Pyridine, 2-methoxy-4-(trifluoromethyl)-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January 6 - February 11, 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Conducted to GLP and recognised guidelines.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: Dow Protocol No: P320.UDP DOW

Deviations:

not applicable

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-methoxy-4-(trifluoromethyl)pyridine

EC Number:

606-870-3

Cas Number:

219715-34-1

Molecular formula:

C7H6F3NO

IUPAC Name:

2-methoxy-4-(trifluoromethyl)pyridine

Details on test material:

- Name of test material (as cited in study report): M-TMP
- Physical state: colourless liquid
- Analytical purity: 99.7%
- Lot/batch No.: 041206-7D
- Expiration date of the lot/batch: n/a
- Stability under test conditions: Test substance was expected to be stable for the duration of testing.
- Storage condition of test material: room temperature
- pH: 6-7 (by wetted pH paper)
- Solubility: Soluble in methanol, ethanol, and acetone.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Received from Charles River Laboratories, Raleigh, NC on December 7 and 28, 2004 and January 11, 2005.
- Age at study initiation: Young adult (9-12 weeks)
- Weight at study initiation: 1128-144 grams at experimental start.
- Fasting period before study: fasted overnight
- 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 Labora aty Animals DHEW (NIH), Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet (e.g. ad libitum): Purina Certified Rodent Diet (PAR 115002)
- Water (e.g. ad libitum): Filtered tap water was supplied ad-libitum by an automatic water dispensing system.
- Acclimation period: 8-31 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24°C
- Humidity (%): 30-66%
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DOSAGE PREPARATION:
Individual doses were calculated based on the initial body weights, taking into account the specific gravity (determined by PSL) of the test substance.
The test substance was administered 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 immediately after dosing.

Doses:

Individual animals were dosed as follows:

Main Test
Dosing Sequence Animal No. Dose Level (mg/kg) Short-Term Outcome Long-Term Outcome
1 9995 175 S S
2 108 550 S S
3 123 1,750 S S
4 134 5000 D D
5 326 1,750 D D
6 471 550 S S
7 478 1,750 D D
8 568 550 S S
9 628 1,750 D D

S - Survival D - Death

The test substance was administered in sequence to the animals as described above, The decision to proceed with the next animal was based on the survival of the previous animal in the short-term period following dosing. Dose progressions and stopping criteria were determined using A statistical program.

No. of animals per sex per dose:

A total of 9 Female, nulliparous and non-pregnant rats were used in this study. (175 mg/kg = 1 animal; 550 mg/kg = 3 animals, 1750 mg/kg = 4 animals, 5000 mg/kg = 1 animal)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for mortality, signs of gross toxicity, and behavioral changes for the first several hours post-dosing and at least once daily thereafter for up to 14 days after dosing. 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.
Individual body weights of the animals were recorded prior to test substance administration (initial) and again on Days 7 and 14 (termination).
- Necropsy of survivors performed: yes
- Other examinations performed: 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. The external surface of the body and all orifices, 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 calcuations.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

1 750 mg/kg bw

Based on:

act. ingr.

95% CL:

651.9 - 2 690

Mortality:

In the 175 & 550 mg/kg Dose Levels, all animals survived exposure to the test substance.
In the 1,750 mg/kg Dose Level, three of four animals died within three days of test substance administration.
In the 5,000 mg/kg Dose Level, this animal died within one day of test substance administration.

Clinical signs:

other: In the 175 & 550 mg/kg Dose Levels, there were no signs of gross toxicity, adverse clinical signs, or abnormal behavior. In the 1,750 mg/kg Dose Level, adverse clinical signs noted prior to death included abnormal posture, hypoactivity, reduced fecal vol

Gross pathology:

In the 175 & 550 mg/kg Dose Levels, no gross abnormalities were noted for this animal when necropsied at the conclusion of the 14-day observation period,
In the 1,750 mg/kg Dose Level, gross necropsy of the decedents revealed discoloration of the intestines. No gross abnormalities were noted for any of the surviving animals when necropsied at the conclusion of the 14-day observation period.
In the 5,000 mg/kg Dose Level, gross necropsy of the decedent revealed discoloration of the intestines.

Any other information on results incl. tables

Individual body weights, closes, and mortalities are presented in Table 1. Individual cage-side and necropsy observations are presented in Tables 2 and 3, respectively.

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the acute oral LD50 of M-TMP was estimated to be 1,750 mg/kg of body weight in female rats with an approximate 95% confidence interval of 651.9 mg/kg (lower) to 2,690 mg/kg (upper).

Executive summary:

An acute oral toxicity test (Up and Down Procedure) was conducted with rats to determine the potential for M-TMP to produce toxicity from a single dose via the oral route. Under the conditions of this study, the acute oral LD50 of the test substance was estimated to be 1,750 mg/kg of body weight in female rats with an approximate 95% confidence interval of 651.9 mg/kg (lower) to 2,690 mg/kg (upper).

A Main Test was conducted using a starting dose level of 175 mg/kg which was administered to one healthy female rat by oral gavage. Following the up and down procedure, eight additional animals were dosed at levels of 550, 1,750, or 5,000 mg/kg. 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 up to 14 days after dosing. Body weights were recorded prior to administration, on Days 7 and 14 (termination). Necropsies were performed on all animals.