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Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11 to 30 November 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Similar to guideline study; GLP. Six hour exposure rather than 4 hour.

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 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Exposed for 6 hours instead of 4 hours.
Principles of method if other than guideline:
not relevant
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Reference substance name:
N,N-dimethylcyclohexylamine
IUPAC Name:
N,N-dimethylcyclohexylamine
Constituent 2
Chemical structure
Reference substance name:
Cyclohexyldimethylamine
EC Number:
202-715-5
EC Name:
Cyclohexyldimethylamine
Cas Number:
98-94-2
Molecular formula:
C8H17N
IUPAC Name:
N,N-dimethylcyclohexanamine
Constituent 3
Reference substance name:
DMCHA
IUPAC Name:
DMCHA
Details on test material:
CAS 98-94-2 (cyclohexyldimethylamine), purity 99.67%, lot/batch no. 03230EM, molecular weight=127, colourless to straw-coloured liquid. Vapour pressure 9.8 mmHg at 38°C

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age: 8 weeks
- Weight at study initiation: 168.4-239.8 g (males), 120.9-143.0 g (females)
- Source: Charles River Breeding Laboratories, Inc., Kingston, NY.
- Housing: Rats were group housed prior to exposure and singly housed during the 2 week post-exposure period.
- Diet: Purina Certified Rodent Chow #5002 ad libitum, except during exposure.
- Water: available ad libitum.

IN-LIFE DATES: From: 11 November 1987 To: 30 November 1987

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: Exposure chamber
- Exposure chamber volume: 157L
- Method of holding animals in test chamber: No data
- Source and rate of air: Vapors of DMCHA were generated using the glass J-tube method. Liquid test material was metered into the J-tube. The rate of air flow was approximately 30L per minute
- Method of conditioning air: Compressed air heated with a flameless heat torch to the minimum extent necessary passed through the J-tube to volatilize the test material.
- System of generating particulates/aerosols: No data
- Method of particle size determination: No data
- Treatment of exhaust air: No data
- Temperature, humidity, pressure in air chamber: Temperature: 24 ± 1°C, Humidity: 40 - 49%

TEST ATMOSPHERE
- Brief description of analytical method used: Airflow through each chamber was determined with a manometer, which was calibrated with a DTM-115 gas meter. The analytical concentration of DMCHA in the chamber was determined at least 3 times/exposure period by gas chromatography using a flame ionization detector. A 6 ft nickel column packed with 10% OV-11 on 100/120 Supelcoport was used. The gas chromatograph was calibrated with air standards of DMCHA. Air standards of known concentrations of the test substance were prepared by injecting measured volumes into bags containing measured volumes of dry, compressed air. The analytical system was checked prior to each exposure with at least one standard of known concentration.
- Samples taken from breathing zone: No data

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: No data
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): No data

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: No data
Analytical verification of test atmosphere concentrations:
yes
Remarks:
3 times/exposure period by gas chromatography with FID
Duration of exposure:
6 h
Remarks on duration:
Exposure period at the highest concentration was restricted to 150 minutes due to mortality
Concentrations:
actual: 88, 320, 1120 ppm; nominal: 106, 303, 1018 ppm
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Details on study design:
- airflow: ~ 12 air changes/hour
- Particle size: not applicable, vapour exposure
- Type or preparation of particles: vapour was generated using the glass J-tube method

EXAMINATIONS: 
-2 week post-exposure observation period mortality/clinical signs daily body weight prior to exposure and on day 2, 4, 8, 12 and 14/15
-ophthalmologic examination prior to exposure
-macroscopy on all animals 
-histopathology: in situ examination of the eyes at 320 ppm
Statistics:
no data

Results and discussion

Preliminary study:
Not relevant
Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1 700 - < 5 800 mg/m³ air
Exp. duration:
6 h
Remarks on result:
other: LC50 = 1.7-5.8 mg/L
Mortality:
- Time of death: within 150 min at 1120 ppm, shortly after end of exposure at 320 ppm
- Number of deaths at each dose: 
dose   males   females
88       0/5      0/5
320      1/5      2/5
1120    5/5      5/5
Clinical signs:
other: 1120 ppm: labored respiration and body tremors during exposure in the visible animals 320 ppm:  (a) during exposure in the visible animals laboured respiration, soiling of the nose and mouth, rough hair coat and body tremors (b) post-exposure bilateral 
Body weight:
decreased 6-9% at 320 ppm, but recovery appparent within a week of treatment. Bodyweights unaffected at 88 ppm.
Gross pathology:
1120 ppm: generalized visceral congestion, soiling of the external nares by clear fluid, urine soiling of the perineum in half of the animals

320 ppm: (a) in animals that died, multiple dark foci in lungs, congestion of the liver, erosions and/or ulcers in the glandular portion of the stomach, hemolyzed blood in the digestive tract and facial and perineal soiling (b) survivors' eye lesions varying from slight haziness of the cornea to dense pale opacification of the cornea. Mineralisation of the corneal basement was noted in the eyes of rats having slight haziness of the corneas, the least severe lesion. This mineralization was present as a thin plaque involvoing large areas of the basement membrane. Rats having more severe involvement had much thicker mineralized plaques involving the corneal basement membrane accompanied by inflammation and neovascularization of hte cornea.
88 ppm:  no treatment-related effects
Other findings:
HISTOPATHOLOGY: mineralization of the corneal basement membrane of the eyes, inflammation (5/7) and neovascularization of the cornea (5/7), corneal ulcer (1/7) in the test group administered 320ppm test substance.

Any other information on results incl. tables

Due to the lethal effect of the test substasnce at the highest dose level, the test was terminated after 150 minutes of exposure.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Under the conditions of this study, the LC50 was determined to be greater than 320ppm (equivalent to 1.7 mg/L) in both sexes. Based on these results, the test substance should be considered to be an Acute Toxicity Category 3 (Inhalation vapours) toxicant and have the hazard statement H331: Toxic if inhaled and the signal word, Danger. According to Directive 67/548/EEC, the test substance should be classified as toxic (T) and have the risk phrase, R23 Toxic by inhalation associated with it.
Executive summary:

In a study conducted by Nitschke et al, (1988) the test substance cyclohexyldimethylamine (DMCHA) was investigated for its ability to cause toxicity when administered to male and female Fischer 344 rats via the inhalation route. The animals were exposed via whole body exposure in exposure chambers at 3 concentrations, specifically, 88, 320 and 1120 ppm. In the top dose group, the exposure period was terminated at 150 minutes while in the two lower concentration groups, the animals were exposed for 6 hours, with a post-exposure observation period of two weeks.

At the highest concentration, 1120 ppm, all animals died within 150 minutes. Body tremors and labored respiration were observed prior to death. At 320 ppm, 1 male and 2 females died shortly after exposure. Tremors, laboured respiration and soiling of the nose and mouth were observed during exposure. Body weight decreased 6 to 9% immediately after exposure but recovered quickly. In animals sacrificed on test day 14, exposure-related lesions were observed in the eye only. Microscopically, slight to severe corneal opacities along with inflammation and neovascularization of the cornea were observed in these animals. These corneal opacities were judged likely to be irreversible although the lens and retina were unaffected. There were no real effects observed following exposure at 88ppm.

Under the conditions of this study, the LC50 was determined to be 320 to 1120ppm (equivalent to 1.7 - 5.8 mg/L).

Based on these results, the test substance should be considered to be an Acute Toxicity Category 3 (Inhalation vapours) toxicant and have the hazard statement H331: Toxic if inhaled and the signal word, Danger. According to Directive 67/548/EEC, the test substance should be classified as toxic (T) and have the risk phrase, R23 Toxic by inhalation associated with it.