Registration Dossier

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Currently viewing:

Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-guideline study, GLP status not known, human experimental study, limitations in design and/or reporting but otherwise adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Coexposure to toluene and p-xylene in man: central nervous functions
Author:
Anshelm Olson B, Gamberale F and Iregren A
Year:
1985
Bibliographic source:
British Journal of Industrial Medicine; 42:117-122

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
acute toxicity: inhalation
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Human volunteers were exposed for 4 hours to 2.84 mmol/m3 and a control condition in an exposure chamber. With the aid of microcomputers, subjects performed tests of simple reaction time, short term memory, and choice reaction time immediately after entering the chamber and after 2 and 4 hours exposure.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
no further details

Method

Subjects:
16 males aged 23-38 years (mean 31 years)


Ethical approval:
not specified
Route of exposure:
inhalation
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
- Exposure chamber: volume 11.5 m3, internal dimensions 1.80 x 2.80 x 2-28 m.
- Generation of atmosphere: airflow to the chamber 115 m3/hour, no further details on atmosphere generation provided.
- Two subjects were studied at a time in the chamber under four exposure conditions: control air, 300 mg/m3 toluene, 300 mg/m3 p-xylene and a mixture of 200 mg/m3 toluene and 100 mg/m3 p-xylene. The exposure of each pair of subjects took place at the same time on the same day of the week and at intervals of 14 days. The period of each exposure was 4 hours.
- At the beginning of the control condition, isoamylacetate (0.02-0.04 mmol/m3) was administered for the first 5 minutes to disguise the absence of solvents.
Examinations:
The subjects were randomly allocated to four sub-groups. Two subjects were studied at a time under four experimental conditions. A 4 x 4 Latin square was used to balance the sequence of exposure conditions between the groups. Three different performance tests were used during each exposure condition. These were administered when the subjects entered the chamber and again after 2 and 4 hours.

Performance tests: These were self-administered using micro-computers.
(i) Simple reaction time – to push a button as soon as a light came on. A total of 176 stimuli were administered during 11 minutes at intervals of 3.75±1-25 seconds.
(ii) Memory - reproduction – 17 series (each lasting 4 seconds) consisted of alternating letters and figures, presented on the screen. The number of characters for each series was gradually increased from 4-8. The subject was required to repeat the series on the keyboard during a response time of 17 seconds. Data were analysed according to the number of correctly reproduced series (max 17) and the number of correctly reproduced elements (max 94).
(iii) Choice reaction time - A cross (105 x 95 mm) with one arm slightly shorter than the others was displayed on the screen. There were 3 levels of difficulty as the arms of the crosses had been reduced by 5, 10, or 15 mm. Using a specially designed response panel the subject had to indicate which arm of the cross had been shortened, as quickly as possible. In total, reaction times were measured for the 144 stimuli of the test which were administered at 4 second intervals. The heart rate of eight subjects was recorded every second minute of the performance tests.
Subjective reactions: The subjects assessed their condition at the end of each exposure condition using four 7-point scales, the extremes of which were designated: alert/tired, concentrating/not concentrating, calm/under stress and energetic/lazy. The subjects also documented the extent to which they experienced nausea, headache, or irritation in the eyes, nose, and oesophagus using four response categories: no, negligibly, slightly, quite considerably. In order to determine if the masking of the control condition had been effective and whether the subjects had been able to distinguish between the three solvent conditions each subject asked to which condition they thought they had been subjected as they left the exposure chamber.

Results and discussion

Results of examinations:
Exposure to p-xylene (300 mg/m3, 4 hours) was without measurable effect on selected CNS functions.

Any other information on results incl. tables

Simple reaction time: No significant differences between exposure conditions (although differences were obtained both as a result of day sequence and of varying times of day). Memory reproduction: No significant differences between exposure conditions (although significant improvements in performance were found that related both to day sequence and to time of day when the analysis was performed on the number of correctly reproduced elements). Choice reaction times: No significant differences between exposure conditions. Heart rate: No significant differences between exposure conditions. Subjective symptoms: No differences between exposure conditions. Most subjects (12 of 16) succeeded in identifying the control condition. Only a few were able to distinguish between the various solvent conditions.

Applicant's summary and conclusion

Conclusions:
Exposure to p-xylene (300 mg/m3, 4 hours) was without measurable effect on selected CNS functions in human volunteers.

Executive summary:

Sixteen male volunteers were exposed to a series of solvents including 300 mg/m3 p-xylene for 4 hours and simple reaction time, short term memory and choice reaction time and subjective symptoms assessed. Performance of the tests together with reporting of subjective symptoms did not differ between the control and p-xylene-exposed conditions. The results indicate that 300 mg/m3 p-xylene is without measurable effect on selected human CNS functions.