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Diss Factsheets

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
Study period:
not specified
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.
Justification for type of information:
N/A

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
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
o-xylene
EC Number:
202-422-2
EC Name:
o-xylene
Cas Number:
95-47-6
Molecular formula:
C8H10
IUPAC Name:
o-xylene
Details on test material:
Analytical purity: >99%
Source: Acros, Geel, Belgium
Specific details on test material used for the study:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
not specified
Sex:
male
Details on test animals or test system 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
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
N/A
Details on inhalation exposure:
- Exposure apparatus: 200 L stainless steel inhalation chambers designed to maintain a dynamic and adjustable airflow (10-30 m^3/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 m^3/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 followed by 8 week recovery period
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm (nominal)
Dose / conc.:
450 ppm (nominal)
Remarks:
1954 mg/m^3
Dose / conc.:
900 ppm (nominal)
Remarks:
3908 mg/m^3
Dose / conc.:
1 800 ppm (nominal)
Remarks:
7817 mg/m^3
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.
Positive control:
N/A

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
Other examinations:
N/A
Statistics:
Continuous, parametric variables - Bartlett's test for homogeneity of variances (Bartlett 1937) and by analysis of variance. If the analysis of variance was significant, individual mean comparisons were made with Scheffe's multiple range test to realize comparisons between any pair of groups. Non-parametric data (audiometric thresholds) - Kruskal-Wallis test (Kruskal & Wallis 1952; Gad & Weil 1986). The probability value of P<0.05 was used as the critical level of significance.

Results and discussion

Results of examinations

Clinical signs:
not specified
Description (incidence and severity):
N/A
Mortality:
no mortality observed
Description (incidence):
N/A
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The difference in weight gain between the controls and the 1800 ppm group was significant 11th - 13th week of exposure only. The reduction in body weight was -6% at the end of the exposure period.
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
N/A
Food efficiency:
not examined
Description (incidence and severity):
N/A
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
N/A
Ophthalmological findings:
not examined
Description (incidence and severity):
N/A
Haematological findings:
not examined
Description (incidence and severity):
N/A
Clinical biochemistry findings:
not examined
Description (incidence and severity):
N/A
Endocrine findings:
not examined
Description (incidence and severity):
N/A
Urinalysis findings:
not examined
Description (incidence and severity):
N/A
Behaviour (functional findings):
not examined
Description (incidence and severity):
N/A
Immunological findings:
not examined
Description (incidence and severity):
N/A
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
N/A
Gross pathological findings:
not examined
Description (incidence and severity):
N/A
Neuropathological findings:
no effects observed
Description (incidence and severity):
No effect on the latency or amplitudes of brainstem auditory evoked responses or audiometric thresholds.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
not specified
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
N/A
Other effects:
not examined
Description (incidence and severity):
N/A
Details on results:
MORPHOLOGICAL STUDY: There was no loss of hair cells either in the inner or outer hair cell rows of the organ of Corti.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
1 800 ppm
Sex:
male
Basis for effect level:
other: equivalent to 7817 mg/m^3, minor (-6%) reduction in bodyweight gain at highest dose tested
Dose descriptor:
NOAEC
Remarks:
ototoxicity
Effect level:
1 800 ppm
Sex:
male
Basis for effect level:
other: equivalent to 7817 mg/m^3, no alteration in auditory evoked response or structure / ultrastructure of the organs of hearing at highest dose tested

Target system / organ toxicity

Key result
Critical effects observed:
not specified

Any other information on results incl. tables

N/A

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 o-xylene.
Executive summary:

Male Sprague-Dawley rats were exposed to o-xylene by inhalation (0, 450, 900 and 1800 ppm (equivalent to 0, 1954, 3908, 7817 mg/m3) 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 (7.8 mg/L) for ototoxicity.