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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented report which meets basic scientific principles. Study performed according to standard NTP protocols.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2009

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): diethylamine
- Physical state: colorless liquid with a strong ammonia odor
- Analytical purity: approximately 99.9%
- Lot/batch No.: BE/07/01
- Stability under test conditions: no degradation of the bulk chemical was detected
- Storage condition of test material: at controlled room temperature

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: males: 110 g (mean), female: 93 g (mean)
- Housing: individually in stainless steel wire bottom (Lab Products, Inc., Seaford, DE), changed weekly and rotated daily
- Diet: NTP-2000 irradiated wafers (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, except during exposure periods
- Water: Tap water (Richland municipal supply) via automatic watering system (Edstrom Industries, Waterford, WI), available ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3 °C (72°±3 °F)
- Humidity (%): 50% ± 15%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were drawn from each exposure chamber approximately every 30 minutes during each 6-hour exposure period using stream-select and gas sampling valves in a separate heated valve oven.
Duration of treatment / exposure:
93 days
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 8, 16, 32, 62, 125 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Dose selection rationale: Because exposure to 250 or 500 ppm diethylamine for 16 days caused significantly decreased body weights in rats, a high concentration of 125 ppm was selected for both sexes in the 3-month study. Although nasal lesions were present in rats exposed to 125 ppm for 16 days, these lesions were generally mild and were not likely to compromise the 3-month study. Diethylamine exposure concentrations of 0, 8, 16, 32, 62, and 125 ppm were selected for both sexes of rats in the 3-month study.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 7 and weekly afterwards

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 0, 23 and 93
- Anaesthetic used for blood collection: Yes
- How many animals: all
- Parameters examined: Erythrocyte count, Mean corpuscular volume, Hemoglobin, Packed cell volume, Mean corpuscular hemoglobin, Mean corpuscular hemoglobin concentration, Erythrocyte morphologic assessment, Leukocyte count, Leukocyte differential, Reticulocyte count, Platelet count and morphologic assessment

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: days 0, 23 and 93
- How many animals: all
- Parameters examined: Sorbitol dehydrogenase (SDH), Alkaline Phosphatase (ALP), Creatine Kinase (CK), Creatinine, Total Protein, Albumin, Urea Nitrogen (BUN), Total Bile Acids, Alanine Aminotransferase (ALT), Glucose

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: Organs weighed were heart, right kidney, liver, lung, right testis, and thymus
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, a complete necropsy is performed on all treated and control animals that either die or are sacrificed

HISTOPATHOLOGY: Complete histopathology was performed on 0 and 125 ppm core study rats. In addition to gross lesions and tissue masses, the following tissues were examined to a no-effect level: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, eyes, Harderian gland, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lungs, lymph nodes (bronchial, mandibular, mediastinal, and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
All rats survived to the end of the study. The only clinical finding was a single occurrence of a torso lateral ulcer/abscess in a 125 ppm male.

BODY WEIGHT AND WEIGHT GAIN
Final mean body weights and body weight gains of all exposed groups were similar to those of the chamber control groups.
HAEMATOLOGY
There were no exposure-related changes in hematology endpoints.

CLINICAL CHEMISTRY
There were no exposure-related changes in clinical chemistry endpoints.

ORGAN WEIGHTS
The relative kidney weights of all groups of exposed females were increased and were significantly greater than those of the chamber controls, except in the 32 ppm group. The relative liver weight of 125 ppm males was significantly increased.
HISTOPATHOLOGY: NON-NEOPLASTIC
Exposure-related histopathology findings in rats were limited to the nose and were seen primarily in rats exposed to 62 or 125 ppm. These lesions included turbinate necrosis, suppurative inflammation, respiratory epithelial hyperplasia, squamous metaplasia of the respiratory epithelium, and olfactory epithelial atrophy.

There were no inflammatory changes of the eye as had been observed in the 2-week study at higher concentrations.

OTHER FINDINGS
There was a dose-related decrease seen in the motility of sperm from male rats with the values of those exposed to 32, 62, or 125 ppm diethylamine being significantly lower (5-26%) than those of the chamber controls; no significant differences were observed in the estrous cyclicity of female rats administered 32, 62, or 125 ppm diethylamine when compared to the chamber controls.

Effect levels

Dose descriptor:
NOAEC
Effect level:
16 ppm
Sex:
male/female
Basis for effect level:
other: histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

90 (12 minutes) per day, 5 days per week for 14 weeks. All rats survived to the end of the study. Mean body weights of all exposed groups were similar to those of the chamber control groups. There were significant exposure concentration-related decreases in sperm motility in 32, 62, and 125 ppm males; there were no significant differences in the length of estrous cycles between chamber control and exposed groups of females. Exposure-related nasal lesions were seen primarily in rats exposed to 62 or 125 ppm. These lesions included turbinate necrosis, suppurative inflammation, respiratory epithelial hyperplasia, squamous metaplasia of the respiratory epithelium, and olfactory epithelial atrophy.