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Neurotoxicity

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Description of key information

Acute CNS effects:

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

NOAEC in mice (Hydrocarbons C10-C11, isoalkanes, <2% aromatics): 1000 ppm (5800 mg/m3).

NOAEC in rats (Hydrocarbons C10-C12, isoalkanes, <2% aromatics): >1500 mg/m3

NOAEL in rabbits (Hydrocarbons, C11-C14, n-alkanes, <2% aromatics): >2000 mg/Kg bw

Subchronic (13 weeks) neurotoxicity:

NOAEC in rats: >24.3 g/m3 (6646ppm)

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:
read-across from supporting substance (structural analogue or surrogate)
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:
The justification for read across is provided 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
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
11 600 mg/m³
Study duration:
subacute
Species:
mouse

Effect on neurotoxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: short-term dermal
Remarks:
subacute
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1993/04/20-1993/04/27
Reliability:
2 (reliable with restrictions)
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:
equivalent or similar to guideline
Guideline:
OECD Guideline 424 (Neurotoxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Products
- Age at study initiation: Males: 13 weeks; Females: 11-12 weeks
- Weight at study initiation: Males: 1.96-2.19 g; Females: 1.90-2.26g
- Housing: Single Housed
- Diet (e.g. ad libitum): Agway Certified Diet RCA Rabbit, restricted feeding
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65 to 70
- Humidity (%): 40 to 60
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
other: occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: dorsal surface
- % coverage: 10
- Type of wrap if used: appled under the gauze patch and secured with a piece of Saran wrap
- Time intervals for shavings or clipplings: twice per week


REMOVAL OF TEST SUBSTANCE
- Washing (if done): washed the dosed site with 1.0% mixture of baby shampoo
- Time after start of exposure: after 6 hours of exposure, the test material was washed off

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hours a day; applied once a day for the duration of the experiment
Frequency of treatment:
once a day
Remarks:
Doses / Concentrations:
doses: 500, 1000, 2000 mg/kg positive control (n-hexane): 2000 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
2 males and 2 females per treatment group
Control animals:
yes, concurrent no treatment
Details on study design:
The study was conducted to assess the dermal irritation potential and systemic toxicity of repeated topical application of MRD-92-405 at dose levels of 500, 1000, and 2000 mg/kg in the rabbit when administered daily for 7 days. Four groups consisting of 2 rabbits/sex/group were used. To serve as a comparison control, one group of animals was treated with n-hexane.

Clinical observations were made daily as to the nature, onset, severity, and duration of toxicological signs. Dermal irritation was assessed prior to dosing on days 0, 4, and 7 and immediately after dosing on Day 0. Body weights were recorded the week prior to dosing, on day 0 and day 7. Food consumption was measured once during the test period. The study was terminated after 7 days of dosing and all rabbits in the 2000 mg/kg group and n-hexane group were subjected to whole body perfusion fixation. A modified gross necropsy, which did not include examination of the cranial cavity, was conducted on each of these animals. A gross necropsy was performed on the 500, 1000 mg/kg dosed animals and tissues with gross abnormalities were taken and preserved. Positive control (n-hexane): 2000 mg/kg
Observations and clinical examinations performed and frequency:
Clinical observations were made daily as to the nature, onset, severity, and duration of toxicological signs. Dermal irritation was assessed prior to dosing on days 0, 4, and 7 and immediately after dosing on Day 0. Body weights were recorded the week prior to dosing, on day 0 and day 7. Food consumption was measured once during the test period.
Sacrifice and (histo)pathology:
The study was terminated after 7 days of dosing and all rabbits in the 2000 mg/kg group and n-hexane group were subjected to whole body perfusion fixation. A modified gross necropsy, which did not include examination of the cranial cavity, was conducted on each of these animals. A gross necropsy was performed on the 500, 1000 mg/kg dosed animals and tissues with gross abnormalities were taken and preserved.
Statistics:
Means and standard deviations of body weight, body weight change, and food consumption.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
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):
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
All animals survived to the end of the study. All animals in the 1000 and 2000 mg/kg dose groups were observed with erythema, ranging from very slight to severe, throughout the study. The severity of erythema for these two groups increased as the study progressed. Two of the four 500 mg/kg dose group animals were observed with very slight to well-defined erythema on days 4 and 7. All animals in the n-hexane group were observed with erythema on days 4 and 7, ranging from very slight to severe. One n-hexane group animal was observed with very slight erythema on day 0. Edema, ranging from very slight to slight, was observed in all dose groups on days 4 and 7. Supplemental dermal observations consisting of desquamation and/or exfoliation, atonia, and cracking were observed in all dose groups on day 7. Fissuring was observed in the 1000 mg/kg and 2000 mg/kg groups and in the n-hexane group. One n-hexane dose group animal was observed with eschar on day 7. No additional observable abnormal clinical signs were noted in treated animals except for one female animal that was observed with mucoidal stool on day 2.

BODY WEIGHT AND WEIGHT GAIN
There were small decreases in body weight from the day 0 weights observed in individual animals from all groups.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no apparent differences in food consumption between the groups.

GROSS PATHOLOGY
Dermal irritation was the most significant postmortem finding and was consistent with the supplemental dermal observations noted. No other finding was considered the result of test material administration.

NEUROTOXICITY
Topical application of MRD-92-405 for seven days did not cause any gross signs of neurotoxicity.
Dose descriptor:
NOAEL
Remarks:
LD50
Effect level:
>= 2 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: no sub-acute neurotoxicity noted
Remarks on result:
other:
Conclusions:
Dermal application of 2000mg/kg MRD-92-405 for seven days did not cause any gross signs of neurotoxicity or any clinical signs except for skin irritation. All animals survived to study termination; NOAEL >2000 mg/kg.
Executive summary:

The study was conducted to assess the dermal irritation potential and systemic toxicity of repeated topical application of MRD-92-405 at dose levels of 500, 1000, and 2000 mg/kg in the rabbit when administered daily for 7 days. Four groups consisting of 2 rabbits/sex/group were used. To serve as a comparison control, one group of animals was treated with n-hexane. Dermal application of 2000 mg/kg MRD-92-405 for seven days did not cause any gross signs of neurotoxicity or any clinical signs except for skin irritation, with erythema ranging from very slight to severe. All animals survived to study termination; NOAEL >2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
One supporting read across study from a structural analogue available for assessment.

Additional information

There is no data available for Hydrocarbons, C9-C10, n-alkanes, isoalkanes, cyclics, < 2% aromatics. However, data is available for structural analogues, Hydrocarbons, C9-C11, cyclics, <2% aromatics; n-Decane; Hydrocarbons, C10-C12, isoalkanes, <2% aromatics; Hydrocarbons, C11-C12, isoalkanes, <2% aromatics; Hydrocarbons, C11-C14, n-alkanes, <2% aromatics; and light alkyl naphtha distillate. 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, 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 (ExxonMobil, 2001). 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.

n-Decance

Short-term, high-level exposure to n-decane induced mild, reversible neurobehavioral effects on functional observations and measurements of learned performance (ExxonMobil, 1999). Effects were observed during or after 3 consecutive 8 hour exposures at the highest tested concentration of 5 g/m3of n-decane. Exposure to 0.5 g/m3or 1.5 g/m3of n-decane 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.

Hydrocarbons, C11-C14, n-alkanes, <2% aromatics

A short-term dermal study (ExxonMobil, 1993) was conducted to assess the dermal irritation potential and systemic toxicity of repeated topical application of the test material (Hydrocarbons, C11-C14, n-alkanes, <2% aromatics) at dose levels of 500, 1000, and 2000 mg/Kg in the rabbit when administered daily for 7 days. Four groups consisting of 2 rabbits/sex/group were used. To serve as a comparison control, one group of animals was treated with n-hexane. Dermal application of 2000 mg/kg test material for seven days did not cause any gross signs of neurotoxicity or any clinical signs except for skin irritation, with erythema ranging from very slight to severe. All animals survived to study termination and the NOAEL was determined to be >2000 mg/Kg.

Sub-chronic Neurotoxicity

Light Alkyl Naphtha Distillate

In a 13 week sub-chronic inhalation study (Schreiner et al. 1998), the neurotoxicity of light alkylate naphtha distillate (LAND-2; carbon range C5-C8) was examined in male and female rats. Locomotor activity and a functional operational battery were performed during the pre-test week, weeks 5, 9, 14, and 18 (recovery group). Other than acute central nervous system effects, there were no treatment related neurotoxic effects in any of the treatment groups. The NOAEC was determined to be > 24.3 g/m3(6646ppm).

Justification for classification or non-classification

There is no substance specific neurotoxicity study available for Hydrocarbons, C9-C10, n-alkanes, isoalkanes, cyclics, < 2% aromatics.

In a 13 week sub-chronic inhalation study (Schreiner et al. 1998), the neurotoxicity of light alkylate naphtha distillate (LAND-2; carbon range C5-C8) was examined in male and female rats. Locomotor activity and a functional operational battery were performed during the pre-test week, weeks 5, 9, 14, and 18 (recovery group). Other than acute central nervous system effects, there were no treatment related neurotoxic effects in any of the treatment groups. The weight of evidence based on available date from structural analogues indicates that Hydrocarbons, C9-C10, n-alkanes, isoalkanes, cyclics, < 2% aromatics is unlikely to present a hazard as a neurotoxicant.