Alkenes, C13-14, hydroformylation products, low boiling

Neurotoxicity

Administrative data

Endpoint:

neurotoxicity: acute inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

2007

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented study report which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

Model studies for evaluating the neurobehavioral effects of complex hydrocarbon solvents - II. Neurobehavioral effects of white spirit in rat and human

Author:

Lammers, J.H.C.M., Emmen, H.H., Muijser, H., Hoogendijk, E.M.G., McKee, R.H., Owen, D.E., Kulig, B.M.

Year:

2007

Bibliographic source:

Neurotoxicology 28(4): 736-750

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Evaluation of the neurobehavioral effects of hydrocarbon solvents to establish a working model for extrapolating animal test data to humans.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

white spirit

IUPAC Name:

white spirit

Details on test material:

white spirit

Test animals

Species:

other: Rat and Human

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

The animals at time of testing were approximately 15 weeks old with body weights of 242 to 296 g. Animals were housed in suspended wire mesh steel cages under normal housing conditions in temperature-controlled (20¿25 8C) animal rooms with a relative humidity between 40 and 70%. Animals were maintained on a 12-h light:dark cycle. Feed and drinking water were available ad libitum from the arrival of the rats until the end of the study.

Administration / exposure

Route of administration:

inhalation

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

8 h/day for 3 consecutive days

Frequency of treatment:

3 consecutive days

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 600, 2400 or 4800 mg/m3
Basis:
other: Rat doses

Doses / concentrations 2

Remarks:

Doses / Concentrations:
57 or 570 mg/m3
Basis:
other: Human

No. of animals per sex per dose:

Rats: 3-4 animals per exposure
Humans: 12 volunteers

Control animals:

yes, concurrent no treatment

Details on study design:

Groups of rats were exposed to WS at target concentrations of 0 mg/m3 (control group), 600 mg/m3 (102 ppm), 2400 mg/m3 (410 ppm) and 4800 mg/m3 (820 ppm) in modified H1000 inhalation chambers. Each chamber had a pyramidal top and bottom and was constructed of stainless steel with glass doors on two sides. The test atmosphere was generated by pumping liquid WS by means of a peristaltic pump in stainless steel tubing that led through an oven at 240 deg C. The vapor was transported with an air stream from a compressed air source and added to the main airflow system. During exposure, samples were automatically drawn from each exposure chamber on an hourly basis and analyzed by gas chromatography for total hydrocarbons. Gas chromatograph readings were calibrated by measuring the contents of Tedlar1 bags filled with air and 500, 2500 or 5000 mg/m3 WS. Each bag was measured three times. The total area under the curve of the chromatogram was used in a linear model, i.e. reading of GC was proportional to concentration.

Humans: For the kinetic study subjects were exposed to WS by inhalation for 4 h at a targeted exposure level of 583 mg/m3 (100 ppm). The exposure level was approximately the maximal allowable concentration of 570 mg/m3 for WS in the Netherlands. Subjects were exposed in a specially controlled exposure room (2.9 m l x2.3 m w x 2.1 m h). The temperature and relative humidity in the room were kept between 19.9 and 21.9 deg C and 55.6 and 63.3%, respectively, as documented by continuous monitoring. The room was equipped with a transparent viewing window, an intercom system, three chairs and tables. The air ventilation system serving the exposure room allowed for the partial recirculation of the test atmosphere. Subjects entered the exposure chamber following the stabilization of WS at the targeted concentration levels. The test atmosphere was generated by total evaporation of liquid white spirit (WS) at an elevated temperature (126¿ 128 deg C) into a constant flow of fresh air. During exposure, the concentration of WS vapor, measured as total hydrocarbon, was continuously monitored by infrared absorption spectrophotometry at 3.55 um using a path length of 11.25 m and plotted on a chart recorder. The measured WS concentrations in the exposure room were recorded at approximately 15-min intervals and averaged to calculate a mean exposure concentration. Prior to the start of exposure, the spectrophotometer was calibrated at 573 mg/m3 by comparison to the content of Tedlar bags filled with 67.4 L dry nitrogen gas into which 38.6 mg liquid white spirit (WS) was injected and allowed to evaporate.

Results and discussion

Results of examinations

Details on results:

In rats, exposure to WS for 8 h on three consecutive days produced small but statistically significant effects in the domains of neuromuscular function, sensorimotor reactivity, motor activity and performance of learned behavior. These effects were most evident at 4800 mg/m3, but statistically significant differences were also observed at 2400 mg/m3. There were no statistically significant differences at 600 mg/m3. In humans, one small but statistically significant CNS effect was associated with a single 4 h exposure to 570 mg/m3 WS. Due to the nature and magnitude of this effect and the number of statistical comparisons performed, it was unclear as to whether this effect was due to treatment or chance.

Effect levels

1

Dose descriptor:

NOAEC

Remarks:

RATS: acute CNS depression

Effect level:

600 mg/m³ air

Sex:

male

Remarks on result:

other:

2

Dose descriptor:

NOAEC

Remarks:

HUMAN: acute CNS depression

Effect level:

570 mg/m³ air

Sex:

male

Remarks on result:

other:

Applicant's summary and conclusion

Executive summary:

To evaluate the neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, studies were conducted, which involved inhalation exposure of rats and humans to white spirit (WS). The specific objectives of these studies were to evaluate the behavioral effects of exposure to WS in rats and humans and to determine relationships between internal levels of exposure and behavioral effects. In both animals and volunteers, methods for assessment of similar functional effects were used to enable interspecies comparisons. A battery of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute central nervous system (CNS) depression. Groups of rats were exposed to WS at target concentrations of 0, 600, 2400 or 4800 mg/m3, 8 h/day for 3 consecutive days. Blood and brain concentrations of two WS constituents; 1,2,4-trimethylbenzene (TMB) and n-decane (NDEC), were used as biomarkers of internal exposure. The NOAEL for acute CNS effects in rats was determined to be 600 mg/m3. In a volunteer study, 12 healthy male subjects were exposed for 4 hours to either 57 or 570 mg/m(3) WS in two test sessions spaced 7 days apart, and neurobehavioral effects were measured using a computerized neurobehavioral test battery. Blood samples were taken at the end of the exposure period to measure internal concentrations of TMB and NDEC. Results of the behavioral tests in rats indicated WS-induced changes particularly in performance and learned behavior. In humans, some subtle performance deficits were observed, particularly in attention. The results indicated that the NOAEL for acute CNS effects in humans was at or near 570 mg/m3. The behavioral effects were related to concentrations of the WS components in the central nervous system. These studies demonstrated a qualitative similarity in response between rats and humans, adding support to the view that the rodent tests can be used to predict levels of response in humans and to assist in setting occupational exposure levels for hydrocarbon solvents.