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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-guideline animal experimental study, published in peer-reviewed literature, GLP status unknown, fully adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2001

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Brain morphological investigations 8 weeks following exposure. Brainstem auditory-evoked responses used to determine auditory thresholds at different frequencies. The cochlea and organ of Corti examined by light and electron microscopy, respectively.
GLP compliance:
not specified
Type of method:
in vivo
Endpoint addressed:
repeated dose toxicity: inhalation

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Analytical purity: >99%
Source: Acros, Geel, Belgium

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, Domaine des Oncines, Saint-Germain-sur l’Arbresle, France
- Age at study initiation: 14 weeks
- Diet: UAR-Alimentation, Villemoisson, Epinay-sur-Orge, France; sterilized with γ-ray, ad libitum
- Water: Filtered tap water (pore size 0.3 µm) ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C
- Humidity: 55 ± 5% %
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
other: air
Details on exposure:
TYPE OF EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 200 L stainless steel inhalation chambers designed to maintain a dynamic and adjustable airflow (10-30 m3/hr), maintained at negative pressure (2-3 mm H2O)
- System of generation: An additional airflow was bubbled through xylene and the output vapour was diluted with air to the required concentration before entering the exposure chamber.
- Temperature, humidity, pressure in air chamber: no data
- Air flow rate: 10-30 m3/hr

TEST ATMOSPHERE
- Brief description of analytical method used: m-xylene concentrations in the exposure chambers were continuously monitored using a gas liquid chromatograph.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Achieved exposure concentrations were determined once during each 6 hr exposure period (sample collection on activated charcoal and analysis by gas chromatography).
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Post exposure period:
8 week recovery period
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 450, 900, 1800 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
16
Control animals:
yes, sham-exposed
Details on study design:
Study aim – evaluation of potential ototoxicity in rats of xylene isomer by electrophysiological methods. Auditory thresholds at different frequencies were determined by brainstem auditory evoked responses. A quantitative morphological study (histocochleogram) and scanning electron microscopy of the organ of Corti used to determine whether there were any microscopic alterations.

Dose selection rationale – based on preliminary range-finding studies. The highest exposure concentration was chosen to produce a reduction in body weight gain of less than 10% and no mortality after four weeks of exposure.

Examinations

Examinations:
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes

NEUROPHYSICAL MEASUREMENTS: Yes

Sacrifice and pathology
GROSS PATHOLOGY: No data

MORPHOLOGY: Yes

Results and discussion

Details on results:
No alteration in auditory evoked response or structure/ultrastructure of the organs of hearing at highest dose tested. The NOAEC (ototoxicity) for male rats was >=1800 ppm (equivalent to 7817 mg/m3).

Any other information on results incl. tables

CLINICAL SIGNS AND MORTALITY: No mortality, all rats remained in good health.

BODY WEIGHT AND WEIGHT GAIN: No statistically significant differences.

NEUROPHYSICAL EXAMINATION: No effect on the latency or amplitudes of brainstem auditory evoked responses or audiometric thresholds.

MORPHOLOGICAL STUDY: There was no loss of hair cells either in the inner or outer hair cell rows of the organ of Corti.

Applicant's summary and conclusion

Conclusions:
There were no changes in brainstem auditory evoked responses or alterations in structure of the cochlea or ultrastructure of the organ of Corti in male rats 8 weeks after cessation of sub-chronic exposure to m-xylene.
Executive summary:

Male Sprague-Dawley rats were exposed to m-xylene by inhalation (0, 450, 900 and 1800ppm, 6 hr/day, 5 days/week for 13 weeks) and brainstem auditory-evoked responses were determined 8 weeks after treatment ended. The cochlea and organ of Corti were examined using light or electron microscopy, respectively. No functional or structural alterations were present, with an overall NOAEC of >=1800 ppm for ototoxicity.