Registration Dossier

Toxicological information

Neurotoxicity

Currently viewing:

Administrative data

Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1994-03-17 to 1994-07-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was conducted according to OECD 424 guidelines and was GLP compliant.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in Section 13.
Cross-reference
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1994-03-17 to 1994-07-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was conducted according to OECD 424 guidelines and was GLP compliant.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in Section 13.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 424 (Neurotoxicity Study in Rodents)
Deviations:
yes
Remarks:
Animals were dosed for 42 to 47 days and 8 instead of 10 animals per sex per dose were used.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, Michigan
- Age at study initiation: Males were 6 weeks old and females were 8 weeks old.
- Weight at study initiation: Males: 159 to 220 grams; females: 184 to 242
- Fasting period before study: None
- Housing: Individually except during cohabitation; males were housed 2-3 per cage during the first 4 days of acclimation
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 25 °C
- Humidity (%): 21 to 79%
- Air changes (per hr): 10 to 12
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

IN-LIFE DATES: From:1994-03-17 To: 1994-05-03
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: After stirring the blended test material for 15 minutes, a specified amount of test material was added to a flask with half of the corn oil. The flasks were capped and inverted several times, then the remaining corn oil was added and the procedure repeated. The solution was then stirred for 15 minutes. Preparations were kept for a maximum of 28 days.

VEHICLE
- Concentration in vehicle: 0, 20, 100, or 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): APR0695A, OCT0494A, and DEC2194A
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Top, middle, and bottom samples of a 20 and 200 mg/mL dose formulation were tested to determine homogeneity. All samples were within 6% of the nominal concentration indicating that the dose formulations were homogeneous. Stability was tested on the 20 and 200 mg/mL dose formulation stored in the refrigerator and sampled at 3, 8, 15, and 29 days. The dose formulations were found to be stable under these conditions with all samples with 7% of the nominal value. All dose formulations were tested during weeks 1, 3, and 7 and were all found to be within 4% of the nominal concentration.
Duration of treatment / exposure:
Males: 43 to 47 days; females: 46 to 47 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 100, 50, 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
Eight randomly selected males and eight females (from a satellite group).
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were selected based on a range finding study.
- Rationale for selecting satellite groups: The females used in the neurotoxicity portion of the study were considered a satellite group in a combined repeat dose/reproduction/developmental study and were not breed.
Observations and clinical examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily except mortality which was checked twice a day.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No
Specific biochemical examinations:
NEUROPATHY TARGET ESTERASE (NTE) ACTIVITY: No

CHOLINESTERASE ACTIVITY: No
Neurobehavioural examinations performed and frequency:
FUNCTIONAL OBSERVATIONAL BATTERY: Yes
- Parameters checked in table 1 were examined.
- Description of procedures: Eight randomly selected males and the eight nonbreed females were tested. Animals were observed in their cage, then during removal from the cage, in an open field for approximately 1.5 minutes, and then a manipulation test was performed. Three trials were performed for each animal for motor activity using automated activity recording equipment for a 1 hour period.
- Minimization of bias:
- Technicians were blind to treatment status of animals: Yes
- Time schedule for examinations: At the end of dosing on day 44, 45, or 46
- Duration of observation period for open field observations: 1.5 minutes

LOCOMOTOR ACTIVITY: Yes
- Replicates used: No data
- Type of equipment used: An automated activity recording equipment (Flex-Field Animal Activity System, San Diego Instruments). Each chamber is divided up into grids by photobeams.
- Length of session, number and length of subsessions: 1 hour
- Parameters measured: Number of central, peripheral, and total squares entered
Sacrifice and (histo)pathology:
- Time point of sacrifice: Day 46 or 47
- Number of animals sacrificed: All animals
- Parameters measured:
- Brain weight: Yes
- Length and width of brain: No
Tissues evaluated: Brain, eye with optic nerve, peripheral nerve (sciatic), and spinal cord
- Type of staining: Haematoxylin and eosin
- Number of animals evaluated from each sex and treatment group: Five males and females from the control and high-dose groups
Other examinations:
None
Positive control:
None
Statistics:
A one-way ANOVA followed by either Dunnett's test or a modified Dunnett's test was used for continuous data and a Chi-square test was used for count data. All tests were two-tailed with a p<0.05.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
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: There was no mortality or clinical signs related to neurotoxicity.

BODY WEIGHT AND WEIGHT GAIN: There were no differences in body weight.

FOOD CONSUMPTION: Food consumption was not affected.

NEUROBEHAVIOUR: There was a significant increase in the number of centre square entries in the 1000-mg/kg/day females. Although there was also an increase in the peripheral squares and total squares entered, the results were no statistically significant due to the high variability. Lacking any other indication of neurological effects this is considered due to variability and not treatment related.


GROSS PATHOLOGY: There were no abnormalities noted in relation to the nervous system.


NEUROPATHOLOGY: Histopathology did not indicate any abnormal findings in the nervous system.

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Overall effects
Remarks on result:
other:
Conclusions:
A NOAEL of 1000 mg/kg/day was established for neurotoxicity in both males and females.
Executive summary:

In this neurotoxicity study, eight Sprague-Dawley Crl:CDBR VAF/Plus rats/sex/dose were administered a blend of equal amounts of Neodene 14 alpha olefin, alpha olefin C14 1-tetradecene, and 1-tetradecene Gulftene 14 at doses of 0, 100, 500, or 1000 mg/kg/day (administered as 5 mL/kg of 0, 20, 100, or 200 mg/mL concentrations) for 43 to 47 days.

This neurotoxicity study was part of a combined repeated dose toxicity study/reproduction/developmental toxicity screening test in rats. The repeated dose toxicity study and reproduction/developmental study are written as separate study reports. There were no mortality, no effects on clinical signs, gross pathology, brain weights, or histopathology that would indicate neurotoxicity. There were no treatment-related changes in the functional observational battery (FOB) tests. Therefore, there was no LOAEL for neurotoxicity and the NOAEL was 1000 mg/kg/day.

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was conducted according to OECD 424 guidelines and was GLP compliant.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 424 (Neurotoxicity Study in Rodents)
Deviations:
yes
Remarks:
Animals were dosed for 42 to 47 days and 8 instead of 10 animals per sex per dose were used.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Blended from equal amounts of Neodene 14 alpha olefin, alpha olefin C14 1-tetradecene, and 1-tetradecene Gulftene 14
- Substance type: C14 alpha olefin
- Physical state: Clear colourless liquid
- Analytical purity: 99.0% to 99.98%
- Lot/batch No.: Neodene 14 alpha olefin 20202-45-1050, alpha olefin C14 1-tetradecene 300-954, and 1-tetradecene Gulftene 14 CBN0048
- Expiration date of the lot/batch: Only provided for Neodene 14 alpha olefin, 1994-12
- Storage condition of test material: Room temperature under nitrogen

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, Michigan
- Age at study initiation: Males were 6 weeks old and females were 8 weeks old.
- Weight at study initiation: Males: 159 to 220 grams; females: 184 to 242
- Fasting period before study: None
- Housing: Individually except during cohabitation; males were housed 2-3 per cage during the first 4 days of acclimation
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 25 °C
- Humidity (%): 21 to 79%
- Air changes (per hr): 10 to 12
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

IN-LIFE DATES: From:1994-03-17 To: 1994-05-03

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: After stirring the blended test material for 15 minutes, a specified amount of test material was added to a flask with half of the corn oil. The flasks were capped and inverted several times, then the remaining corn oil was added and the procedure repeated. The solution was then stirred for 15 minutes. Preparations were kept for a maximum of 28 days.

VEHICLE
- Concentration in vehicle: 0, 20, 100, or 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): APR0695A, OCT0494A, and DEC2194A
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Top, middle, and bottom samples of a 20 and 200 mg/mL dose formulation were tested to determine homogeneity. All samples were within 6% of the nominal concentration indicating that the dose formulations were homogeneous. Stability was tested on the 20 and 200 mg/mL dose formulation stored in the refrigerator and sampled at 3, 8, 15, and 29 days. The dose formulations were found to be stable under these conditions with all samples with 7% of the nominal value. All dose formulations were tested during weeks 1, 3, and 7 and were all found to be within 4% of the nominal concentration.
Duration of treatment / exposure:
Males: 43 to 47 days; females: 46 to 47 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 50, 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
Eight randomly selected males and eight females (from a satellite group).
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were selected based on a range finding study.
- Rationale for selecting satellite groups: The females used in the neurotoxicity portion of the study were considered a satellite group in a combined repeat dose/reproduction/developmental study and were not breed.

Examinations

Observations and clinical examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily except mortality which was checked twice a day.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No
Specific biochemical examinations:
NEUROPATHY TARGET ESTERASE (NTE) ACTIVITY: No

CHOLINESTERASE ACTIVITY: No
Neurobehavioural examinations performed and frequency:
FUNCTIONAL OBSERVATIONAL BATTERY: Yes
- Parameters checked in table 1 were examined.
- Description of procedures: Eight randomly selected males and the eight nonbreed females were tested. Animals were observed in their cage, then during removal from the cage, in an open field for approximately 1.5 minutes, and then a manipulation test was performed. Three trials were performed for each animal for motor activity using automated activity recording equipment for a 1 hour period.
- Minimization of bias:
- Technicians were blind to treatment status of animals: Yes
- Time schedule for examinations: At the end of dosing on day 44, 45, or 46
- Duration of observation period for open field observations: 1.5 minutes

LOCOMOTOR ACTIVITY: Yes
- Replicates used: No data
- Type of equipment used: An automated activity recording equipment (Flex-Field Animal Activity System, San Diego Instruments). Each chamber is divided up into grids by photobeams.
- Length of session, number and length of subsessions: 1 hour
- Parameters measured: Number of central, peripheral, and total squares entered
Sacrifice and (histo)pathology:
- Time point of sacrifice: Day 46 or 47
- Number of animals sacrificed: All animals
- Parameters measured:
- Brain weight: Yes
- Length and width of brain: No
Tissues evaluated: Brain, eye with optic nerve, peripheral nerve (sciatic), and spinal cord
- Type of staining: Haematoxylin and eosin
- Number of animals evaluated from each sex and treatment group: Five males and females from the control and high-dose groups
Other examinations:
None
Positive control:
None
Statistics:
A one-way ANOVA followed by either Dunnett's test or a modified Dunnett's test was used for continuous data and a Chi-square test was used for count data. All tests were two-tailed with a p<0.05.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
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: There was no mortality or clinical signs related to neurotoxicity.

BODY WEIGHT AND WEIGHT GAIN: There were no differences in body weight.

FOOD CONSUMPTION: Food consumption was not affected.

NEUROBEHAVIOUR: There was a significant increase in the number of centre square entries in the 1000-mg/kg/day females. Although there was also an increase in the peripheral squares and total squares entered, the results were no statistically significant due to the high variability. Lacking any other indication of neurological effects this is considered due to variability and not treatment related.


GROSS PATHOLOGY: There were no abnormalities noted in relation to the nervous system.


NEUROPATHOLOGY: Histopathology did not indicate any abnormal findings in the nervous system.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Overall effects
Remarks on result:
other:

Applicant's summary and conclusion

Conclusions:
A NOAEL of 1000 mg/kg/day was established for neurotoxicity in both males and females.
Executive summary:

In this neurotoxicity study, eight Sprague-Dawley Crl:CDBR VAF/Plus rats/sex/dose were administered a blend of equal amounts of Neodene 14 alpha olefin, alpha olefin C14 1-tetradecene, and 1-tetradecene Gulftene 14 at doses of 0, 100, 500, or 1000 mg/kg/day (administered as 5 mL/kg of 0, 20, 100, or 200 mg/mL concentrations) for 43 to 47 days.

This neurotoxicity study was part of a combined repeated dose toxicity study/reproduction/developmental toxicity screening test in rats. The repeated dose toxicity study and reproduction/developmental study are written as separate study reports. There were no mortality, no effects on clinical signs, gross pathology, brain weights, or histopathology that would indicate neurotoxicity. There were no treatment-related changes in the functional observational battery (FOB) tests. Therefore, there was no LOAEL for neurotoxicity and the NOAEL was 1000 mg/kg/day.

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was conducted according to OECD 424 guidelines and was GLP compliant.