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EC number: 203-558-5 | CAS number: 108-18-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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: 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:
- 2 011
- Report date:
- 2011
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Diethylamine
- EC Number:
- 203-716-3
- EC Name:
- Diethylamine
- Cas Number:
- 109-89-7
- Molecular formula:
- C4H11N
- IUPAC Name:
- N-ethylethanamine
- Test material form:
- other: liquid
- 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
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system 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: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- clean air
- Remarks on MMAD:
- MMAD / GSD: not appropriate for vapors
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The study laboratory designed the inhalation exposure chamber (Harford Systems Division of Lab Products, Inc., Aberdeen, MD) so that uniform vapor concen-trations could be maintained throughout the chamber with the catch pans in place. The total active mixing volume of each chamber was 1.7 m3
- Method of holding animals in test chamber: no data
- Source and rate of air: no data
- Method of conditioning air: no data
- System of generating vapors: Diethylamine was pumped onto glass beads in a heated glass column where it was vaporized. Heated nitrogen flowed through the column and carried the vapor into a short vapor distribution manifold. Concentration in the manifold was determined by the chemical pump rate and nitrogen flow rate. The pressure in the distribution manifold was kept fixed to ensure constant flow through the manifold and into all chambers as the flow of vapor to each chamber was adjusted. Individual Teflon® delivery lines carried the vapor from the manifold to three-way exposure valves at the chamber inlets. The exposure valves diverted vapor delivery to the exposure chamber exhaust until the generation system was stable and exposures were ready to proceed. A metering valve with a flow indicator at the manifold controlled the flow rate to each chamber. To initiate exposure, the chamber exposure valves were rotated to allow the vapor to flow to each exposure chamber inlet duct where it was further diluted with HEPA®-filtered, conditioned air to achieve the desired exposure concentration.
- Temperature, humidity, pressure in air chamber: no data
- Air flow rate: no data
- Air change rate: 15 air changes per hour
- Method of particle size determination: A small particle detector was used with and without animals in the exposure chambers to ensure that diethylamine vapor, and not aerosol, was produced. No particle counts above the minimum resolvable level (approximately 200 particles/cm3) were detected
- Treatment of exhaust air:
TEST ATMOSPHERE
- Brief description of analytical method used: Samples of the test atmosphere from the distribution lines and the low and high exposure concentration chambers were collected prior to the 3-month and also at the beginning and end of one generation day during the 3-month study. The atmosphere samples were collected with adsorbent gas sampling tubes containing an acrylic ester, followed by a tube containing activated coconut charcoal, and extracted with methylene chloride. Chamber and room concentrations of diethylamine were monitored by an on-line gas chromatograph.
- Samples taken from breathing zone: yes - 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 / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
8, 16, 32, 62, and 125 ppm (16.8, 33.6, 67.2, 130.2, and 262.5 mg/m3)
Basis:
other: target conc.
- Remarks:
- Doses / Concentrations:
8.0 ± 0.3, 15.9 ± 0.6, 32.0 ± 1.3, 62.2 ± 2.3, 126 ± 5 ppm
Basis:
analytical conc.
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, sham-exposed
- 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
HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 3, 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 3, 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
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, a complete necropsy is performed on all treated and control animals that either die or are sacrificed
ORGAN WEIGHT: OTHER: Heart, right kidney, liver, lung, right testis, and thymus
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. - Other examinations:
- Sperm Motility and Vaginal Cytology
At the end of the studies, sperm samples were collected from male animals in the 0, 32, 62, and 125 ppm groups for sperm motility evaluations. The following parameters were evaluated: spermatid heads per testis and per gram testis, spermatid counts, and epididymal spermatozoal motility and concentration. The left cauda, left epididymis, and left testis were weighed. Vaginal samples were collected for up to 12 days prior to the end of the studies from females exposed to 0, 32, 62, or 125 ppm for vaginal cytology evaluations. The percentage of time spent in the various estrous cycle stages and estrous cycle length were evaluated.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- a single occurrence of a torso lateral ulcer/abscess in a 125 ppm male
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- a single occurrence of a torso lateral ulcer/abscess in a 125 ppm male
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- 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 (Table G2). 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.
Exposure-related histopathology findings in rats were limited to the nose. Suppurative inflammation of minimal to mild severity was observed in all males and most females in the 125 ppm groups; a few 62 ppm males and females and one 16 ppm female also exhibited inflammation (Table 5). Suppurative inflam-mation was characterized by increased numbers of neutrophils in the nasal tissue and was most obvious on the tips of the nasal turbinates. Necrosis of the nasal turbinates in Level I was noted in one male and one female exposed to 125 ppm and consisted of sloughing of the respiratory epithelium with exposure and partial necrosis of the underlying bone. Respiratory epithelial hyperplasia was present in all 125 ppm males, in most 125 ppm females and 62 ppm males and females, and in a few 16 and 32 ppm males and one 16 ppm female. Hyperplastic respiratory epithelium contained three or more layers of epithelial cell nuclei with loss of the normal orderly, polarized, arrangement. Nonkera-tinizing squamous metaplasia of the respiratory epithelium occurred in all 125 ppm males, five 125 ppm females, one 62 ppm male, and one 16 ppm male. Both hyperplasia and metaplasia of the respiratory epithelium were most commonly observed and most severe on the tips of the nasal turbinates and on the lateral wall of the dorsal half of nasal Level I. Olfactory epithelial atrophy was present in all 125 ppm males and females, most 62 ppm males and females, and two 32 ppm females. Atrophy was most pronounced in the dorsal meatus of nasal Level II and only rarely affected the olfactory epithelium of nasal Level III. The atrophy was characterized by decreased height of the olfactory epithelium associated with a decreased number of olfactory cell nuclei, and was accompanied by a reduction in the number of nerves and Bowman’s glands in the underlying lamina propria.
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 (Table H1); 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 (Table H2).
Effect levels
open allclose all
- Dose descriptor:
- NOAEC
- Remarks:
- local effects
- Effect level:
- 16 other: ppm (analytical) (33.6 mg/m3)
- Sex:
- male/female
- Basis for effect level:
- other: Exposure-related nasal lesions were seen primarily in rats exposed to 62 or 125 ppm
- Dose descriptor:
- NOAEC
- Remarks:
- systemic toxicity
- Effect level:
- 16 other: ppm (analytical) (33.6 mg/m3)
- Sex:
- male
- Basis for effect level:
- other: significant exposure concentration-related decreases in sperm motility in 32, 62, and 125 ppm males
- Dose descriptor:
- NOAEC
- Remarks:
- systemic toxicity
- Effect level:
- >= 125 other: ppm (analytical) (262.5 mg/m3)
- Sex:
- female
- Basis for effect level:
- other: no relevant effect
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
TABLE H1: Summary of Reproductive Tissue Evaluations for Male Rats in the 3-Month Inhalation Study of Diethylaminea
|
Chamber Control |
32 ppm |
62 ppm |
125 ppm |
n |
10 |
10 |
10 |
10 |
Weights (g) |
|
|
|
|
Necropsy body wt |
347 ± 6 |
350 ± 7 |
355 ± 7 |
338 ± 6 |
L. Cauda epididymis |
0.1871 ± 0.0052 |
0.1802 ± 0.0061 |
0.1873 ± 0.0044 |
0.1736 ± 0.0043 |
L. Epididymis |
0.4913 ± 0.0094 |
0.4861 ± 0.0119 |
0.4947 ± 0.0114 |
0.4662 ± 0.0069 |
L. Testis |
1.5165 ± 0.0238 |
1.4772 ± 0.0350 |
1.5102 ± 0.0278 |
1.4473 ± 0.0264 |
Spermatid measurement Spermatid heads (103/mg testis) Spermatid heads (106/testis) |
123.55 ± 5.72
171.00 ± 7.16 |
125.24 ± 5.86
168.63 ± 9.72 |
125.76 ± 3.96
173.38 ± 6.35 |
128.93 ± 4.48
169.38 ± 4.01 |
Epididymal spermatozoal measurements Sperm motility (%) |
93.01 ± 0.72 |
88.60 ± 1.45** |
87.27 ± 1.57** |
68.44 ± 2.78** |
Sperm (103/mg cauda epididymis) |
669 ± 37 |
660 ± 30 |
660 ± 22 |
598 ± 34 |
Sperm (106/cauda epididymis) |
124.3 ± 5.7 |
118.0 ± 4.6 |
123.3 ± 3.6 |
103.9 ± 6.3 |
** Significantly different (P=0.01) from the chamber control group by Shirley’s test
a Data are presented as mean ± standard error. Differences from the chamber control group are not significant by Dunnett’s test (body and tissue weights) or Dunn’s test (spermatid, sperm/mg cauda epididymis, and sperm/cauda epididymis measurements).
TABLE H2: Estrous Cycle Characterization for Female Rats in the 3-Month Inhalation Study of Diethylaminea
|
Chamber Control |
32 ppm |
62 ppm |
125 ppm |
Number weighed at necropsy |
10 |
10 |
10 |
10 |
Necropsy body wt (g) |
204 ± 6 |
200 ± 4 |
202 ± 3 |
201 ± 5 |
Proportion of regular cycling femalesb |
10/10 |
10/10 |
10/10 |
10/10 |
Estrous cycle length (days) |
5.0 ± 0.05 |
5.0 ± 0.05 |
5.0 ± 0.00 |
5.0 ± 0.05 |
Estrous stages (% of cycle) |
|
|
|
|
Diestrus |
58.3 |
54.2 |
53.3 |
55.0 |
Proestrus |
16.7 |
15.8 |
16.7 |
14.2 |
Estrus |
20.0 |
17.5 |
20.0 |
20.8 |
Metestrus |
5.0 |
12.5 |
10.0 |
10.0 |
a Necropsy body weights and estrous cycle length data are presented as mean ± standard error. Differences from the chamber control group are not significant by Dunnett’s test (body weight) or Dunn’s test (estrous cycle length). By multivariate analysis of variance, exposed females do not differ significantly from the chamber control females in the relative length of time spent in the estrous stages. The tests for equality of transition probability matrices among exposure groups and between the chamber control group and each exposed group indicated the exposed females did not have extended estrus or diestrus.
b Number of females with a regular cycle/number of females cycling
Applicant's summary and conclusion
- Executive summary:
In a study conducted similar to OECD TG 413 (Subchronic Inhalation Toxicity: 90-Day), groups of ten Fischer 344 rats/sex were exposed to the test substance by whole body vapor inhalation for six hours/day, five days/week for 93 days at concentrations of 0, 8, 16, 32, 62, or 125 ppm (0, 16.8, 33.6, 67.2, 130.2, and 262.5 mg/m3) (NTP, 2011). There were no deaths. A single occurrence of a torso lateral ulcer/abscess occurred in a 0.37 mg/L male. Clonic seizures were seen in males (1/50, 2/50, 7/50, 9/50) and in females (2/50, 7/50, 11/50, 13/50) [doses not stated but the lowest numbers presumably were in controls – i.e., 1/50 males and 2/50 females]. There were no effects on body weights, clinical chemistry or hematology findings. The relative kidney weights of all groups of exposed females were increased and were significantly greater than those of the chamber controls (p< 0.05 or 0.01), except in the 0.096 mg/L group (which had an n=9). The relative heart weight was increased in females at 0.37 mg/L (p< 0.05). The relative liver weight of 0.37 mg/L males was significantly increased (p < 0.05). Exposure-related histopathology findings in rats were limited to the nose (primarily at 0.19 or 0.37 mg/L). These lesions included turbinate necrosis, suppurative inflammation, respiratory epithelial hyperplasia, squamous metaplasia of the respiratory epithelium, and olfactory epithelial atrophy. The NOAEC for the local irritation and the systemic toxicity was 16 ppm (33.6 mg/m3) based on histopathology findings.
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