Undiluted product was held in continuous, 24 hour contact with shaved skin

Duration of exposure:

24 hours

Doses:

132, 263, 525 and 1050 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
- Other examinations performed: clinical signs, body weight, skin irritation, gross autopsy

Statistics:

No data

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

370 mg/kg bw

Based on:

test mat.

95% CL:

>= 235 - <= 605

Mortality:

5/5 animals died in the 1050 mg/kg dose group (1 animal between 6 and 24 hours, 2 animals after 2 days, 1 animal after 3 days and 1 animal between 8 and 14 days)
3/5 animals died in the 525 mg/kg dose group (3 animals between 8 and 14 days)
2/5 animals died in the 263 mg/kg dose group (1 animal after 7 days and 1 animal between 8 and 14 days)
0/5 animals died in the 132 mg/kg dose group

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

Mean body weight at termination: 2.78 kg (132 mg/kg group), 2.82 kg (263 mg/kg group), 2.30 kg (2100 mg/kg group)

Gross pathology:

Decedents - adhesions of intestines and abdominal wall.
Survivors - normal

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The acute dermal LD50 in rabbits observed in this study was 370 mg/kg. In addition, severe erythema and edema with gray-black burned areas and destruction of skin and hard eschar formation is observed at 72 hours, persisting until end of 14 day obervation period. Based on these results, the test substance is classified as acute dermal toxicant category 3 according to the criteria laid down in the CLP Regulation .

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1999-11-04 - 1999-12-02

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): JCZR50B (JEFFCAT ZR-50B)
- Substance type: Colorless liquid
- Physical state: Liquid
- Lot/batch No.: 160-0497
- Storage condition of test material: Room temperature

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hare Marland
- Age at study initiation: 12 weeks
- Weight at study initiation: 2.065 - 2.868 kg
- Fasting period before study: no
- Housing: Rabbits were housed individually in stainless steel cages in compliance with USDA guidelines
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum of 5 days prior to treatment initiation during which each rabbit was observed at least once daily for any abnormalities or for the development of infectious disease.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 -21 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours artificial light/12 hours dark

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal trunk
- % coverage: no data
- Type of wrap if used: gauze patch

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At unwrapping, animals were wiped with water and gauze to remove any residual test article and prevent ingestion
- Time after start of exposure: no data

Duration of exposure:

The test article is applied once and remains in contact with the skin site for twenty-four hours.

Doses:

500 and 1000 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:
Clinical observations: Recorded at unwrapping and once daily upto day 15. Signs of toxicity were recorded at least once daily as they were observed, including time of onset, degree and duration.
Body weight: Recorded on day 1 and on days 8 and 15 (terminal sacrifice)
- Necropsy of survivors performed: yes, all surviving rabbits were sacrificed on day 15 by lethal injection, and gross necropsies were performed, which included examination of the external body surface, all orifices and the thoracic and abdominal cavities and their contents.

Statistics:

Body weights are summarized in descriptive statistics (mean and standard deviation).

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 500 - < 1 000 mg/kg bw

Based on:

test mat.

Mortality:

Three of ten animals (1 male and 2 females) at 500 mg/kg dose level and six of ten (4 males and 2 females) at the 1000 mg/kg dose level were found dead during the study. Deaths occurred on days 4 through 12.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

All surviving animals gained weight over the course of the study.

Gross pathology:

No visible lesions were observed in the surviving animals at the day 15 necropsy. The predominate observations at necropsy on found dead animals at 500 and 1000 mg/kg were:
intestines - yellow and/or fluid-filled;
stomach - mucous contents;
kidneys - pale or mottled;
lungs - mottled and liver mottled.
Red/black lesions (spots) on stomach lining and mottled spleens were also observed at 1000 mg/kg.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The dermal LD50 of the test substance was estimated to be between 500 and 1000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

370 mg/kg bw

Additional information

Acute toxicity: oral

Mallory (2000, K1) investigated the acute oral toxicity via the oral route at 500, 1000, 1250 and 1600 mg/kg bw doses of the test substance in 5 male/female Sprague-Dawley rats per dose. After 14 days of observation, no mortality was observed at 500 and 1000 mg/kg. Three of ten rats and ten of ten were found dead at 1250 and 1600 mg/kg, respectively. The acute oral LD50 was determined to be situated between 1250 and 1600 mg/kg bw. As in this study the lowest LD50 value was observed, this study was selected as key study.

In addition, a K2 supporting acute oral toxicity study was conducted in rats and the acute oral LD50 observed in this study was 2250 mg/kg (American Cyanamid Company, 1964).

Based on the available information it could be concluded that LD50 is 1250 mg/kg. This value is proposed to be used for risk assessment purposes.

 

Acute toxicity: inhalation

Two K2 studies were used in weight of evidence approach (Jipina, 1978 and American Cyanamid Company, 1964).

Jipina (1978) performed an acute inhalation study in Sprague-Dawley rats. Animals were exposed to saturated vapors directed into a 26.5 -liter glass exposure chamber containing the test animals for a period of 1.0 hour. A total of 0.63 grams of the test material was delivered, yielding a nominal exposure concentration of 2.63 milligrams per liter. No abnormal signs were observed in any test animal during the exposure period. During the 14 -day observation period, signs observed were dry rales (seven of ten rats), mucoid nasal discharge (three of ten rats), red nasal discharge and gasping (one of ten rats, each). Necropsy examination revealed lung discoloration in four of ten animals. Transient decrease in body weight has been observed in 8 of 10 rats. The LC50 was determined to be > 2.63 mg/L air under testing conditions.

The American Cyanamid Company (1964) performed an acute inhalation study in CF Nelson rats, no animals died, no signs of intoxication were observed and gross autopsy was normal after exposure to near-saturated vapor for 7 1/4 hours at 23°C. No LC50 value was derived in this study. 

 

In addition, an acute inhalation toxicity study does not need to be conducted as the substance is classified as corrosive to the skin.

 

Acute toxicity: dermal

A K2 acute dermal toxicity study was conducted in New Zealand White male/female rabbits (American Cyanamid Company, 1964). The LD50 observed in this study after 24 hours of exposure was 370 mg/kg. In addition, severe erythema and edema with gray-black burned areas and destruction of skin and hard eschar formation is observed at 72 hours, persisting until the end of the 14 day observation period. As in this study the lowest LD50 value was observed, this study was selected as key study.

In addition, in a supporting study, Mallory (2000) investigated acute dermal toxicity of the test substance in 5 New Zealand White male/female rabbits per dose after 24 hours of exposure. After 14 days of observation, three of ten animals (1 male and 2 females) at 500 mg/kg dose level and six of ten (4 males and 2 females) at the 1000 mg/kg dose level were found dead during the study. Deaths occurred on days 4 through 12. The LD50 value was determined to be situated between 500 and 1000 mg/kg bw.

Justification for classification or non-classification

Based on the results of this study and according to the criteria of the CLP Regulation, the test substance should be classified as a category 4 acute oral toxicant, H302 and as category 3 acute dermal toxicant, H311.

The available data on acute inhalation toxicity could not be used for derivation of classification as no bounded LC50 value could be derived. Moreover, no new study is to be performed based on corrosive nature of the test substance.