Hydrocarbons, C4, 1,3-butadiene-free, polymd., tetraisobutylene fraction, hydrogenated

Neurotoxicity

Description of key information

Acute CNS effects: NOAEC for in mice (Hydrocarbons C11-C12, isoalkanes, <2% aromatics): ≥ 2000 ppm (11600 mg/m³).

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: acute inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1997

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

no guideline available

Principles of method if other than guideline:

Locomotor Activity and Operant Behavior will be measured after brief inhalation exposure.

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

other: CFW

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Weight at study initiation: 30-35g
- Housing: Individual
- Diet (e.g. ad libitum): Rodent Lab Chow (Ralston-Purina Co.)
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

Vapor exposures for the locomotor activity studies were conducted in 29L cylindrical jars (47cm H x 35 cm diameter; total floor space 962 cm2. Briefly, vapor generation commenced when liquid solvent was injected through a port onto filter paper suspended below the sealed lid. A fan, mounted on the inside of the lid, was then turned on, which volatilized and distributed the agent within the chamber. Exposure chambers were located in a fume hood. Mouse operant conditioning chambers were modified to allow for solvent vapor exposure. The exposure/behavioral chamber was a 4.25-L stainless steel canister with a loosely fitting stainless steel lid. Vapor generation occurred by initially directing air flow through a bubbler that was immersed in a 500 mL solvent bath contained in a 1-liter round-bottom flask. Air saturated with vapor exited the bath and was mixed with filtered fresh air from outside the building that was then delivered to the exposure chamber. Control of the vapor concentrations was accomplished with a Dyna-blender, which monitored and controlled the air flow rate through two valves-one for fresh air and one for vapor-laden air. The total flow entering the chambers was held constant at 10 liters per mm. Animals were regularly cycled from one of four air-only chambers on non-test days (Monday. Wednesday, Thursday) to the vapor exposure chambers on test days (Tuesday and Friday), Air-only and vapor-exposure chambers were identical except that the latter were placed in a fume hood. Control tests using air-only exposures were also conducted in the vapor exposure chambers, Vapor concentrations in the chamber exhaust were monitored on line during all sessions using a single wavelength monitoring infrared spectrometer.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chamber concentrations were verified by continuous analysis using single wavelength monitoring infrared spectrometry. A visual record of chamber concentrations over time was obtained by plotting absorbance on an X-Y recorder. These analyses revealed that chamber concentrations did not vary from nominal (calculated) final concentrations by more than 10% and, for each volume of liquid injected, were very repeatable from day to day. After chamber concentrations were verified by chemical analysis routine monitoring was not necessary. All vapor exposures were limited to 30 min in duration to preclude problems with waste gas accumulation within these sealed chambers.

Duration of treatment / exposure:

Isoparaffin Exposure: The selection of test concentrations of the isoparaffins was guided by knowledge on the potency of Hydrocarbons, C8-C9, isoalkanes, <2% aromatics obtained in a previous study and by the upper limit of their volatility under our exposure conditions.

Hydrocarbons, C11-C12, isoalkanes, <2% aromatics, in particular, was difficult to completely vaporize so it could not be tested at higher concentrations.

For locomotor activity testing, the following isoparaffins (with target test concentrations) were tested in the order shown:
Hydrocarbons, C7-C8, isoalkanes, <2% aromatics - 1000, 4000, 6000 ppm;
Hydrocarbons, C8-C9, isoalkanes, <2% aromatics - 1000, 4000, 6000 ppm;
Hydrocarbons, C10-C11, isoalkanes, <2% aromatics - 1000, 4000, 6000 ppm;
Hydrocarbons, C11-C12, isoalkanes, <2% aromatics - 500, 1000, 2000 ppm.

One of the days before each solvent exposure was selected as an “air” control test for purposes of data analysis. A similar target concentration range of the same products was also tested for effects on operant behavior:
Hydrocarbons, C7-C8, isoalkanes, <2% aromatics - 1000, 2000, 4000, 6000 ppm;
Hydrocarbons, C8-C9, isoalkanes, <2% aromatics - 1000, 2000, 4000, 6000 ppm;
Hydrocarbons, C10-C11, isoalkanes, <2% aromatics – 500, 1000, 2000, 4000 ppm;
Hydrocarbons, C11-C12, isoalkanes, <2% aromatics - 500, 1000, 2000, 4000 ppm.

A 0 ppm (air only) concentration was tested as one of the test concentrations for each isoparaffin.

Frequency of treatment:

twice a week (Tuesday and Friday)

Remarks:

Doses / Concentrations:
Locomotor Activity: C7-C8, isoalkanes, <2% aromatics - 1000, 4000, 6000 ppm; C8-C9, isoalkanes, <2% aromatics - 1000, 4000, 6000 ppm; C10-C11, isoalkanes, <2% aromatics - 1000, 4000, 6000 ppm; C11-C12, isoalkanes, <2% aromatics - 500, 1000, 2000 ppm
Basis:
other: nominal conc. Note: Isopar G and H were not completely volatilized at the start of the test

Remarks:

Doses / Concentrations:
Operant Behavior: C7-C8, isoalkanes - 1000, 2000, 4000, 6000 ppm; C8-C9, isoalkanes - 1000, 2000, 4000, 6000 ppm; C10-C11, isoalkanes – 500, 1000, 2000, 4000 ppm; C11-C12, isoalkanes - 500, 1000, 2000, 4000 ppm
Basis:
other: nominal conc. Note: Isopar G and H were not completely volatilized at the start of the test

No. of animals per sex per dose:

10 animals per dose per test (locomotor activity); 10 animals per dose per test (operant activity)

Control animals:

yes, sham-exposed

Details on study design:

Locomotor Activity: Locomotor activity was measured unobtrusively via two sets of photocells (Micro Switch, Freeport, IL) that bisected the static exposure chambers. Each of the two photocells and their respective detectors were mounted on 1 inch wooden bases and placed on the sides of the exposure chambers. The second photocell detector unit was placed at a 90o angle to the first, resulting in a bisection at the center of the exposure tank. Interruptions of these photo beams resulted in an analog signal being delivered by the photocell, which in turn triggered a counter. Mice were placed individually into the same exposure chamber in the same sequence each day Activity was monitored once daily (Monday-Friday) for 30 min for approximately 5 days prior to solvent exposures. This resulted in stable day to day level of activity which served as a baseline against which solvent effects could be determined. The same animals were used for all subsequent testing. Solvent exposure tests were conducted on Tuesdays and Fridays, with placement in the exposure chambers with air only exposure occurring between test days (Mondays. Wednesdays and Thursdays),

Operant Behavior
The subjects were trained to lever press in two-lever mouse operant-conditioning chambers, which also served as exposure chambers as described above. The response levers were located on the front wall 8 cm apart, 2.5 cm above a stainless steel floor, and extended 0.8 cm into the chamber. The response lever was held forward by an electromagnet and when the subject pressed the lever (requiring 4-5 g force) an
optoelectronics device detected the movement. Located midway between the levers was a 3-cm diameter opening containing a trough into which 0.02 ml of sweetened-condensed milk (1 part sugar, 1 part condensed milk, and 2 parts water by volume) could be delivered via a calibrated peristaltic infusion pump. Illumination of a house light, located above the right lever, signaled that the session was in progress. Mice were trained to press the right lever only during daily (5 days per week), 30- min sessions under a FR-20 schedule. Responses on the left lever were ineffective and not counted, Animals ware trained daily for approximately 2 months before entering into the testing phase of the experiment.

Observations and clinical examinations performed and frequency:

none

Specific biochemical examinations:

none

Neurobehavioural examinations performed and frequency:

Locomotor Activity and Operant Behavior

Sacrifice and (histo)pathology:

none

Other examinations:

none

Positive control:

none

Statistics:

Data Analysis
Concentration effect curves for each test compound were analyzed using repeated measures analysis of variance (ANOVA; and Tukey post hoc comparisons; p < 0.05). When a test of sphericity was unsuccessful, an appropriate adjustment was made to the degrees of freedom for the averaged tests of significance using the Greenhouse-Geisser factor. For the locomotor activity study, the control activity levels were determined by averaging motor activity on one control air-only test session for each animal prior to determination of each of the isoparaffin concentration effect curves so that each animal served as its own control. For operant behavior, planned comparisons were made with the 0 ppm test concentration. To determine the reversibility of isoparaffin effects on schedule controlled behavior, rates of responding on the first non test session following each test session were compared to the 0 ppm test session for each compound. For Tuesday tests, the next non test session was on Wednesday. For Friday tests, the next non test session was normally on the following Monday except when holidays intervened.

Clinical signs:

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Clinical biochemistry findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Other effects:

not examined

Description (incidence and severity):

Migrated information from 'Further observations for developmental neurotoxicity study'



Details on results (for developmental neurotoxicity):N/A (migrated information)

Details on results:

Locomotor Activity. All mice maintained steady baseline levels of locomotor activity during the study. The mean (SE) baseline counts/min for the air-only test sessions before solvent testing in the static system was 16.8+/- 4.6. Locomotor activity returned to baseline levels during air-only session, which occurred between solvent test sessions. This reversibility was generally seen in the very next motor activity-control session after each test session (i.e. Wednesday or Monday). Exposure to Isopar C, E, and G produced concentration dependent increases in locomotor activity with a minimally effective concentration of 4000 ppm. At 6000 ppm Isopar C, locomotor activity was significantly increased nearly twofold above air control, whereas an identical concentration of Isopar H increased behavior almost threefold as compared to air-only exposures. For Isopar G, maximal increases were approximately one and half times the level of air-only exposures. In contrast, Isopar H was without significant effects on locomotor activity, and higher concentrations could not be obtained under these test conditions; the 4000 ppm test concentration of Isopar H was not completely volatilized within the 30-min exposure possibly accounting for its lack of effects.

Operant Behavior. All mice maintained steady baseline rates of responding throughout all studies. In addition, responding always returned to baseline rates between solvent test sessions showing that all effects were reversible. Isopar C and E produced concentration-dependent decreases in response rates with the highest testable concentration of Isopar C suppressing response rates to approximately 40% of control values. The maximal effects of Isopar E were less. Both compounds produced increases in rates of responding at 1000 ppm in 6 of the 10 subjects, but only response rate-decreasing effects were statistically significant. Higher concentrations of Isopar C and E were not tested because several seizures were observed at the 6000 ppm concentration. Isopar C was about twice as potent as Isopar E with minimally effective concentrations of 2000 and 4000, respectively. Neither Isopar G nor Isopar H had reliable effects on overall rates of responding under these test conditions. Inspection of individual subject data revealed that only one Isopar H exposed subject and none of the Isopar G exposed subjects showed possible evidence of effects.

The average rates of responding as a function of concentration are shown for successive 3 min segments of the exposure. In general, both Isopar C and E exhibited effects by the second 3 mins of exposure, with Isopar C producing a pronounced progressive disruption with continued exposure. At 6000 ppm of Isopar C, subjects were maximally affected after 12-15 min of exposure. A similar pattern was observed at 2000 and 4000 ppm, in which a progressive decrease in response rates was obtained after 6-9 min of exposure. For Isopar E, each of the higher concentrations (4000 and 6000 ppm) exhibited effects by the second 3 min of exposure without a pronounced progressive disruption with continued exposure. For Isopar G and Isopar H the results had a large variability between subjects in the magnitude of response rate disruption and the concentrations at which they occurred resulted in no significant differences from air control rates.

Dose descriptor:

NOAEC

Remarks:

locomotor activity

Effect level:

1 000 ppm (nominal)

Sex:

male

Basis for effect level:

other: NOAEC = 5800 mg/m^3 For: Hydrocarbons, C7-C8, isoalkanes, <2% aromatics Hydrocarbons, C8-C9, isoalkanes, <2% aromatics Hydrocarbons, C10-C11, isoalkanes, <2% aromatics

Remarks on result:

other:

Dose descriptor:

NOAEC

Remarks:

locomotor activity

Effect level:

>= 2 000 ppm (nominal)

Sex:

male

Basis for effect level:

other: NOAEC >= 11600 mg/m^3 Hydrocarbons, C11-C12, isoalkanes, <2% aromatics

Remarks on result:

other:

Dose descriptor:

NOAEC

Remarks:

operant behavior

Effect level:

1 000 ppm (nominal)

Sex:

male

Basis for effect level:

other: NOAEC = 5800 mg/m^3 For: Hydrocarbons, C7-C8, isoalkanes, <2% aromatics Hydrocarbons, C8-C9, isoalkanes, <2% aromatics Hydrocarbons, C10-C11, isoalkanes, <2% aromatics

Remarks on result:

other:

Dose descriptor:

NOAEC

Remarks:

operant behavior

Effect level:

>= 2 000 ppm (nominal)

Sex:

male

Basis for effect level:

other: NOAEC >= 11600 mg/m^3 Hydrocarbons, C11-C12, isoalkanes, <2% aromatics

Remarks on result:

other:

Conclusions:

The locomotor activity and operant behavior NOAEC for C7-C8, isoalkanes, C8-C9, isoalkanes, and C10-C11, isoalkanes was determined to be 1000ppm (5800 mg/m^3). The locomotor activity and operant behavior NOAEC for , C11-C12, isoalkanes was determined to be greater than or equal to 2000ppm (11600 mg/m^3).

Executive summary:

Four isoparaffinic hydrocarbon solvent products differing in predominant carbon number and volatility (C8-C12 isoalkanes) were tested for their acute effects on locomotor activity and operant performance after inhalation exposure in mice. For both measures, concentration effect curves were obtained for 30 min exposures using a within-subject design. The more volatile products, C7-C8 isoalkanes and C8-C9 isoalkanes, were as easily vaporized under the test conditions as vapors. C10-C11 isoalkanes were slowly volatilized and C11-C12 isoalkanes could not be completely volatilized within the 30 min exposures, suggesting that acute human exposures may be less likely. C7-C8 isoalkanes, C8-C9 isoalkanes, and C10-C11 isoalkanes produced reversible increases in locomotor activity of mice at 4000 and 6000 ppm and reversible decreases in rates of schedule controlled operant behavior in the same concentration range. The locomotor activity and operant behavior NOAEC for C7-C8 isoalkanes, C8-C9 isoalkanes, and C10-C11 isoalkanes was determined to be 1000ppm (5800 mg/m³). The locomotor activity and operant behavior NOAEC for , C11-C12 isoalkanes was determined to be greater than or equal to 2000ppm (11600 mg/m³). 

Endpoint conclusion

Dose descriptor:

NOAEC

11 600 mg/m³

Study duration:

subacute

Species:

mouse

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There is no data available for Hydrocarbon, C4, 1,3-butadiene-free, polymd,, tetraisobutylylene fraction, hydrogenated. However, data is available for structural analogues Hydrocarbons, C10-C12, isoalkanes, <2% aromatics and C11-C12, isoalkanes, <2% aromatics. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Acute Neurotoxicity

Hydrocarbons, C7-C8, isoalkanes, <2% aromatics; Hydrocarbons, C8-C9, isoalkanes, <2% aromatics; Hydrocarbons, C10-C11, isoalkanes, <2% aromatics and Hydrocarbons, C11-C12, isoalkanes, <2% aromatics

Four isoparaffinic hydrocarbon solvent products differing in predominant carbon number and volatility (C8-C12 isoalkanes) were tested for their acute effects on locomotor activity and operant performance after inhalation exposure in mice (Bowen and Balster, 1998). For both measures, concentration effect curves were obtained for 30 min exposures using a within-subject design. The more volatile products, C7-C8 isoalkanes and C8-C9 isoalkanes, were as easily vaporized under the test conditions as vapors. C10-C11 isoalkanes were slowly volatilized and C11-C12 isoalkanes could not be completely volatilized within the 30 min exposures, suggesting that acute human exposures may be less likely. C7-C8 isoalkanes, C8-C9 isoalkanes, and C10-C11 isoalkanes produced reversible increases in locomotor activity of mice at 4000 and 6000 ppm and reversible decreases in rates of schedule controlled operant behavior in the same concentration range. The locomotor activity and operant behavior NOAEC for C7-C8 isoalkanes, C8-C9 isoalkanes, and C10-C11 isoalkanes was determined to be 1000 ppm (5800 mg/m³). The locomotor activity and operant behavior NOAEC for , C11-C12 isoalkanes was determined to be greater than or equal to 2000 ppm (11600 mg/m³). 

Hydrocarbons, C10-C12, isoalkanes, <2% aromatics

Short-term, high-level exposure to Hydrocarbons, C10-C12, isoalkanes, <2% aromatics induced mild, non-persistent neurobehavioral effects on measures of learned performance (ExxonMobil Corp., 2001). Effects were observed during or after 3 consecutive 8 hour exposures at the highest tested concentration of 5 g/m³. Exposure to 0.5 g/m³or 1.5 g/m³of Hydrocarbons, C10-C12, isoalkanes, <2% aromatics did not induce exposure-related neurobehavioral effects.

Justification for classification or non-classification

There are no neurotoxicity specific studies available for Hydrocarbon, C4, 1,3-butadiene-free, polymd,, tetraisobutylylene fraction, hydrogenated. However, the weight of evidence based on an analogue approach indicates that Hydrocarbon, C4, 1,3-butadiene-free, polymd,, tetraisobutylylene fraction, hydrogenated is unlikely to present a hazard as neurotoxicant.