Bis(2-dimethylaminoethyl)(methyl)amine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study, with acceptable restrictions (14-day-exposure only)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

PMDETA

IUPAC Name:

PMDETA

Test material form:

other: vapour

Details on test material:

Pale yellow liquid
Molecular Weight: 173.3 daltons
Boiling Point: 203.5 °C
Vapor Pressure: 0.422 mmHG @ 2S°C
PMDETA was obtained from the BASF Corporation, Parsippany, New Jersey (Lot #6872641).
Analysis by GC-MS and infrared spectroscopy conducted by the analytical laboratories of the Dow Chemical Company, Midland, Michigan.
The compositional analysis :
N,N,N',N",N´´-Pentamethyldiethylenetriamine 99.1 %
tetramethyldiethylenetraimine (2 isomers) 0.4%
N,N,N´-trimethylethylenediamine 0.1 %

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source: B Charles River Breeding Laboratories, Inc., Kingston, New York.
Acclimating period: 2 weeks prior to exposure
Water and Purina Certified Rodent Chow tf5002 (Riilston Purina Co., St. Louis, Missouri) available ad libitum, except during exposures.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

Rats (5/sex/exposure group)
Exposure: 6 hours/day, 5 days/week.
Number of exposures: 9 exposures in the 0, 3, and 12 ppm groups; 5 exposures in the 48 ppm group.
Chamber airflow maintained at approximately 225 liter/minute.
The air supplied to the chambers controlled by a system designed to maintain temperature at approximately 22°C and relative humidity at approximately 50%.
The temperature and relative humidity in each chamber were recorded approximately hourly during each exposure period.
Vapors of the liquid test material were generated using a J-tube assembly as described by Miller et al. (1980).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The nominal concentration was calculated for each chamber on a daily basis. The analytical chamber concentrations were determined at least 3 times/ exposure period by GC with a flame ionization detector (Varian 1400, Palo Alto, California).
The GC conditions were nitrogen flow = 100 ml/minute, hydrogen flow = 30 ml/minute, and air flow = 300 ml/minute.
A 6' x 1 /8" stainless steel column packed with 10% OV-11 on 100/120 Supelcoport (lot # F16243) was used to separate the test material from air.

Duration of treatment / exposure:

6 hours / day

Frequency of treatment:

5 days / week, 2 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0,3,12, or 48 ppm (0,21,85, or 340 mg/m3)
Basis:
analytical conc.

No. of animals per sex per dose:

5

Control animals:

yes, concurrent no treatment

Details on study design:

Duration of exposure - up to 14 days
- Frequency of observations: daily
- Examinations performed: necropsy, histopathology of major organs and tissues, urinalysis, hematology, and clinical chemistry determinations, body weights, major organs weighed.

Positive control:

---

Examinations

Observations and examinations performed and frequency:

All rats were observed after each exposure period for changes in appearance and overt signs of toxicity.
The observations included evaluation of the eyes, skin, fur, mucous membranes, and respiration. Behavior pattern and nervous system activity was assessed by specific observation for salivation, lacrimation, diarrhea, tremors, convulsions, lethargy, and other signs of central nervous system depression. Records of mortality were maintained. An additional daily observation and observations on weekends
were made. The laboratory veterinarian conducted a pen-light ophthalmological examination on each animal from all exposure groups prior to initiation of exposures and immediately prior to necropsy of animals in the 0,3, and 12 ppm exposure groups. All surviving rats were weighed on
test days 1,3,5,8, and 11 except male and female rats exposed to 48 ppm which were sacrificed on day 8 because of poor clinical condition.

Sacrifice and pathology:

Rats exposed to 0,3, or 12 ppm PMDETA were fasted overnight and sacrificed the day following the last exposure.
Major organs were weighed and tissues evaluated histopathologically. Appropriate samples for urinalysis, hematology, and clinical
chemistry determinations were obtained, body weights recorded, major organs weighed, and tissues were collected for histologic examination.
Nonfasted rats exposed to 48 ppm PMDETA were anesthetized, sacrificed, and necropsied prior to the sixth exposure; blood samples for clinical laboratory determinations, body weights, and organ weights were not obtained.

Other examinations:

Blood samples were obtained by orbital sinus puncture from all surviving rats under slight methoxyflurane anesthesia immediately prior to
necropsy.
Urine was obtained from all rats exposed to 0,3, or 12 ppm PMDETA during the second week of exposure and evaluated for color and
character.

Statistics:

All parameters examined statistically were tested for equality of variances using Bartlett's test. Then, one-way and two-way ANOVA and three-way repeated measures ANOVA were used.
Descriptive statistics (means and SD) were reported for chamber concentrations, temperature, relative humidity, and WBC differential counts.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

irritation of tissues in a direct contact with the test material

Mortality:

mortality observed, treatment-related

Description (incidence):

irritation of tissues in a direct contact with the test material

Body weight and weight changes:

effects observed, treatment-related

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:

effects observed, treatment-related

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Differences were due to decreased mean final body weight in animals.

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

irritation of nasal cavity, skin and cornea

Histopathological findings: neoplastic:

no effects observed

Details on results:

ANIMAL OBSERVATIONS:
All rats exposed to 3 ppm survived until termination of the study with no indication of clinical signs as a result of the exposures.
All rats exposed to 12 ppm developed unilateral or bilateral cloudy corneas by test day 5 and these changes persisted throughout
the study.
Following exposure to 48 ppm on test day I, all rats had bilateral cloudy corneas. Most of these rats, after subsequent exposures, developed chromodacryorrhea and swollen, hyperemic ear pinnae with superficial incrustations. Animals from this exposure group were sacrificed
on test day 8 (following 5 exposures) because of their poor physical condition.
BODY WEIGHTS:
The body weights of rats exposed to 3 ppm were comparable to respective control values. An exposure-related time-dose interaction for both
males and females was statistically identified for the 12 and 48 ppm exposure groups. The mean body weights of male rats exposed to 12 ppm were decreased approximately 10% from the corresponding control male value on test day 5 and by test day 11, the difference was approximately 13%.
The mean body weights of male and female rats exposed to 48 ppm were decreased from corresponding control values beginning on test day day 3 and by test day 8, male body weight was decreased approximately 29% from controls while females were decreased approximately 25%.
ORGAN WEIGHTS:
Differences in organ weights were due to decreased mean final body weight in animals.
PATHOLOGY:
Exposure-related gross changes occurred in male and female rats exposed to 12 or 48 ppm while rats exposed to 3 ppm were similar to controls.
Rats exposed to 12 ppm had bilateral cloudy corneas. The 48 pprn exposure group was necropsied on test
day 8 because of their poor physical condition and one female rat from this exposure group was found dead on test day 7. Gross pathologic changes were bilateral cloudy corneas, decreased fat in the abdominal cavity, crusts on the external nares and ear pinnae, and bilateral chromodacryorrhea.
HISTOPATHOLOGY:
Exposure-related and concentration-dependent microscopic changes occurred in the nasal cavity of male and female rats exposed to 3, 12, or 48 ppm, mainly vacuolar degeneration of respiratory epithelium and the underlying submucosal glands. Rats exposed to 12 ppm had vacuolar degeneration of respiratory epithelium and vacuolar degeneration of olfactory epithelium. Additionally, there was vacuolar degeneration of submucosal glands beneath both types of epithelia and the epithelium lining the floor of the anterior portion of the nasopharynx. Several male and female rats in this exposure group had more severe morphologic damage to the nasal cavity as indicated by rnultifocal erosions of respiratory epithelium and inflammatory exudate into the nasal meati. Microscopic changes in the nasal cavities of rats exposed to 48 ppm were vacuolar degeneration of respiratory and submucosal glands throughout all 4 levels of the nasal cavity. There were also extensive areas of erosions, necrosis, and squamous metaplasia of respiratory epithelium. Vacuolar degeneration of nasopharyngeal epithelium extended throughout the nasopharynx.
No additional target organs were identified after microscopic examination of tissues from rats exposed to 3 ppm; however, exposure-related microscopic changes in tissues from rats exposed to 12 or 48 ppm included the eyes, skin, larynx (48 ppm only), trachea (48 ppm only), and bronchi (48 ppm only). Ocular changes were vacuolar degeneration of corneal epithelium.

Effect levels

1

Dose descriptor:

conc. level: 3 ppm

Effect level:

3 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: localised irritation of nasal cavity

2

Dose descriptor:

conc. level: 12 ppm

Effect level:

12 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: local irritation of nasal cavity, skin and cornea

3

Dose descriptor:

conc. level: 48 ppm

Effect level:

48 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weight loss, poor clinical condition, extensive irritation of upper respiratory tract, skin and eyes.

4

Dose descriptor:

LOAEC

Remarks:

local

Effect level:

3 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The morphologic appearance of the histopathologic changes was primarily characterized as vacuolar degeneration of epithelium lining the
airways and covering the cornea or skin (superficial layers of the epidermis).
Observed changes were indicative of nonselective localized irritation to tissues at risk by exposure to sufficient
vapor concentrations of the test material. Even at the highest concentration tested (48 ppm), there was no indication of damage to organs or
tissues that were not directly exposed to PMDETA vapors.