Tripropylamine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No GLP. Acceptable well documented publication which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

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

Author:

Lynch, D., W., Moorman, W., J., Lewis, T.,R., Stober, P., Hamlin, R., D., and Schueler, R., L.

Year:

1990

Bibliographic source:

Toxicology and Industrial Health 6(3/4): 403-414.

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

yes

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

yes

Principles of method if other than guideline:

In the present study only two dose levels were used in addition to the concurrent control group. The duration of the study is 28 weeks. Not all examinations are performed.

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:

CAS 121-44-8 (triethylamine), purity >99.9% was obtained from MCB Manufacturing Chemists, Inc., Norwood, OH
Lot number G3M04

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Strain: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.
- 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): except during the exposure periods.
- Water (e.g. ad libitum): except during the exposure periods.
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 12-15/hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

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

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25 and 247 ppm  (0, 103 and 1020 mg/m³)
Basis:
nominal conc.

No. of animals per sex per dose:

50/sex/dose

Control animals:

yes

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: Twice daily observations were made for changes in appearance or demeanor. Body weights were recorded on the day preceding the first day of exposure, at 2-week intervals throughout the study (at the end of an exposure day), and immediately prior to scheduled sacrifice.

Sacrifice and pathology:

10/sex/treatment sacrificed after ~30 and ~60 days of exposure, 20 after  ~ 125 days of exposure (10 in controls) 

GROSS PATHOLOGY: Yes
A complete necropsy was performed, and lungs, liver, kidneys, and heart were weighed.

HISTOPATHOLOGY: Yes
The following tissues were examined histologically: lungs (following infusion with 10% formalin), liver, kidneys, heart, spleen, tracheobronchial lymph nodes, adrenals, urinary bladder, testes, seminal vesicles, uterus, ovaries, trachea, eyes and nasal passages (processed and cut as described by Buckley et al. 1985).

Other examinations:

Clinical Chemistry-Hematoiogy:
The following clinical chemistry indices were measured at each scheduled sacrifice on a Gemsaec Centrifugal Analyzer (Electro-Nucleonics, Inc., Fairfield, NJ): alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CPK), blood urea nitrogen (BUN), creatinine (CRE) and sorbitol dehydrogenase (SDH). Hematology evaluations, conducted only at the terminal sacrifice, included hemoglobin, hematocrit, complete blood count and differential;

ECG were recorded at terminal sacrifice in 9-11 rats/sex/treatment

Statistics:

Multiple t-tests were used to compare initial body weights, while a multivariate analysis of variance was used to compare weight gains at each additional weighing period. Organ weights, organ-to-body weight ratios, hematology, clinical chemistry and electrocardiographic indices of the groups were compared by sex and length of exposure using the Kruskal-Wallis test (Hollander and Wolfe, 1973). Pathology incidence data were evaluated using a x² test. All comparisons between control and exposed animals were made at a statistical significant level of a = 0.05. Results were considered significant when p < 0.05.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

clinical signs

Mortality:

mortality observed, treatment-related

Description (incidence):

clinical signs

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

no statistical difference

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

only sporadic changes

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

no statistical difference

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

no statistical significance

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

but unrelated to chemical exposure

Details on results:

CLINICAL SIGNS AND MORTALITY:
Rats of both sexes tolerated the exposure at 25 ppm without exhibiting overt signs of toxicity. At 247 ppm TEA the rats kept their eyes closed and noses buried in their fur during the entire exposure period.
All rats survived the exposures except for one female rat in the 25 ppm TEA group which was sacrificed due to malocclusion (week 6), two 250 ppm TEA female rats which died following an accidental injury (week 3), and one 250 ppm male rat which died during the exposure period (week 8). These deaths could not be attributed to TEA exposure.

BODY WEIGHT AND WEIGHT GAIN
Body weight was not statistically affected; however there was a slight dose-related reduction which occured in the TEA exposed male rats compared to the control

HAEMATOLOGY
Hematologic analyses revealed no statistical differences in male or female rats exposed to TEA for 28 weeks.

CLINICAL CHEMISTRY
Several clinical chemistry indices, i.e. SDH, ALT and creatinine, were elevated in one group of rats, or in only one sex of rats, at one of the scheduled interim sacrifices. These changes were not attributed to TEA exposure since they were sporadic in occurence and not concentration related.

ORGAN WEIGHTS
No consistent statistically significant differences in absolute or relative organ weights were seen in rats exposed to TEA and killed at any of the sceduled sacrifices. Lung weights and lung-to-body weight ratios were increased in all four groups of male and female rats exposed to TEA for 28 weeks, and absolute heart weights were increased in both groups of male rats exposed to TEA for the same period.

GROSS PATHOLOGY
There were no gross pathologic observations in rats which were considered to be related to treatment.

HISTOPATHOLOGY: NON-NEOPLASTIC
Chronic inflammation of the lungs was seen in all treated and control animals  exposed for 28 weeks. Liver lesions consisiting of minimal foci of necrosis were detected in males of all three groups exposed for 28 weeks. Minimal focal necrosis of myofibers of the heart was observed in males at 25 ppm after 125 exposures.

HISTOPATHOLOGY: NEOPLASTIC
Neoplastic lesions included nephroblastoma in one female at 25 ppm after 30  exposures, one pituitary adenoma in one male at 247 ppm after 125 exposures, and one thyroid follicular cell adenoma in one control female after 125 exposures.

OTHER FINDINGS: ELECTROPHYSIOLOGY:
No statistically significant differences were observed in any of the indices which were recorded and analyzed from rats exposed to either TEA concentration for 28 weeks.

Effect levels

1

Dose descriptor:

NOAEC

Remarks:

systemic effects

Effect level:

1 020 mg/m³ air

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No statistically significant effects or effects related to treatment were observed in any parameter tested

2

Dose descriptor:

NOAEC

Remarks:

local effects and irritation

Effect level:

103 mg/m³ air

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no effects

3

Dose descriptor:

LOAEC

Remarks:

eyes and nose irritation

Effect level:

1 020 mg/m³ air

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: irritation effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Vapor Exposure:

The TEA chamber concentrations for the 28-week exposure period were 24.8 ± 1.3 and 247.3 ± 11.5 (x ± SD). Rats were exposed at 25 or 247 ppm TEA for a maximum of 127 days, with an average of 5.80 and 5.82 hrs of exposure per day, respectively.

Cardiotoxicity:

There was no cardic muscle degenerations or any changes in electrocardiogramms.

Applicant's summary and conclusion

Conclusions:

Triethylamine did not induce systemic toxicity in rats if inhaled.

Executive summary:

Male and female F-344 rats 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 for local effects and irritation, while 247 ppm, the highest concentration tested (corresponds to 1020 mg/m³), repesents a NOAEC for systemic effects and simultaneously a LOAEC for eye and nose irritation.