Alkanes, C7-8

Neurotoxicity

Description of key information

Hydrocarbons, C7-C9, isoalkanes

NOAEC (mouse, operant behavior) = 1000 ppm

 

Octane

NOAEC (rat, functional observational battery and motor activity) > 14000 mg/m³

NOAEC (rat, visual discrimination) > 14000 mg/m³   

 

Based on available read across data, Hydrocarbons, C7-C8, n-alkanes is unlikely to present a hazard as a neurotoxicant.

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

Reference 1

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.

Reference 2

Endpoint:

neurotoxicity: inhalation

Remarks:

other: acute and subacute

Type of information:

experimental study

Adequacy of study:

key study

Study period:

08 Dec 1999 - 11 Dec 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

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:

Neurobehavioral functioning was evaluated using selected measures from a standardized functional observational battery (FOB) and motor activity assessment protocol similar to that used in the WHO/IPCS Collaborative Study on Neurotoxicity Assessment (Moser and MacPhail, 1992; Moser et al., 1997a; Moser et al., 1997b).

GLP compliance:

yes (incl. QA statement)

Remarks:

Ministry of Health, Welfare and Sport, State Supervisory Public Health Service, Veterinary Public Health Inspectorate, GLP Section

Limit test:

no

Species:

rat

Strain:

other: WAG/RijCrlBR

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 14 weeks
- Weight at study initiation: approximately 250 g at randomization

- Housing: Animals were housed in groups of 5 in suspended stainless steel cages under conventional conditions. After randomization animals were moved to the exposure chambers and housed individually in wire-mesh cages.
- Diet (ad libitum): commercial rodent diet (Rat & Mouse No. 3 Breeding Diet, RM3)
- Water (ad libitum): Tap water suitable for human consumption (quality guidelines according to Dutch legislation based on EEC Council Directive 80/778/EEC, see Annex 3) was supplied by N.V. Waterleidingbedrijf Midden-Nederland (WMN).
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24 (lowest 17.5)
- Humidity (%): 30-70 (maximum was 78)
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): artificially illuminated for 12 hours between 7.30 a.m. and 7.30 p.m.


IN-LIFE DATES: From: 1998-11-18 To: 1998-12-11

Route of administration:

inhalation: vapour

Vehicle:

other: air

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test atmosphere was generated by pumping liquid n-octane into stainless steel tubing using peristaltic pumps. The tubing was led through a water bath at 67-68 °C and the resulting vapour was transported with an airstream from a compressed air source and added to the main airflow system.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

During exposure a total carbon analyzer was operated with 4 ports for control and 3 test concentrations. Shortly after the experiment, a stability check of the concentrations was performed.

Duration of treatment / exposure:

8 hours

Frequency of treatment:

single exposure and once daily for 3 consecutive days

Remarks:

Doses / Concentrations:
0 g/m3; 1.4 g/m3 corresponding to 300 ppm; 4.2 g/m3 corresponding to 900 ppm; 14 g/m3 corresponding to 3000 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

8

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment: The rat was selected because this species is considered suitable for this type of study and was the species specified in the TNO EZ Collective project proposal. The strain of rats used in these experiments has been used extensively in behavioral studies within TNO.

Observations and clinical examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations checked: no details given

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to randomization (no details given)


BODY WEIGHT: Yes
- Time schedule for examinations: body weight was recorded during randomization and on days of testing

Neurobehavioural examinations performed and frequency:

FUNCTIONAL OBSERVATIONAL BATTERY: Yes
- Parameters checked:
Neuromuscular: gait, forelimb and hindlimb gripstrength, landing foot splay
Sensorimotor: response to tail pinch, click, touch, approach of a visual object
Convulsive: clonic and tonic movements
Excitability: arousal
Activity: motor activity

- Minimization of bias: Technicians were blind to treatment status of animals: Yes
- Site of testing: open arena (77x55x7 cm)
- Time schedule for examinations: FOBs were carried out 6 days prior to the start of exposure and immediately following the first and third exposure period.
- Duration of observation period for open field observations: 1 minute


LOCOMOTOR ACTIVITY: Yes
- Type of equipment used: automated quantitative microprocessor-based video image analysis system (Ethovision, Noldus Information Technology b.v., The Netherlands)
- Length of session, number and length of subsessions: 30 minutes
- Parameters measured: The position of the rat was continuously monitored throughout the test session concerning distance traversed, number of movements and mean velocity. Spontaneous motor activity was expressed as the total distance run in a test period. In addition, quantitative measures of locomotor speed and patterns of locomotor activity were also recorded.

Statistics:

All data were analyzed using the SAS® statistical software package (release 6.12). For each test measure, probability values of p≤0.05 were consideredsignificant.
Continuous variables from the FOB were analyzed using ANOVA. Treatment effects were analyzed using repeated measures analysis of variance. Group comparisons were made using Dunnett´s multiple comparison tests. Rank data were analyzed by Kruskal-Wallis one-way analysis of variance.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Behaviour (functional findings):

no effects observed

Details on results:

Exposure levels (single exposure and once daily for 3 consecutive days) used in these studies did not induce clear signs of general intoxication. No significant effects of exposure were observed on body weight or on body temperature.

CLINICAL SIGNS AND MORTALITY
No remarkable clinical signs were observed.

BODY WEIGHT AND WEIGHT GAIN
During the 3-day exposure period, mean body weights were only slightly changed. A small decrease was observed in the 14 g/m3 group during the exposure period. Repeated measures analysis of variance of body weight data indicated a significant treatment-by-time interaction. However, analysis of variance of body weight data at each test time point indicated that there were no significant differences between groups.


NEUROBEHAVIOUR
Statistical analysis of functional observations and motor activity data indicated group differences in landing foot splay, hindlimb gripstrength. Significant interaction effects (distance traversed, number of movements, mean velocity) were observed for measures of motor activity.
However, none of the exposed groups appeared to be significantly different from the control group for any of the above measures.
FOB: Following exposure, no changes in functional observational measures were observed that could be related to exposure to n-octane.
Motor activity: Subsequent statistical analysis of motor activity data at each test time point did not indicate any of the exposure groups to be significantly different from the control group.

Key result

Dose descriptor:

NOAEC

Effect level:

> 14 000 mg/m³ air (nominal)

Sex:

male

Basis for effect level:

other: overall effects (no effects) highest dose tested

Remarks on result:

other:

Conclusions:

In conclusion, short-term high-level exposure to n-octane did not induce any toxicologically significant effects on functional observations and measures of motor activity.

Executive summary:

In conclusion, short-term high-level exposure to n-octane did not induce any toxicologically significant effects on functional observations and measures of motor activity.

Reference 3

Endpoint:

neurotoxicity: short-term inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

08 Dec 1999 - 11 Dec 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

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:

Effects of the test compound on cognitive performance were evaluated using a discrete-trial two-choice visual discrimination task.

GLP compliance:

yes (incl. QA statement)

Remarks:

Ministry of Health, Welfare and Sport, State Supervisory Public Health Service, Veterinary Public Health Inspectorate, GLP Section

Limit test:

no

Species:

rat

Strain:

other: WAG/RijCrlBR

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 14 weeks
- Weight at study initiation: approximately 150 g at randomization

- Housing: From the acclimatization period onwards, the animals were housed in groups of 4 in suspended stainless steel cages until they were moved to the exposure chambers. In the exposure chambers animals were housed in groups of 4 in wire-mesh cages. Animals were acclimatized to the exposure chambers 3 days prior to the pre-exposure test week.
- Diet (ad libitum): commercial rodent diet (Rat & Mouse No. 3 Breeding Diet, RM3)
- Water (ad libitum): Tap water suitable for human consumption (quality guidelines according to Dutch legislation based on EEC Council Directive 80/778/EEC, see Annex 3) was supplied by N.V. Waterleidingbedrijf Midden-Nederland (WMN).
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24 (lowest 17.5)
- Humidity (%): 30-70 (maximum was 78)
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): artificially illuminated for 12 hours between 7.30 a.m. and 7.30 p.m.


IN-LIFE DATES: From: 1998-10-14 To: 1998-12-11

Route of administration:

inhalation: vapour

Vehicle:

other: air

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test atmosphere was generated by pumping liquid n-octane into stainless steel tubing using peristaltic pumps. The tubing was led through a water bath at 67-68 °C and the resulting vapour was transported with an airstream from a compressed air source and added to the main airflow system.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

During exposure a total carbon analyzer was operated with 4 ports for control and 3 test concentrations. Shortly after the experiment, a stability check of the concentrations was performed.

Duration of treatment / exposure:

8 hours

Frequency of treatment:

once daily for 3 consecutive days

Remarks:

Doses / Concentrations:
0 g/m3; 1.4 g/m3 corresponding to 300 ppm; 4.2 g/m3 corresponding to 900 ppm; 14 g/m3 corresponding to 3000 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

8

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment: The rat was selected because this species is considered suitable for this type of study and was the species specified in the TNO EZ Collective project proposal. The strain of rats used in these experiments has been used extensively in behavioral studies within TNO.

Observations and clinical examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations checked: no details given

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical signs of ill health recorded prior to randomization and on Mondays during operant training: no details given

BODY WEIGHT: Yes
- Time schedule for examinations: body weight was recorded during randomization and on a weekly basis until the end of the study, and further after testing was completed on each day of exposure.

Neurobehavioural examinations performed and frequency:

LEARNING AND MEMORY TESTING: Yes
(1) Overall testing design
Visual discrimination performance: Effects of the test compound on cognitive performance were evaluated using a discrete-trial two-choice visual discrimination task.
Parameters evaluated:
General measures: trials responded to, % reinforcements obtained
Stimulus control: discrimination ratio, % ITI periods responded to
Disinhibition: repetitive errors, repetitive ITI responses
Psychomotor slowing: two choice S+ latency, short latency responses, long-latency responses, within-subject variability and single-choice SR+ latency, within-subsject variability
(2) Equipment used
- Type of equipment: The apparatus consisted of 16 operant chambers and programming and recording equipment programmed with the MedState® notation system (Med Associates, Inc., Georgia, VT). Each of the operant chambers (32x30x28 lxwxh) was equipped with two levers, two stimulus lights and a water dipper for delivering water reinforcement. A photocell assembly was mounted in the water trough in order to detect the entry of the rat´s head when obtaining the reinforcement. Each operant chamber was located in a ventilated sound-attenuated cubicle.
Although 32 rats were randomly assigned to the test groups before the start of the study, a total of 36 animals were trained.
(3) Testing and training procedures
Prior to treatment, water-deprived rats were first trained to obtain water reinforcements and to lever press using autoshaping techniques. The rats subsequently received four weeks of training on a discrete-trial light-dark visual discrimination task in order to stabilize baseline responding. Animals were trained 5 days/week, from Monday to Friday.
Test sessions consisted of 100 trials or 60 minutes whichever came first and were conducted at approximately the same time each day. On days of exposure, rats were tested immediately following the end of the exposure period. A post-exposure test was performed the day after the last exposure period in order to evaluate the persistence of effects.
Trials were signaled by the illumination of either the left or right stimulus light (S+) and the rat´s task was to depress the lever under the illuminated light in order to obtain water reward. Illumination of right and left stimulus lights was counterbalanced and occured in a predetermined semi-random order. If the rat pressed the correct lever (S+ response), the stimulus light was extinguished and a water reward (SR+) was delivered. If the initial response during a trial was on the incorrect lever (S- response), the rat was allowed to correct its mistake by pressing the lever under the illuminated stimulus light. A given trial remained in effect until the correct lever had been pressed. Trials were separated by an intertrial interval (ITI) of 10 seconds. A response during the ITI reset the ITI timer and the rat was required to wait a further 10 seconds before the initiation of the following trial.
(4) Control procedures
The correctness of the initial response on each trial was recorded.
Examination of baseline performance averaged across 5 days in the week preceding exposure (pre-day) for each rat indicated that all animals were well-trained prior to exposure.
(5) Performance measures
If the initial trial response was correct (S+ response), the latency of the lever press was also recorded (S+ response latency). If the initial response was incorrect (S- response), the number of incorrect lever responses made by the rat switching to the correct lever was recorded. During the intertrial period, lever responses were measured to determine the number of ITI periods on which 1 or more lever presses occured and the number of repetitive ITI lever responses.
From these measures, a number of dependent variables were defined to describe effects on general levels of responding, stimulus control and disinhibition, and response speed.

Statistics:

All data were analyzed using the SAS® statistical software package (release 6.12). For each test measure, probability values of p≤0.05 were consideredsignificant.
Body weights were analyzed using one-way ANOVA followed by Dunnett´s multiple comparison tests.
One-way ANOVA was conducted to examine baseline performance prior to exposure.
Treatment effects were analyzed using repeated measures analysis of variance of the data recorded during the 3-day exposure period. Huynh-Feldt adjustment of p-values of the repeated measures factor was applied in case the assumption of sphericity of observations was violated. When a significant treatment effect was demonstrated, pairwise group comparisons were performed in order to determine which solvent-treated group significantly differed from the control group. When a significant treatment-by-time interaction was demonstrated, one-way analysis of variance was performed at each test time point followed by Dunnett´s multiple comparison tests. Persistence of effects was evaluated by analysis of variance of post-exposure data.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Behaviour (functional findings):

no effects observed

Details on results:

Exposure levels used in these studies did not induce clear signs of general intoxication. No significant effects of exposure were observed on body weight.

CLINICAL SIGNS AND MORTALITY
No remarkable clinical signs were observed.

BODY WEIGHT AND WEIGHT GAIN
During the 3-day exposure period, both increases and decreases in body weight were observed in animals of all groups. However, changes in body weight were small and statistical analysis of body weight or body weight changes did not indicate any significant differences between groups.


NEUROBEHAVIOUR (Visual discrimination performance)
With respect to effects on measures of learned performance, no toxicologically relevant effects of exposure were observed. No significant effects of exposure to n-octane were observed on any measure during the 3-day exposure period. Most pronounced difference between groups was a slight increase in lever response latency in the highest exposure groups after the first 8-hour exposure period, but these group differences were not statistically significant.
During pre-week testing, pre-day testing and post-day testing a number of statistically significant differences between groups were found that were considered not to be related to exposure.

Key result

Dose descriptor:

NOAEC

Effect level:

> 14 000 mg/m³ air (nominal)

Sex:

male

Basis for effect level:

other: overall effects (no effects) highest dose tested

Remarks on result:

other:

Conclusions:

In conclusion, short-term high-level exposure to n-octane did not induce any toxicologically significant effects on measures of learned performance.

Executive summary:

In conclusion, short-term high-level exposure to n-octane did not induce any toxicologically significant effects on measures of learned performance.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

1 000 ppm

Study duration:

subacute

Species:

mouse

Quality of whole database:

Three key and three supporting read across studies from structural analaogues available for assessment.

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No neurotoxicity data is available for Hydrocarbons, C7-C8, n-alkanes. However, data is available for structural analogues, Hydrocarbons, C7-C9, isoalkanes, Octane, and light alkylate naphtha distillate and presented in the dossier. 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.

 

Hydrocarbons, C7-C9, isoalkanes

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).

 

Octane

In a short-term neurotoxicity study (CEFIC, 2000), groups of male rats (8/dose level) were exposed by inhalation to 0, 1400, 4200 or 14000 mg/m³ (corresponding to ca. 300, 900 and 3000 ppm) octane, 8 h per day, for 3 consecutive days. Animals were tested daily for effects on motor activity, functional observation measures and learned performance of a visual discrimination task. No clear signs of general intoxication and no significant effects on any of these parameters were observed up to and including the highest dose, therefore the NOAEC was considered to be greater than 14000 mg/m³.

 

Light alkylate naphtha distillate

In a supporting study (Schreineret al., 1998), rats (12/sex/group) were exposed by inhalation to a light alkylate naphtha distillate ( LAND-2, C4–C10; CAS No. 64741-66-8) at 0, 668, 2220 or 6646 ppm, 6 h per day, 5 days per week, for 13 weeks; 12 additional rats per sex in the control and high dose groups were selected for a 4-week recovery period after the final exposure. Besides standard parameters of subchronic toxicity, neurotoxicity evaluations were conducted and consisted of motor activity and a functional operational battery (FOB) measured pretest, during weeks 5, 9, and 14 of the study, and after the 4-week recovery period. No exposure-related mortality or signs of general intoxication were observed. Significant increases both in absolute and relative kidney weights were noted in males at the highest dose and correlated with hyaline droplet formation and renal nephropathy observed microscopically. These effects in male rats, however, were considered to be of no toxicological significance for humans. In both sexes, liver weights were increased at the highest dose, but no correlation was seen in microscopic examinations. Moreover, the effect appeared to reversible after the 4-week recovery period. Exposure to LAND-2 did not result in neurotoxicity as assessed by motor activity measurements, FOB, or neuropathology. The no-observed-effects level (NOAEC) for LAND-2 was 2220 ppm (corresponding to ca. 8100 mg/m³) for subchronic toxicity and ≥ 6646 ppm (corresponding to 24300 mg/m³) for neurotoxicity.

 

Several other analogues have been tested, namely normal-heptane; hydrocarbons, C6-C7, n-alkanes, isoalkanes, cyclics, < 5% n-hexane; and alkanes, C7-10-iso- (analogue substance for iso-octane). Studies on neurotoxic effects were performed in rodents upon single and/or repeated dose inhalation exposure to the test substances at maximum concentrations ranging from 12000 up to 24300 mg/m³. In the majority of cases, measurement of various parameters of neurobehavioral response showed minimal to no adverse effects. In some cases, however, reversible neurobehavioural effects occurred at the higher dose levels. NOAEC values for neurobehavioural effects were ≥ 1000 ppm (ca. 3500-5200 mg/m³ depending on composition), mice being much more sensitive than rats (Frantik et al., 1994; CEFIC, 2000, 2001; Lammers, 2001; Balster et al., 1997; Bowen and Balster, 1997; Schreiner et al. 1998).

 

Therefore, Hydrocarbons, C7-C8, n-alkanes are unlikely to present a hazard as a neurotoxicant.

 

References:

 

CEFIC (2001). The Effects of Short-term Inhalatory Exposure to Iso-octane on Behaviour in the Rat. Unpublished. Testing laboratory: TNO Nutrition and Food Research Institute. Report no.: V99.430 Final. Owner company: CEFIC. Study number: 40.144/01.09. Report date: 2001-02-15.

 

Frantik, E. et al. (1994). Relative Acute Neurotoxicity of Solvents: Isoeffective Air Concentrations of 48 Compounds Evaluated in Rats and Mice. Environmental Research 66: 173-185.

 

Lammers, J. H. C. M. (2001). The Effects of Short-term Inhalatory Exposure to Cypar 7 on Behaviour in the Rat. Unpublished. Testing laboratory: TNO Nutrition and Food Research Institute. Report no.: V99.1115 Final. Owner company: CEFIC. Study number: 40.144/01.10. Report date: 2001-02-15.

Justification for classification or non-classification

Based on available read across data from structural analogues, Hydrocarbons, C7-C8, n-alkanes is unlikely to present a hazard as a neurotoxicant.