N,N-dimethyl-p-toluidine

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from authoritative databases

Data source

Reference

Reference 1

Reference Type:

other: authoritative database

Title:

Hazardous Substances Data Bank

Author:

U.S. National Library of Medicine

Year:

2015

Bibliographic source:

HSDB

Reference 2

Reference Type:

other: authoritative database

Title:

Acute Inhalation Toxicity - Test chemical

Author:

U.S. National Library of Medicine

Year:

2018

Bibliographic source:

ChemIDplus

Reference 3

Reference Type:

review article or handbook

Title:

Summary of Data for Chemical Selection

Author:

NTP

Year:

1999

Bibliographic source:

NTP

Reference 4

Reference Type:

other: secondary source

Title:

Test Substance - Acute Toxicity

Author:

United States Environmental Protection Agency

Year:

2019

Bibliographic source:

HPVIS

Reference 5

Reference Type:

secondary source

Title:

Acute toxicity study of test chemical was performed in rodents.

Author:

NTRL

Year:

1997

Bibliographic source:

NTRL REPORT,1997

Reference 6

Reference Type:

other: secondary database

Title:

Human health tier II assessment.

Author:

NICNAS

Year:

2019

Bibliographic source:

NICNAS

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Acute inhalation toxicity study of the test chemical was performed in rat.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N-dimethyl-p-toluidine

EC Number:

202-805-4

EC Name:

N,N-dimethyl-p-toluidine

Cas Number:

99-97-8

Molecular formula:

C9H13N

IUPAC Name:

N,N,4-trimethylaniline

Details on test material:

- IUPAC Name: N,N-dimethyl-p-toluidine
- InChI: 1S/C9H13N/c1-8-4-6-9(7-5-8)10(2)3/h4-7H,1-3H3
- Smiles: c1(N(C)C)ccc(C)cc1
- Molecular formula :C9H13N
- Molecular weight :135.209 g/mole
- Substance type:organic
- Physical state:Clear colorless Liquid
- Purity: 99%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Animals for this study were received in two shipments. Animals from the first shipment were used for the first three exposures and those from the second shipment were used for the fourth exposure.
- Age at study initiation: At arrival, the rats were approximately 36-43 days of age. The rats were approximately 43-58 days of age at exposure.
- Weight at study initiation: The body weight ranges at arrival were 121-158 g for male rats and 124-143 g for female rats from the first shipment and 130-156 g for male rats and 126-160 g for female rats from the second shipment.
- Housing: During the quarantine, exposure, and post-exposure observation periods, the rats were housed individually in stainless steel cages (18.4 x 16.5 x 15.9 cm).
- Diet (e.g. ad libitum): The NIH-07 open formula pellet diet, ad libitum
- Water (e.g. ad libitum): Water from an automatic watering system, ad libitum
- Acclimation period: The animals were held in quarantine for at least one week before use.
ENVIRONMENTAL CONDITIONS
- Temperature (°C):18-25°C
- Humidity (%):28-63%RH
- Photoperiod (hrs dark / hrs light): Fluroscent lighting was provided automatically on a 12 hours light : 12 hours dark schedule.

Administration / exposure

Route of administration:

inhalation: mixture of vapour and aerosol / mist

Type of inhalation exposure:

whole body

Vehicle:

not specified

Mass median aerodynamic diameter (MMAD):

> 0.23 - <= 0.57 µm

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass Rochester-type inhalation exposure chamber
- Exposure chamber volume: 500 liter
- Source and rate of air: Conditioned room air, which was passed through coarse and HEPA filters before entering the exposure chamber, was used as supply air.
- Method of conditioning air: The air was passed through coarse and HEPA filters.
- System of generating particulates/aerosols: Test atmospheres of the chemical were generated by aerosolizing the test substance and approximately diluting the aerosols with filtered air. Test chemical aerosols were generated by a stainless-steel aspirator device (Laskin type) for the two higher exposure concentrations (5.27 and 1.73mg/l} and a modified commercial nebulizer (DeVilbiss, Mode! 40, Somerset, PA) for the two lower exposure concentrations (0.99 and 0.30 mg/l).
The Laskin fixture consisted of 1/4-inch diameter stainless-steel tube with two to four orifices spaced evenly around the periphery. At each orifice & 1/16-inch diameter stainless-steel aspirator tube was attached for delivery of the test substance. The test material was delivered from 3 reservoirs to the aspirator (by head pressure and suction) through Teflon tubing and a manifold equipped with a metering valve. The output of the generator was directed against an impaction surface to remove coarse particles and control particle size. Aerosol concentration was maintained at a constant level by adjusting air pressure to the aspirator and delivery rate of the test material.
- Method of particle size determination: Aerosol particle size was monitored with a Guartz Crystal Microbalance cascade impactor (California Measurements, inc., Sierra Madre, CA).
- Treatment of exhaust air: Chamber exhaust was passed through a HEPA filter.
- Temperature, humidity, pressure in air chamber: Chamber temperature and relative humidity were monitored with an electronic thermo hygrometer. The chamber airflow rate was monitored continuously with a Calibrated differential pressure gauge. Chamber temperature, relative humidity and airflow rate were recorded at approximately 30 min. intervals during tie exposures. The chamber oxygen concentration was Measured at least three times during the exposures using a Lynn Model 6200 or servomex Series 1490 oxygen analyzer.

TEST ATMOSPHERE
- Brief description of analytical method used: The sampling train consisted of a pre-weighed filter in series with two mini impingers filled with isopropyl alcohol connected to a constant flow vacuum pump. The filter and impinger samples were analyzed by a gas chromatographic method provided by the Sponsor and modified by quantitatively determine the amount of test substance. A dry-gas meter connected to the positive pressure side of the pump was used to record the corresponding volume of chamber air sampled and the weight to volume ratio was determined. In addition appropriate real-time sensors (aerosol sensor for the two high exposure levels and an infrared vapor sensor for the two low exposure levels) were used to monitor exposure concentrations. These sensors were used only as continuous indicators of short term changes In exposure concentration to guide laboratory personnel in correcting concentration excursions.
- Samples taken from breathing zone: yes, Mass concentration of test chemical in the breathing zone of the rats was determined chemically by analyzing filter samples (aerosol phase collection) and impinger samples (vapor phase collection) collected once each hour during the exposure.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5.27, 1.73, 0.99, and 0.30 mg/l.

No. of animals per sex per dose:

four treatment groups of five male and five female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All rats were observed carefully for signs af toxicity immediately after removal from the exposure chamber and at least once per day during the 14-day observation period. To the maximum extent possible, animals were also observed during the exposures. During the two highest concentration exposures, most or all rats could not be adequately observed to allow any documentation of clinical signs.
Body Weights: All test rats were weighed immediately before exposure, on post-exposure day 7 and just before necropsy.
- Necropsy of survivors performed: yes, All test animals found dead were subjected to gross necropsy. At the end of the 14-day observation period, all surviving rats were euthanized following an intraperitoneal injection of sodium pentobarbital or CO2 asphyxiation (by exsanguination) and subjected to gross necropsy. The necropsy included examination of all body surfaces and openings and of the external surface of the brain, heart, lungs end respiratory tract, liver, Spleen, kidneys, adrenals, gastrointestinal tract, gonads and urinary bladder. The gastrointestinal tract and urinary bladder were opened and examined if lesions were observed.

Statistics:

not specified

Results and discussion

Preliminary study:

Animals were initially exposed to a target concentration of 5 mg/I. Target concentrations for the three subsequent exposures were selected based on mortality due to this initial
exposure end the results of each subsequent exposure.

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1.4 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Mortality occurred as – At 5.27 mg/l – All animals found dead;
At 1.73 mg/l – 3 males and 5 females found dead and no mortality was observed at 0.30 and 0.99 mg/l.

Clinical signs:

other:

Body weight:

For the 5.27, 1.73, 0.99 and 0.30 mg/! exposure groups, MEAN pre-exposure body weights ranged from 137 to 262 g for male rats and 169 to 1392 g for female rats.
For male survivors of exposure to 1.72 mg/l and male and female Survivors of exposure to 0.99 or 0.20 mg/l (all rats), weight gain was observed during both the first and second weeks of the observation period. Mean cumulative weight gain ranged from 73 to 91 g for male rats and 28 to 33 g for female rats.

Gross pathology:

No gross lesions were found in animals exposed to 0.99 or 0.30 mg/l. In rats exposed to the two higher concentrations, mottled lungs and red ovaries were frequently found and may have been exposure-related. Several rats from these groups also had gas-filled gastrointestinal organs. A few other lesions were observed in individual rats, but were not considered to be toxicologically significant.

Other findings:

not specified

Applicant's summary and conclusion

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

Acute inhalation toxicity dose (LC50) value was considered to be 1.4 mg/L (1400 mg/m3), when 40 male and female Sprague-Dawley rats were treated with the given test chemical via inhalation route to whole-body exposure by aerosol/vapor for 4-h period.

Executive summary:

Acute inhalation toxicity study was conducted by using the given test chemical in 40 Sprague-Dawley rats at the doses of 5.27, 1.73, 0.99, and 0.30 mg/l via inhalation route to whole-body exposure by aerosol/vapor for 4-h period. Animals were initially exposed to a target concentration of 5 mg/I. Test concentrations for the three subsequent exposures were selected based on mortality due to this initial exposure end the results of each subsequent exposure.All rats were observed carefully for signs af toxicity immediately after removal from the exposure chamber and at least once per day during the 14-day observation period. To the maximum extent possible, animals were also observed during the exposures. During the two highest concentration exposures, most or all rats could not be adequately observed to allow any documentation of clinical signs.All test rats were weighed immediately before exposure, on post-exposure day 7 and just before necropsy. All test animals found dead were subjected to gross necropsy. At the end of the 14-day observation period, all surviving rats were euthanized following an intraperitoneal injection of sodium pentobarbital or CO2 asphyxiation (by exsanguination) and subjected to gross necropsy. The necropsy included examination of all body surfaces and openings and of the external surface of the brain, heart, lungs end respiratory tract, liver, Spleen, kidneys, adrenals, gastrointestinal tract, gonads and urinary bladder. The gastrointestinal tract and urinary bladder were opened and examined if lesions were observed. Mortality occurred as – At 5.27 mg/l – All animals found dead; At 1.73 mg/l – 3 males and 5 females found dead and no mortality was observed at 0.30 and 0.99 mg/l.Clinical signs in rats exposed to 1.73 mg/l included hypo activity, a comatose / prostrate condition, dyspnea or rapid respiration and salivation. Other incidental signs observed for some animals from this group included urine stains, eye discharge, ptosis, limb paralysis, nasal discharge, red material around the nose and red material around the eyes. The most frequently observed signs in rats exposed to 0.99 or 0.30 mg/l were nasal discharge and red material around the nose. Two male rats and one female rat from the 0.30 mg/l group were also reported to have dyspnea immediately after the exposure. Rats exposed to one of the two lower concentrations were free of signs by 1-2 days post-exposure.For the 5.27, 1.73, 0.99 and 0.30 mg/! exposure groups, MEAN pre-exposure body weights ranged from 137 to 262 g for male rats and 169 to 1392 g for female rats.

For male survivors of exposure to 1.72 mg/l and male and female Survivors of exposure to 0.99 or 0.20 mg/l (all rats), weight gain was observed during both the first and second weeks of the observation period. Mean cumulative weight gain ranged from 73 to 91 g for male rats and 28 to 33 g for female rats. No gross lesions were found in animals exposed to 0.99 or 0.30 mg/l. In rats exposed to the two higher concentrations, mottled lungs and red ovaries were frequently found and may have been exposure-related. Several rats from these groups also had gas-filled gastrointestinal organs. A few other lesions were observed in individual rats, but were not considered to be toxicologically significant. Under the condition of the study, the LC50 value was considered to be 1.4 mg/L (1400 mg/m3), when 40 male and female Sprague-Dawley rats were treated with the given test chemical via inhalation route to whole-body exposure by aerosol/vapor for 4-h period.