3-butoxypropylamine

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26 February 2014 - 28 April 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

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:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-butoxypropylamine

EC Number:

240-566-8

EC Name:

3-butoxypropylamine

Cas Number:

16499-88-0

Molecular formula:

C7H17NO

IUPAC Name:

3-butoxypropylamine

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 8291-11-20
- Expiration date of the lot/batch: 31 December 2014
- Purity: 99.3 wt%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature, 19-26°C
- Stability under test conditions: Test article was not characterized for stability. The impact on the study was considered minimal since an expiration date of 31 December 2014 was provided and the study was conducted within that timeframe.
- Solubility and stability of the test substance in the solvent/vehicle: no data
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: no data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
The test article was dosed as received for the dose level of 550 mg/kg. The specific gravity of 0.8466 g/mL as per the MSDS was factored into the dosing calculations for the dose level of 550 mg/kg. The dose levels of 55 mg/kg and 175 mg/kg were prepared by weighing out the appropriate amount of test article in a graduated cylinder. The vehicle was added to obtain the proper volume and placed on a stir plate for stirring. For all test article preparations at all dose levels, the stock bottle was inverted several times prior to dispensing.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories, Inc.
- Age at study initiation: ~9-14 weeks at start of dosing
Protocol deviation:
The protocol stated that the age range of the animals on study was to be 8-12 weeks. The actual ages of the following animals were out of the protocol range: animal 3855F was ~ 13 weeks, animal 3849 was ~13 weeks, and animal 3850 was ~ 14 weeks. This deviation was not of a magnitude to affect the outcome of the study since the animals were within the protocol stated overall body weight range of 150 - 300 g and were still considered healthy young adults.
- Weight at study initiation: 191 to 250 grams
Protocol deviation:
The protocol stated the body weight ranges for the animals should be ± 20% of the mean initial weight at the outset (Day 1) of the study. Animal 3850 was over 20% of the mean initial weight (body weight was 250 g) of the first animal dosed (3851) which weighed 204 g. This deviation had no impact on the outcome of the study since they were of small magnitude and the animals were just slightly outside of the 20% mean initial weight of the first animal dosed and were still within the overall protocol specified range and all animals were still considered young healthy adults.
- Fasting period before study: yes, animals were fasted overnight prior to dose administration (not longer than 24 hours). Food was returned to the animals 30 minutes (± 15 minutes) after dosing.
- Housing: Animals were housed - group housed by sex upon receipt, individually housed upon assignment to study in compliance with the National Research Council "Guide for the Care and Use of Laboratory Animals." Calvert is a USDA registered and fully AAALAC accredited facility. No other species were kept in the same room.
- Diet (e.g. ad libitum): All animals had access to Harlan Teklad Rodent Diet (certified) ad libitum, except during the fasting period
- Water (e.g. ad libitum): Water was available ad libitum, to each animal via an automatic watering device.
- Acclimation period: A minimum of five days prior to dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C):18 to 27°C
- Humidity (%): 8 to 88%
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark
Protocol deviations:
The protocol required the temperature range in the animal room to be 20-26°C and the relative humidity range to be 30-70%. The temperature range was 18-27°C and the humidity range was 8-88%. Humidity did not record from ~ 12:00 PM on 23 Feb 2014 to ~ 6:00 AM on 28 Feb 2014. These deviations were not of a magnitude or duration to have had an impact on the study since the animals' health was not affected. The temperature and humidity recorder malfunction was considered to have minimal impact on the study since the rooms within the immediate vicinity of the room where the study animals were housed did not experience a major shift from the normal room temperature/humidity ranges during the times that the humidity was not recorded.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

DOSAGE PREPARATION (if unusual): The test article was dosed as received for the dose level of 550 mg/kg. The specific gravity of 0.8466 g/ml as per the MSDS was factored into the dosing calculations for the dose level of 550 mg/kg. The dose levels of 55 mg/kg and 175 mg/kg were prepared by weighing out the appropriate amount of test article in a graduated cylinder. The vehicle was added to obtain the proper volume and placed on a stir plate for stirring. For all test article preparations at all dose levels, the stock bottle was inverted several times prior to dispensing.

Dose volumes were 5 mL/kg (55 mg/kg and 175 mg/kg) and 0.65 mL/kg (550 mg/kg).

Method of study performance:
The first animal was dosed at an initial dose level of 550 mg/kg. Since the animal died, the second animal received 175 mg/kg. Since toxicity at the dose of 175 mg/kg resolved by Day 2, a dose level of 550 mg/kg was administered to an additional female rat. Mortality was observed at 550 mg/kg and dosing continued at a dose level of 175 mg/kg. Mortality was observed and dosing continued at a dose level of 55 mg/kg. Toxicity was not observed so dosing continued at 175 mg/kg. Mortality was observed at 175 mg/kg and dosing continued at 55 mg/kg. Since no mortality was observed at 55 mg/kg, dosing continued at 175 mg/kg. A total of 8 females were dosed. The test continued based on the fixed time interval outcomes of all the animals up to the point and until one of the stopping criteria was met. There were three possible stopping criteria.
- 3 consecutive animals servive at the limit dose;
- 5 reversals occur in any 6 consecutive animals tested;
- or at least 4 animals have followed
Dose progression and stopping criteria were calculated using a dedicated software program [Acute Oral Toxicity (Guideline 425) Statistical Program] provided by the EPA.

Doses:

55, 175 and 550 mg/kg

No. of animals per sex per dose:

55 mg/kg: 2 female rats
175 mg/kg: 4 female rats
550 mg/kg: 2 female rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Morbidity: recorded once daily
Clinical observations: Clinical observations were collected manually. On the day of dosing (Day 1) animals were observed prior to dosing and approximately 30 minutes and 4 hours post-dose. Animals were observed once daily thereafter (Days 2-15).
Body weights - Animal weights were manually recorded prior to dosing on Day 1, and on Days 8 and 15 or upon death
- Necropsy of survivors performed: yes
All surviving rats were sacrificed by CO2 asphyxiation and a gross necropsy was performed at termination of the study and on animals 3851, 3853, 3854, 3849 when the animals were found dead.
The necropsy included examination of the external body surface, all orifices and the cranial, thoracic and abdominal cavities and their contents.
All abnormalities were described completely and recorded. At the completion of necropsy, carcasses were disposed of according to laboratories' SOP.

Statistics:

The LD50 was calculated for the main test (when the data allowed) using the AOT425StatPgm developed by Westat May, 2001 (available via EPA website).

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

175 mg/kg bw

Based on:

test mat.

Mortality:

For the dose of 550 mg/kg: animals 3851 and 3853 were found dead 30 minutes post done.
For the dose of 175 mg/kg: animals 3854 and 3849 were found dead 30 minutes post done. No mortality was observed in the remaining two animals (3852 and 5798) that received this dose level.
For the dose of 55 mg/kg: no mortality was observed in any of the animals.

Clinical signs:

other: Animal 3851F dosed at 550 mg/kg was found dead 30 minutes post dose. The next animal (3852F) was dosed at 175 mg/kg. At 30 minutes post dose, it exhibited abnormal gait and stance, tremors, and decreased body tone. At 4 hours post dose, only abnormal gait

Gross pathology:

Terminal necropsy revealed no visible lesions in the any of the animals receiving test article at 55 mg/kg. Necropsy of animal 3854 treated at 175 mg/kg that was found dead 30 minutes post dose on Day 1, revealed no visible lesions, test article visible in stomach. Necropsy of animal 3849 treated at 175 mg/kg that was found dead 30 minutes post dose on Day 1, revealed intestines dark red. Terminal necropsy of all other animals treated at 175 mg/kg revealed no visible lesions. Terminal necropsy of animal 3851 revealed no visible lesions. Necropsy of animal 3853 that was found dead 30 minutes post dose on Day 1 revealed intestines bright red.

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Based on the results of this study, the estimated oral LD50 for Surfonamine MW 781 in rats is 175 mg/kg and is listed as a GHS Category 3 test article.
Surfonamine MW 781 is classified under HMIS as "2 (Moderately Toxic)", it is an EPA Category II test article, and is WHMIS Controlled: Class D - Toxic. An EEC Risk Phrase of R-25 - Toxic is required for Surfonamine MW 781.