N-[3-(dimethylamino)propyl] C6-9 alkyl amides

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From January 05, 2009 to January 30, 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reference substance 001

Cas Number:

1044764-00-2

Molecular formula:

RCONHCH2CH2CH2N(CH3)2

Test material form:

liquid

Test animals

Species:

rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals
Number of Animals: 9
Sex: Female, nulliparous and non-pregnant.
Species/Strain: Rat/Sprague-Dawley derived, albino.
Age/Body weight: Young adult (9-11 weeks)/160-225 grams at experimental start.
Source: Received from Ace Animals, Inc., Boyertown, PA on December 16 and 30, 2008 and January 13, 2009.

Husbandry
Housing: The animals were singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals DHEW (NIH). Litter paper was placed beneath the cage and was changed at least three times per week.
Animal Room Temperature and Relative Humidity Ranges: 20-21ºC and 15-60%, respectively. The low humidity reading was due to a temporary malfunction of the environmental control system.
Photoperiod: 12-hour light/dark cycle
Acclimation Period: 6-22 days
Food: Purina Rodent Chow #5012
Water: Filtered tap water was supplied ad libitum by an automatic water dispensing system.
Contaminants: There were no known contaminants reasonably expected to be found in the food or water at levels which would have interfered with the results of this study. Analyses of the food and water are conducted regularly and the records are kept in the study fecility.
Cage: Each cage was identified with a cage card indicating at least the study number, dose level, identification and sex of the animal.
Animal: A number was allocated to each rat on receipt and a stainless steel ear tag bearing this number was attached to the rat. This number, together with a sequential animal number assigned to study number 26611, constituted unique identification.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Selection of Animals
Prior to each dosing, experimentally naive rats were fasted overnight by removing the feed from their cages. During the fasting period, the rats were examined for health and weighed (initial). Nine healthy, naive female rats (not previously tested) were selected for test.

Dose Calculations
Individual doses were calculated based on the initial body weights, taking into account the specific gravity (determined by EPSL) of the test substance.

Dosing
The test substance was administered to the stomach using a stainless steel ball-tipped gavage needle attached to an appropriate syringe. Following administration, each animal was returned to its designated cage. Feed was replaced approximately 3-4 hours after dosing.
Initially, a single animal received a limit dose of 5000 mg/kg. Due to the mortality of this animal, a Main Test was conducted. For the Main Test, the test substance was administered to the animals in sequence described below in the table. The decision to proceed with the next animal was based on the survival of the previous animal following dosing.

Doses:

175 mg/kg; 550 mg/kg; 1,1750 mg/kg and 5,000 mg/kg

No. of animals per sex per dose:

Main study:
175 and 550 mg/kg Dose Levels (1 animal each); 1,750 mg/kg Dose Level (3 animals); 5,000 mg/kg Dose Level (4 animals)

Control animals:

no

Details on study design:

Body Weights
Individual body weights of the animals were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination) following dosing or after death.

Cage-Side Observations
The animals were observed for mortality, signs of gross toxicity, and behavioral changes during the first several hours post-dosing and at least once daily thereafter for 14 days after dosing or until death occurred (see Section 9). 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
Surviving rats were euthanized via CO2 inhalation at the end of the 14-day observation period. Gross necropsies were performed on all decedents and euthanized animals. Tissues and organs of the thoracic and abdominal cavities were examined.

Statistics:

The Acute Oral Toxicity (Guideline 425) Statistical Program (Weststat, version 1.0, May 2001) was used for all data analyses including: dose progression selections, stopping criteria determinations and/or LD50 and confidence limit calculations.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 129 mg/kg bw

Based on:

test mat.

95% CL:

> 1 750 - < 5 000

Remarks on result:

other: female

Mortality:

175 and 550 mg/kg Dose Levels (1 animal each): both animals survived.
1,750 mg/kg Dose Level (3 animals): all animals survived test substance administration.
5,000 mg/kg Dose Level (4 animals): all animals died within three hours of test substance administration.

Clinical signs:

other: 175 and 550 mg/kg Dose Levels (1 animal each): both animals appeared active and healthy during the study. 1,750 mg/kg Dose Level (3 animals): following administration, one animal was hypoactive and exhibited facial staining. All animals exhibited ano-gen

Gross pathology:

175 and 550 mg/kg Dose Levels (1 animal each): there were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior. No gross abnormalities were noted for these animals when necropsied at the conclusion of the 14-day observation period.
1,750 mg/kg Dose Level (3 animals): no gross abnormalities were noted for the animals when necropsied at the conclusion of the 14-day observation period.
5,000 mg/kg Dose Level (4 animals): gross necropsy of the decedents revealed red intestines.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the study conditions, the acute oral LD50 of the test substance was estimated to be 3129 mg/kg bw in female rats (based on an assumed sigma of 0.5) with an approximate 95% PL confidence interval of 1750 mg/kg (lower) to 5000 mg/kg (upper).

Executive summary:

A study was conducted to determine the potential for the test substance to produce toxicity from a single dose via the oral route according to OECD Guideline 425 and EPA OPPTS Method 870.1100, in compliance with GLP. An initial limit dose of 5000 mg/kg bw was administered to one healthy female rat by oral gavage. Due to mortality in this animal, the study proceeded to the main test using the default starting level of 175 mg/kg bw and following the up and down procedure, eight additional females were dosed at levels of 175, 550, 1750 or 5000 mg/kg bw. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 d after dosing or until death occurred. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing or after death. Necropsies were performed on all animals. Under the study conditions, the acute oral LD50 of the test substance was estimated to be 3129 mg/kg bw in female rats (based on an assumed sigma of 0.5) with an approximate 95% PL confidence interval of 1750 mg/kg (lower) to 5000 mg/kg bw (upper) (Oley, 2010).