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Neurotoxicity

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Description of key information

No neurotoxicity specific studies are available for hydrocarbons, C9-C11, n-alkanes, isoalkanes, <2% aromatics. Reliable data are therefore read across from related substances in the relevant carbon number range.

Acute CNS effects:

NOAEC in mice: Hydrocarbons, C7-C8, isoalkanes, Hydrocarbons, C8-C9, isoalkanes, Hydrocarbons, C10-C11, isoalkanes = 1000ppm (5800 mg/m3)

NOAEC in mice (operant behaviour): Hydrocarbons, C7-C9, isoalkanes, <2% aromatics = 1000 ppm

NOAEC in rats (neurotoxicity):Hydrocarbons, C7-C9, isoalkanes, <2% aromatics >= 24300 mg/m³

NOAEC 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

Referenceopen allclose all

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.
Key result
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:
Key result
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:
Key result
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:
Key result
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:
neurotoxicity: acute inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication/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
Principles of method if other than guideline:
Functional observation battery (FOB) and operant behaviour testing after exposure to ISOPAR E
GLP compliance:
not specified
Limit test:
yes
Species:
mouse
Strain:
other: CFW (ChasRiver Swiss)
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Weight at study initiation: 27-40 g
- Housing: Mice were housed individually in 18x29x13 cm plastic cages containing wood chip bedding and fitted with steel wire tops.
- Diet (ad libitum): Animals used in the operant and discrimination studies were allowed to gain weight to a maximum of 35 ± 5 g by post-session feeding of 3-4 g/day of rodent chow (Rodent Laboratory Chow, Ralston-Purina, St. Louis, MO).
- Water (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:
Static exposure chambers were used for mice tested in FOB and ethanol discrimination protocols. Vapor generation was carried out in 29 l cylindricaljars into which liquid solvent was injected through a port onto filter paper suspended below the sealed lid. A fan then volatilized and dispersed the solvent.
Dynamic exposure chambers were used for operant conditioning and cross-dependence protocols. Operant conditioning chambers were modified for solvent vapor exposure. Vapor was generated by airflow through a bubbler in a 500 ml solvent bath. Air saturated with vapor mixed with filtered room air and was delivered to the exposure chamber.
For dependence studies, exposures were conducted in a 20.8 l rectangular tank fitted with a Teflon-lined lid into which vapors were continuously delivered in the airflow.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations were measured by single wavelength monitoring infrared spectrometry [Miran 1A].
Vapor concentrations were controlled by a multiple Dyna-blender interfaced with an IBM-compatible microcomputer that dictated flow rates for each test concentration.
Duration of treatment / exposure:
30 min [5 min pre-exposure to air followed by 20 min exposure to the substance (either at a single constant concentration or at increasing concentrations every five min) and 5 min post-exposure to air]
Frequency of treatment:
single exposure
Remarks:
Doses / Concentrations:
0, 2000, 4000 and 6000 ppm
Basis:
nominal conc.
functional observation battery
Remarks:
Doses / Concentrations:
0, 500, 1000, 2000, 4000, 6000 ppm
Basis:
nominal conc.
operant behaviour
No. of animals per sex per dose:
8-10 (depending on behavioral test)
Control animals:
yes, sham-exposed
Neurobehavioural examinations performed and frequency:
For the FOB studies, groups of 8 mice were each exposed to 0, 2000, 4000 or 6000 ppm ISOPAR-E for 20 minutes. During the last 2 minutes of exposure, mice were evaluated for clinical signs of toxicity and movement. Immediately after termination of exposure, mice were removed and evaluated forease of removal and handling. Righting reflex, fore- and hind-limb grip strength, landing foot splay and other behavioral parameters were also measured.

Ethanol discrimination: 9 mice/group were trained to press a lever for milk presentation. Once trained, an intraperitoneal injection of 1.25 g/kg ethanol or saline was administered, followed by further training to reinforce response to only one lever until acquisition of discrimination between 1.25 g/kg ethanol or saline in liquid was completed. Animals were then exposed to 500, 1000, 2000 or 6000 ppm ISOPAR-E for 20 min then removed and placed in behavioral test chambers.

Operant behavior: Mice were trained in two-lever operant conditioning chambers for 2 months under a fixed ratio 20 schedule of milk reinforcement.In the 1st exposure regimen, each mouse was exposed to a single concentration of 500 to 6000 ppm ISOPAR-E for 20 min, preceded and followed by 5 min air only. In the 2nd regimen, each mouse was exposed to all 5 concentrations of solvent [500, 1000, 2000, 4000, 6000 ppm] during successive 5 min periods to provide for determination of a complete concentration-effect curve within a 30 min session. This within-session method was performed in duplicate.

Cross-dependence: groups of 10 mice were continuously exposed to 2000 ppm TCE for 4 days, then TCE exposure was discontinued. Mice were evaluated for withdrawal behavior by monitoring convulsions elicited by handling, hourly for 12 hours, then at 12-24 hr intervals until recovery was complete. To assess the ability of TCE or ISOPAR-E to modify withdrawal reaction, each was administered before the 3-4 hr post-exposure assessment during the period of peak withdrawal effects [measured at 80% mice with convulsions] at concentrations of 2000 or 4000 ppm for 20 or 60 min.


Positive control:
1,1,1-trichloroethane [TCE] was tested as a positive control for comparison.
Statistics:
Concentration-effects curves for operant response rates analyzed by analysis of variance and Tukey's post-hoc comparisons. FOB used linear models approach with modification for between-subject data versus repeated measures. Continuous and count measures analyzed by means of separate general linear model procedures. Tukey's post hoc tests used to specify differences from controls.
Behaviour (functional findings):
effects observed, treatment-related
Details on results:
NEUROBEHAVIOUR:
FOB: few effects were produced for these endpoints, seen mostly at 6000 ppm. Effects included decreased arousal during the last 2 min of exposure, decreased hind-limb footsplay, increased rearing behavior at high concentrations. No effect on motor coordination was seen.

Operant conditioning: Concentration related decreases in response rates occurred in the between session protocol at 2000-6000 ppm and the within session protocol at 4000-6000 ppm.

Ethanol-like discriminative stimulus effects: Following ISOPAR-E exposure percentage of ethanol lever responses increased in a concentration-dependent manner to a maximum of 65 % at 6000 ppm. However, substitution behavior induced by ISOPAR-E for ethanol occurred at concentrations which decreased the rate of responding, indicating that responses took place at concentrations that impaired performance.

TCE cross dependence: Exposure of TCE withdrawn mice to 2000 ppm ISOPAR-E for 30-60 min or to 4000 ppm for 30 minutes caused a 40-50 % decrease in mice convulsing. At the higher concentration of 4000 ppm for 60 minutes, convulsions were suppressed by 100 %. Withdrawal reactions returned over 2 hours as ISOPAR-E suppressive effect subsided.

The narrower separation between of acute effects (6000 ppm) and lethal effect (8000 ppm) compared to TCE which showed CNS effects over a wide range of dose concentrations, indicate that the abuse levels needed to produce CNS effects would be very toxic.


Key result
Dose descriptor:
NOAEC
Remarks:
operant behaviour
Effect level:
ca. 1 000 ppm
Sex:
male
Remarks on result:
other:
Conclusions:
Exposure at 8000 ppm caused convulsions resulting in death and was not used thereafter in this study.

In this acute neurobehavioural study very few functional observational effects were seen and only at 6000 ppm. The test substance induced ethanol substitution behaviour only at 6000 ppm, a concentration that impaired performance. Operant rates were affected variously over the range of 2000 to 6000 ppm. Based on these results the NOAEC for operant behaviour was considered to be 1000 ppm.
Executive summary:

Exposure at 8000 ppm caused convulsions resulting in death and was not used thereafter in this study.

In this acute neurobehavioural study very few functional observational effects were seen and only at 6000 ppm. The test substance induced ethanol substitution behaviour only at 6000 ppm, a concentration that impaired performance. Operant rates were affected variously over the range of 2000 to 6000 ppm. Based on these results the NOAEC for operant behaviour was considered to be 1000 ppm.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 800 mg/m³
Study duration:
subacute
Species:
mouse
Quality of whole database:
Two key read across studies available from structural analogues.

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no data available for Hydrocarbons, C9-C11, n-alkanes, isoalkanes, <2% aromatics. However, data are available for structural analogues Hydrocarbons, C7-C9, isoalkanes, <2% aromatics; Hydrocarbons, C10-C11, isoalkanes, <2% aromatics, Hydrocarbons, C10-C12, isoalkanes, <2% aromatics, and Hydrocarbons, C9-C11, cyclics, <2% aromatics. These data are read across to Hydrocarbons, C9-C11, n-alkanes, isoalkanes, <2% aromatics 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, C7-C9, isoalkanes.<2% aromatics

The weight of evidence based on an analogue approach indicates that hydrocarbons, C7-C9, isoalkanes are unlikely to present a hazard as neurotoxicant.

An acute neurobehavioural study was reported for hydrocarbons, C7-C9, isoalkanes, in which male mice were exposed to 0, 500, 1000, 2000, 4000, or 6000 ppm in a single 20 to 30 min exposure. The study was conducted to determine if this solvent produced behavioural and pharmacologic effects similar to commonly abused inhalable solvents such as 1,1,1-trichloroethane (TCE) or ethanol. Animals were evaluated in the functional observational battery (FOB), for operant behaviour, ethanol discrimination and cross-dependence with TCE. Exposure at 8000 ppm caused convulsions resulting in death and was not used thereafter in this study. Very few FOB effects were seen and only at 6000 ppm. The test substance induced ethanol substitution behaviour only at 6000 ppm, a concentration that impaired performance. Operant rates were affected variously over the range of 2000 to 6000 ppm. Based on these results the NOAEC for operant behaviour was considered to be 1000 ppm (Balster et al., 1997).

In another study with hydrocarbons, C7-C9, isoalkanes, 10 male mice per dose were exposed by inhalation to 0, 1000, 2000, 4000 and 6000 ppm for 30 min, and then tested for their acute effects on locomotor activity and operant performance. The test substance produced reversible increases in locomotor activity starting at a concentration of 4000 ppm. At the same time, reversible concentration-dependent decreases in rates of schedule-controlled operant activity were observed. However, the operant performance was already impaired at 2000 ppm (Bowen and Balster, 1998). In the same publication, the results of tests perfomed with an identical study design, the test substance (under a different trade name) produced reversible increases in locomotor activity starting at a concentration of 4000 ppm. At the same time and dose, reversible concentration-dependent decreases in rates of schedule-controlled operant activity were observed. The effects caused in this case were less pronounced than those described previously (Bowen and Balster, 1998).

Hydrocarbons, C9-C11, cyclics, <2% aromatics

Short-term high level exposure to Hydrocarbons, C9-C11, cyclics, <2% aromatics induced mild and non-persistent neurobehavioral effects on functional observations and measures of learned performance. Minimal effects were observed during or after 3 consecutive 8 hour exposures to Hydrocarbons, C9-C11, cyclics, <2% aromatics at an exposure level of 5 g/m3. Exposure to 1.0 or 2.5 g/m3on a group basis did not induce exposure-related neurobehavioral effects.

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 Hydrocarbons, C9-C11, n-alkanes, isoalkanes, <2% aromatics. However, the weight of evidence based on an analogue approach indicates that hydrocarbons, C9-C11, n-alkanes, isoalkanes, <2% aromatics is unlikely to present a hazard as neurotoxicant. Effects on the central nervous system such as narcosis, dizziness and drowsiness observed in animals and by human experience justify classification as STOT SE category 3.