4-chloro-N-methylpiperidine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data is from NTRL

Data source

Reference

Reference Type:

publication

Title:

Subchronic inhalation of triethylamine vapor in Fisher-344 rats: organ system toxicity

Author:

NTRL

Year:

1987

Bibliographic source:

NTRL ,source; OTS0515254, 1987

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

To evaluate the toxic potential of Triethylamin in Fischer 344 male and female rats by chronic inhalation.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triethylamine

EC Number:

204-469-4

EC Name:

Triethylamine

Cas Number:

121-44-8

Molecular formula:

C6H15N

IUPAC Name:

N,N-diethylethanamine

Details on test material:

- Name of test material (as cited in study report): Triethylamin
Substance Type : Organic

Specific details on test material used for the study:

- Name of test material (as cited in study report): Triethylamin
Purity ; 99.9%

Test animals

Species:

rat

Strain:

Fischer 344

Details on species / strain selection:

Weanling caesarean-derived Fisher F344 [CDF (F-344)/Crl BR]Rats were screened for serological evidence of Mycoplasma pulmonis infection prior to the initiation of exposures and all results were negative.-

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source: Charles River breeding Laboratories, Wilmington MA- Age at study initiation: not reported- Weight at study initiation: not reported
- Fasting period before study: no
- Housing: individually
- Diet (e.g. ad libitum): PURINA LABORATORY CHOW. RALSTON PURINA. ST. LOUIS, MO ad libitum, except during the exposure periods
- Water (e.g. ad libitum): tap water ad libitum ; except during the exposure periods
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±3°C
- Humidity (%):50±lO% R
- Air changes (per hr): 12-15/hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

not specified

Remarks on MMAD:

Not specified.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION- Exposure apparatus: Exposures were conducted in three 4.5 m³ stainless steel and glass inhalation chambers (Hinners et al., 1968) operated under dynamic flow conditions.- Temperature, humidity in air chamber: 23 ± 3°C and 50 ± 10% RH, respectively.- Air flow rate: 12-15 air changes per hr- Treatment of exhaust air: A fresh batch of TEA was used in the generation reservoir each day.

TEST ATMOSPHERE- Brief description of analytical method used: Wilks-Miran 1A Infrared Analyzer (Foxboro Analytical, Norwalk, CT) using the following instrument settings: wavelength 9 µm, pathlength 6.2 m, slit 1.0 mm. The instrument was calibrated by the closed loop calibration method. Adjustments were made to the generation system, as required, to maintain the exposure levels at the targeted concentrations.- Samples taken from breathing zone: yes. TEA concentrations in the chamber were monitored 2-4 times per hour using a Wilks-Miran 1A Infrared Analyzer (Foxboro Analytical, Norwalk, CT)

VEHICLE (if applicable) no

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

2-4 times/hour with a Wilks-Miran Infrared Analyzer

Duration of treatment / exposure:

28 weeks

Frequency of treatment:

6 hours/day, 5 days/week 127 maximum exposure days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm (nominal)

Remarks:

(0 mg/m3)

Doses / concentrations 2

Dose / conc.:

25 ppm (nominal)

Remarks:

103 mg/m3

Doses / concentrations 3

Dose / conc.:

247 ppm (nominal)

Remarks:

1020 mg/m3

No. of animals per sex per dose:

50/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Exposure concentrations were selected to provide comparisons to previous toxicity determinations conducted in this laboratory with diethylamine at 25 and 250 ppm (Lynch et al., 1986).
- Rationale for animal assignment (if not random): randomised

Positive control:

No

Examinations

Observations and examinations performed and frequency:

Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: The day preceding the first day of exposure and at 2-week intervals throughout the study

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available.


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available.


OPHTHALMOSCOPIC EXAMINATION: No data available.


HAEMATOLOGY: Yes
- Parameters checked in table [No.?] were examined; Hemoglobin, hematocrit, complete blood count and differential count.


CLINICAL CHEMISTRY: Yes
- Parameters checked in table [No.?] were examined. Alanine
aminotransferase ,Aspartate aminotransferase, creatine
phosphokinase ,blood urea nitrogen (bun), creatinine (cre) and
sorbital dehydrogenase

Organ weight: Yes

URINALYSIS: Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified

OTHER: ECG were observed from 10 anesthetized rats/sex/group
cketamine/xylazine, ip) at the terminal sacrifice. data were recorded with rats lying in a prone position using an electronics for medicine dr-12 photographic oscillograph (white plains, ny). ecg waveforms were sampled and analyzed using a healthgard cpt-s computer system (salt lake city, ut).leads i, ii and iii. avr. avl, and AVF were recorded from each animal for five sec durations. heart rate, axes and amplitudes of the P wave. QRS complex, and T wave, as well as durations of various intervals. Were computed and compared among exposure groups. Each ECG tracing was also evaluated "in blind" by a veterinary cardiologist.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes , Ten male and ten female rats were randomly- selected and sacrificed (35 mg/kg
pentobarbital sodium. ip after 30 and 60 days of exposure, 20 after 125 days of exposure (10 in controls) . Prior to sacrifice they were fasted overnight.A complete gross necropsy was performed and lungs, liver, kidney, and heart were weighed.

Histopathology: Yes ,lungs, liver, heart, spleen, kidneys, tracheobronchial lymphnodes, adrenals, urinary bladder, testes, seminal vesicles, uterus, ovaries, trachea, eyes, nasal passages were observed.

Statistics:

t-test, multivariate analysis of variance, Kruskal-Wallis and chi-square test

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 247 ppm animals closed eyes and noses buried in fur in treated group .No statistically significant effect were observed at the dose level of 25 ppm in treated group compare to control.

Mortality:

mortality observed, treatment-related

Description (incidence):

1 female at 25 ppm (week 6), 1 male(week 8) and 2 females (week 3)(both accidentally) at 247 ppm Clinical .No statistically significant effect were observed at the dose level of 25 and 247 ppm in treated group compare to control.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

No statistically significant effect were observed at the dose level of 25 and 247 ppm in treated group compare to control.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

No statistically significant effect were observed at the dose level of 25 and 247 ppm in treated group compare to control.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

No statistically significant effect were observed at the dose level of 25 and 247 ppm in treated group compare to control.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

No statistically significant effect were observed at the dose level of 25 and 247 ppm in treated group compare to control.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

No statistically significant effect were observed at the dose level of 25 and 247 ppm in treated group compare to control.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

No statistically significant effect were observed at the dose level of 25 and 247 ppm in treated group compare to control.

Histopathological findings: neoplastic:

not specified

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Electrophysiology; No statistically significant effect were observed at the dose level of 25 and 247 ppm in treated group compare to control.

Effect levels

Dose descriptor:

NOAEC

Effect level:

25 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

gross pathology

haematology

mortality

neuropathology

organ weights and organ / body weight ratios

other: ECG

Remarks on result:

other: No inhalatory toxic effect were observed.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The NOAEC was also refered as 103.3 mg/m³(25 ppm) as per study .

Applicant's summary and conclusion

Conclusions:

NOAEC was considered to be 25 ppm (corresponds to 103.3 mg/m³) for Triethylamin(121-44-8) in male and female F-344 rats by oral inhalation.

Executive summary:

A repeated inhalation study for Triethylamin was conducted inmale and female F-344 rats . They were exposed at 0, 25, or 247 ppm triethylamine (TEA) vapor, 6 hr per day, 5 days per week for up to 28 weeks in order to characterize the subchronic organ system toxicity. Rats were weighed biweekly and scheduled sacrifices were performed following about 30, 60, and 120 days of exposure. No statistically significant treatment-related effects on organ weights, hematology, clinical chemistry, or electrocardiographic indices were observed. Body weight gain was not affected by TEA treatment. No physiologic or pathologic evidence of cardiotoxicity was seen in rats exposed to either TEA concencentrations for up to 28 weeks. No gross or histopathological lesions attributable to TEA exposure were noted in any of the organs examined, including the nasal passages.Based on the study results 25 ppm (corresponds to 103.3 mg/m³) is considered to be a NOAEC forTriethylamin . Hence the substance can not be classified as toxicant.