bis(diethylamino)-N,N-diethylmethaniminium chloride

Endpoint summary

Description of key information

Acute oral toxicity

Under the conditions of the study, the acute oral LD50 of the test material was evaluated to be 550 mg a.i./kg with a 95 % confidence Interval of 114.7 to 824 mg a.i./kg. 

 

Acute dermal toxicity

Under the conditions of this study, the LD50 of the test material following a single topical application would be expected to be within the range of 500 to 1500 mg/kg. 

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:

25 February 2003 to 19 March 2003

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:

2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

Deviations:

no

GLP compliance:

yes

Remarks:

OECD GLP

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

not specified

Remarks:

(albino)

Sex:

female

Details on test animals or test system and environmental conditions:

Eight female outbred albino rats weighed 239.2 - 279.1 g and were at least 49 days old. They were single housed upon arrival in polycarbonate cages with hardwood chip bedding. The animals were acclimated for at least 5 days prior to dosing. Tap water was provided ad libitum throughout the study and feed was provided ad libitum, with the exception of overnight prior to dosing. The temperature and humidity were maintained at 68 ± 5 °F and 30 - 70 %, respectively. Room lights were on a 12-hour light/dark cycle.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DOSAGE PREPARATION: None. Used as supplied

Doses:

175, 550 and 2000 mg a.i./kg

No. of animals per sex per dose:

8 females

Control animals:

no

Details on study design:

Food was withheld from the animals the night prior to dosing. Animals were administered a single dose of the test substance by oral gavage. After dosing, the animals were returned to their cages and supplied with feed and water ad libitum.

The first animal was dosed at 175 mg a.i. /kg as the Sponsor indicated that the test substance may have an LD50 of 300 mg/kg. Single animals were dosed sequentially at 48-hour intervals. The interval between dosing was determined by the onset, duration and severity of toxic signs.

The survival of each animal determined if the next animal would receive a higher or lower dose. Dosing continued on the fixed time interval outcome of all the dosed animals. The dosing was terminated when one of the following criteria was met: 1) 3 consecutive animals survived the upper bound; 2) 5 reversals occurred in any 6 consecutive animals tested; or 3) at least 4 animals were dosed following the first reversal and the specified likelihood-ratios exceeded the critical value.

The dose progression factor was chosen as the antilog of 1 (the estimated slope of the dose response curve).

Careful clinical observations were made at least twice daily on the day of dosing. Special attention was given during the first four hours. Animals were observed daily for 14 days for clinical manifestations. Animals were weighed on Day 0, prior to dose administration, Day 7 and Day 14.

Any animal found dead was necropsied as soon as possible, but in no case later than 12 hours. A gross necropsy was performed on all animals whether found dead, euthanized in extremis, or sacrificed at the end of the study.

Any other information on materials and methods, including tables: An evaluation of acute toxicity data included the relationship, if any, between the animals exposed to the test substance and the incidence and severity of all abnormalities, including behavioral and clinical abnormalities, gross lesions, bodyweight changes, effects on mortality, and any other toxic effects. Calculation of the LD50 and the confidence intervals of the test substance were determined by using the maximum likelihood method. A statistical computer program (AOT425StatPgm) developed by the U.S. EPA was used for the calculation.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

550 other: mg a.i./kg

95% CL:

>= 114.7 - <= 824

Mortality:

Animals dosed at 175 mg a.i./kg survived to study termination. Three of four animals dosed at 550 mg a.i./kg died prior to the end of the study, two at four hours post-dose and one on Day 3. The two animals dosed at 2000 mg a.i./kg were found dead within four hours post-dose.

Clinical signs:

other: Animals dosed at 175 mg a.i./kg did not exhibit any clinical signs throughout the course of the study. Prior to death, the animal dosed at 550 mg a.i./kg that died on Day 3 was observed with piloerection, severe tremors and cyanosis. The animals dosed a

Gross pathology:

No unusual findings were found during necropsy for the animals dying on study or euthanized at study termination.

Interpretation of results:

other: EU Criteria: Category 4: Harmful if swallowed (H302)

Conclusions:

Under the conditions of the study, the acute oral LD50 of the test material was evaluated to be 550 mg a.i./kg with a 95 % confidence Interval of 114.7 to 824 mg a.i./kg.

Executive summary:

The acute oral toxicity of the test material to female rats was investigated using an Up and Down procedure, in accordance with the standardised guidelines, OECD 425 and EPA OPPTS 870.1100, under GLP conditions. 

 During the study the animals were administered a single dose of the test material by intragastric intubation by means of a ball tip gavaging needle and a syringe. After dosing, the animals were returned to their cage and supplied with feed and water ad libitum.

Under the conditions of the study, the acute oral LD50 of the test material was evaluated to be 550 mg a.i./kg with a 95 % confidence Interval of 114.7 to 824 mg a.i./kg. 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

550 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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:

10 December 2003 to 9 March 2004

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

yes

Remarks:

An actual LD50 was not determined.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

1998

Deviations:

yes

Remarks:

An actual LD50 was not determined.

GLP compliance:

yes

Remarks:

US EPA GLP 40 CFR, Part 792 and OECD GLP

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female New Zealand White rabbits weighed 2.14 - 2.93 kg and were 12 - 15 weeks old and were individually housed upon arrival in stainless steel suspended cages. The animals were acclimated for at least 5 days prior to dosing. Water and feed were provided ad libitum. The temperature and humidity were maintained at 68 ± 5 °F and 30 - 70 %, respectively. Room lights were on a 12-hour light/dark cycle.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The application site, not less than 10% of the body surface, was prepared approximately 24 hours prior to dosing by clipping the skin of the trunk free of hair. The test substance was dosed as received from the Sponsor. In the limit test, the test substance was dosed at 2000 mg/kg. In the Range finding Test, 1 rabbit/sex were dosed at 250, 500, 1000, 1500 and 2000 mg/kg. The test substance was introduced under gauze patches (two single layers thick) and applied directly to the skin of 10 animals. The animals were immobilized and the patches were secured in place by wrapping the entire trunk of the animal with an impervious bandage. Test sites were secured to prevent the animals from ingesting the test substance. After the completion of the 24-hour exposure period, the wrapping was removed and the skin was gently wiped and rinsed with water to remove any test substance still remaining.

Duration of exposure:

24 hours

Doses:

Limit Test: 2000 mg/kg
Range finding: 250, 500, 1000, 1500 and 2000 mg/kg

No. of animals per sex per dose:

Range finding: 1/sex; Limit test: 5/sex

Control animals:

no

Details on study design:

Five animals/sex were dosed at 2000 mg/kg (limit test). All animals died at this dose. Therefore, a range-finding test was conducted with 1 rabbit/sex dosed at: 250, 500, 1000, 1500 and 2000 mg/kg. The animals were observed frequently during the first day and then a careful clinical examination was made at least once a day through 14 days. The test site of each animal was also observed for signs of erythema and edema after the exposure period according to the Draize Scale for Scoring Skin Reactions. Animals were weighed at Day 0 (prior to dose administration), Day 7 and Day 14. Changes in body weights were calculated and recorded. A gross necropsy was performed on all animals whether found dead in extremis (dead no longer than 12 hours) or sacrificed by an injectable barbiturate at the end of the study.

Preliminary study:

As no animals died at 500 mg/kg, one of two animals died at 1000 mg/kg and all animals died at doses of 1500 mg/kg and above, and as a definitive LD50 was not performed, the LD50 of the test substance following a single topical application would be expected to be within the range of 500 to 1500 mg/kg.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 500 - <= 1 500 mg/kg bw

Based on:

test mat.

Remarks on result:

not measured/tested

Mortality:

For the limit test, 8/10 animals died within two hours of dose administration. The remaining animals were found dead at the 24-hour time point. For the range finding test, both animals dosed at 2000 and 1500 mg/kg and one female dosed at 1000 mg/kg died within the first 24 hours. The remaining animals (1000 mg/kg male, both male and female animals dosed at 500 mg/kg and 250 mg/kg) survived to study termination.

Clinical signs:

other: For the limit test, ataxia was observed in 5/10 animals while somnolence was observed in 1/10 animals prior to death. For the range finding test, the male animal dosed at 2000 mg/kg was observed with dyspnea and lethargy prior to death. The surviving ma

Gross pathology:

There were no abnormalities or lesions observed at necropsy for any of the animals.

Other findings:

No irritation at the dose site was observed in the two animals surviving to 24 hours in the limit test. For the range finding test, no irritation was observed at the dose site throughout the study for the two animals dosed at 250 mg/kg. Well-defined erythema was observed in both animals dosed at 500 mg/kg on Day 1, which decreased in severity until resolved in the female at Day 3 and the male at Day 4. The surviving animal dosed at 1000 mg/kg was observed with well-defined erythema on Day 1 and severe erythema on Day 2 which persisted until study termination on Day 14.

Given the results of the preliminary study, a definitive study was not performed.

Interpretation of results:

other: EU criteria: Category 4: Harmful in contact with skin

Conclusions:

Under the conditions of this study the LD50 of the test material following a single topical application would be expected to be within the range of 500 to 1500 mg/kg.

Executive summary:

The acute dermal toxicity of the test material to rabbits was investigated in acordance with the standardised guidelines OECD 402 and EPA OPPTS 870.1200, under GLP conditions. 

The study started with a limit test at 2000 mg/kg. All animals died during the course of the study. The test material was therefore considered toxic at 2000 mg/kg and a range-finding study was commissioned.

In the range-finding study, one male and one female rabbit were dosed at 2000 mg/kg, 1500 mg/kg, 1000 mg/kg, 500 mg/kg and 250 mg/kg. Both rabbits dosed with 2000 mg/kg and 1500 mg/kg and the female rabbit dosed with 1000 mg/kg died in the course of the study. The remaining animals (male rabbit dosed with 1000 mg/kg, male and female rabbits dosed with 500 mg/kg and 250 mg/kg) survived the duration of the study. Per Sponsor, a definitive LD50 study was not performed. Since no animals died at 500 mg/kg, one of the two animals died at 1000 mg/kg, and all animals died at doses of 1500 mg/kg and above, the LD50 of the test material following a single topical application would be expected to be within the range of 500 to 1500 mg/kg. 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

>= 500 - <= 1 500 mg/kg bw

Additional information

Acute oral toxicity

The acute oral toxicity of the test material to female rats was investigated using an Up and Down procedure, in accordance with the standardised guidelines, OECD 425 and EPA OPPTS 870.1100, under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Animals were administered a single dose of the test material by intragastric intubation by means of a ball tip gavaging needle and a syringe. After dosing, the animals were returned to their cage and supplied with feed and water ad libitum.

Under the conditions of the study, the acute oral LD50 of the test material was evaluated to be 550 mg a.i./kg with a 95 % confidence Interval of 114.7 to 824 mg a.i./kg. 

 

Acute dermal toxicity

The acute dermal toxicity of the test material to rabbits was investigated in acordance with the standardised guidelines OECD 402 and EPA OPPTS 870.1200, under GLP conditions. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

The study started with a limit test at 2000 mg/kg. All animals died during the course of the study. The test material was therefore considered toxic at 2000 mg/kg and a range-finding study was commissioned.

In the range-finding study, one male and one female rabbit were dosed at 2000 mg/kg, 1500 mg/kg, 1000 mg/kg, 500 mg/kg and 250 mg/kg. Both rabbits dosed with 2000 mg/kg and 1500 mg/kg and the female rabbit dosed with 1000 mg/kg died in the course of the study. The remaining animals (male rabbit dosed with 1000 mg/kg, male and female rabbits dosed with 500 mg/kg and 250 mg/kg) survived the duration of the study. Per Sponsor, a definitive LD50 study was not performed. Since no animals died at 500 mg/kg, one of the two animals died at 1000 mg/kg, and all animals died at doses of 1500 mg/kg and above, the LD50 of the test material following a single topical application would be expected to be within the range of 500 to 1500 mg/kg. 

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance is classified as Category 4: Harmful if swallowed (H302), and Category 4: Harmful in contact with skin (H312).