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Toxicological information

Neurotoxicity

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Description of key information

An overview of neurotoxic effects are discussed.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: chronic oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not specified.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP. Reported under EC 793/93 for Existing substances regulations. Full methodology etc not available. Deemed reliable as evaluated by the European Commission. This data is considered the property of the data submitter. However it has not been possible to locate the study report due to re-organisation associated with the merger.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Four groups of twenty birds each were administered the test substance by oral gavage daily for 91 days at dosage levels of 10, 20, 90 and 270 mg/kg/day. One group received corn oil only (control) and two other groups received TOCP at 1.5 and 7.5 mg/kg/day (positive controls). Body weights and food consumption were measured weekly and signs of neurotoxicity were looked for daily. At study termination the brain, spinal cord and peripheral nerve were fixed in situ and 10/group were examined microscopically for signs of neurological damage.
GLP compliance:
yes
Limit test:
no
Species:
hen
Strain:
not specified
Sex:
female
Details on test animals and environmental conditions:
Not specified.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Four groups of twenty birds each were administered the test substance by oral gavage daily for 91 days at dosage levels of 10, 20, 90 and 270 mg/kg/day.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data.
Duration of treatment / exposure:
91 days
Frequency of treatment:
daily dose
Remarks:
Doses / Concentrations:
10 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
20 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
90 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
270 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
One group received corn oil only (control) and two other groups received TOCP at 1.5 and 7.5 mg/kg/day (positive controls). Body weights and food consumption were measured weekly and signs of neurotoxicity were looked for daily. At study termination the brain, spinal cord and peripheral nerve were fixed in situ and 10/group were examined microscopically for signs of neurological damage.
Observations and clinical examinations performed and frequency:
Food Consumption: Weekly
Bodyweight: Weekly.
Specific biochemical examinations:
Not specified.
Neurobehavioural examinations performed and frequency:
Neurotoxicity: Daily
Sacrifice and (histo)pathology:
Not specified.
Other examinations:
Not applicable.
Positive control:
Two positive control groups received TOCP at 1.5 and 7.5 mg/kg/day.
Statistics:
Not specified.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Ataxia was observed in 20% and 45% of the birds receiving 90 and 270 mg/kg/day test substance respectively. The hens receiving 10 and 20 mg/kg/day showed no morphological signs of neurotoxicity, while groups receiving 90 and 270 mg/kg/day showed degenerative changes which correlated with the ataxia.
Dermal irritation (if dermal study):
not examined
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Ataxia was observed in 20% and 45% of the birds receiving 90 and 270 mg/kg/day test substance respectively. The hens receiving 10 and 20 mg/kg/day showed no morphological signs of neurotoxicity, while groups receiving 90 and 270 mg/kg/day showed degenerative changes which correlated with the ataxia.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
The hens receiving 10 and 20 mg/kg/day showed no morphological signs of neurotoxicity, while groups receiving 90 and 270 mg/kg/day showed degenerative changes which correlated with the ataxia.
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not examined
Description (incidence and severity):
Migrated information from 'Further observations for developmental neurotoxicity study'
Details on results (for developmental neurotoxicity):Not applicable. (migrated information)
Details on results:
Ataxia was observed in 20% and 45% of the birds receiving 90 and 270 mg/kg/day test substance respectively, and 30% of the birds receiving 7.5 mg/kg/day TOCP. The hens receiving 10 and 20 mg/kg/day showed no morphological signs of neurotoxicity, while groups receiving 90 and 270 mg/kg/day showed degenerative changes which correlated with the ataxia. The test substance produced neurotoxicity at these two dosage levels.
Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day
Sex:
female
Basis for effect level:
other: for 90 day exposure
Remarks on result:
other:
Conclusions:
The NOEL of the test substance for 90 days of exposure was 20 mg/kg/day
Executive summary:

The NOEL of the test substance for 90 days of exposure was 20 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subchronic
Species:
hen
Quality of whole database:
K2-study not conducted to GLP or in compliance with agreed protocols.

Effect on neurotoxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: acute inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not specified.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP. Reported under EC 793/93 for Existing substances regulations. Full methodology etc not available. Deemed reliable as evaluated by the European Commission. This data is considered the property of the data submitter. However it has not been possible to locate the study report due to re-organisation associated with the merger.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Ten hens/group were exposed by inhalation to the aerosol form of the test substance in a single eight-hour period and then examined for the next 21 day period for signs of neurotoxicity.
GLP compliance:
yes
Limit test:
no
Species:
hen
Strain:
not specified
Sex:
female
Details on test animals and environmental conditions:
Not specified.
Route of administration:
inhalation: aerosol
Vehicle:
not specified
Details on exposure:
Ten hens/group were exposed by inhalation to the aerosol form of the test substance in a single eight-hour period and then examined for the next 21 day period for signs of neurotoxicity.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of atmosphere were analysed. No further information is detailed within the report.
Duration of treatment / exposure:
8 hours, 21 day exposure period.
Frequency of treatment:
Single 8 hour exposure.
Remarks:
Doses / Concentrations:
0.62 mg/L
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
2.40 mg/L
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
2.54 mg/L
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
3.09 mg/L
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
not specified
Details on study design:
Not specified.
Observations and clinical examinations performed and frequency:
No data.
Specific biochemical examinations:
No data.
Neurobehavioural examinations performed and frequency:
No data.
Sacrifice and (histo)pathology:
No data.
Other examinations:
Not applicable.
Positive control:
No data.
Statistics:
Not applicable.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mild or moderate ataxia was seen in 2/10 birds exposed to 2.40 mg/L and in 4/10 birds exposed to 3.09 mg/L.
Dermal irritation (if dermal study):
not examined
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Mild or moderate ataxia was seen in 2/10 birds exposed to 2.40 mg/L and in 4/10 birds exposed to 3.09 mg/L.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
Histological examination of nervous tissues confirmed that degenerative changes were observed at these two dosage levels (2.40 mg/L and 3.09 mg/L).
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histological examination of nervous tissues confirmed that degenerative changes were observed at these two dosage levels (2.40 mg/L and 3.09 mg/L).
Histopathological findings: neoplastic:
not specified
Other effects:
not examined
Description (incidence and severity):
Migrated information from 'Further observations for developmental neurotoxicity study'
Details on results (for developmental neurotoxicity):Not applicable. (migrated information)
Details on results:
Mild or moderate ataxia was seen in 2/10 birds exposed to 2.40 mg/L and in 4/10 birds exposed to 3.09 mg/L. Histological examination of nervous tissues confirmed that degenerative changes were observed at these two dosage levels. No effects were observed at the 0.62 mg/L level.
Dose descriptor:
NOEL
Effect level:
0.62 mg/L air (analytical)
Based on:
test mat.
Sex:
female
Remarks on result:
other:
Conclusions:
Mild or moderate ataxia was seen in 2/10 birds exposed to 2.40 mg/L and in 4/10 birds exposed to 3.09 mg/L. Histological examination of nervous tissues confirmed that degenerative changes were observed at these two dosage levels. No effects were observed at the 0.62 mg/L level.
Executive summary:

Mild or moderate ataxia was seen in 2/10 birds exposed to 2.40 mg/L and in 4/10 birds exposed to 3.09 mg/L. Histological examination of nervous tissues confirmed that degenerative changes were observed at these two dosage levels. No effects were observed at the 0.62 mg/L level.

This information is provided as supporting study data only.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
0.62 mg/m³
Study duration:
subacute
Species:
hen
Quality of whole database:
K2-study not conducted to GLP or in compliance with agreed protocols.

Effect on neurotoxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: sub-chronic dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not specified.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non-GLP. Reported under EC 793/93 for Existing substances regulations. Full methodology etc not available. Deemed reliable as evaluated by the European Commission. This data is considered the property of the data submitter. However it has not been possible to locate the study report due to re-organisation associated with the merger.
Qualifier:
no guideline followed
Principles of method if other than guideline:
50 mg/kg of the test material was applied by pipette to the combs of 10 hens and spread evenly over the comb surface. Any residual was placed on the hen wottles. This procedure was repeated 5 days/week for 4 months. Animals were observed for signs of neurotoxicity. At the end of the treatment blood was drawn for haematology and clinical chemistry analysis. All animals received a full gross necroscopy. Brains were removed and analysed for neurotoxic esterase. The spinal and peripheral nerves were examined for signs of neuropathology microscopically. TOCP was used as the positive control and was applied to 10 hens in the same manner as the test material.
GLP compliance:
no
Limit test:
yes
Species:
hen
Strain:
not specified
Sex:
female
Details on test animals and environmental conditions:
Not specified.
Route of administration:
dermal
Vehicle:
not specified
Details on exposure:
50 mg/kg of the test material was applied by pipette to the combs of 10 hens and spread evenly over the comb surface. Any residual was placed on the hen wottles. This procedure was repeated 5 days/week for 4 months.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable.
Duration of treatment / exposure:
4 months
Frequency of treatment:
5 days/week
Remarks:
Doses / Concentrations:
50 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Not specified.
Observations and clinical examinations performed and frequency:
Not specified.
Specific biochemical examinations:
Brains were removed and analysed for neurotoxic esterase.
Neurobehavioural examinations performed and frequency:
Animals were observed for signs of neurotoxicity daily.
Sacrifice and (histo)pathology:
All animals received a full gross necroscopy. Brains were removed and analysed for neurotoxic esterase. The spinal and peripheral nerves were examined for signs of neuropathology microscopically.
Other examinations:
Not specified.
Positive control:
Yes, TOCP applied to 10 hens in the manner as the test material.
Statistics:
Not specified.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Description (incidence and severity):
Migrated information from 'Further observations for developmental neurotoxicity study'
Details on results (for developmental neurotoxicity):Not applicable. (migrated information)
Details on results:
No signs of neurotoxicity were observed during the in-life portion of the study in hens receiving test material. There was no haematological, biochemical or histological evidence of a toxic effect on the hens receiving the test material in this study. TOCP produced ataxia and nerve damage, as expected.
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Conducted over 4 months.
Remarks on result:
other:
Conclusions:
No signs of neurotoxicity were observed during the in-life portion of the study in hens receiving test material. There was no haematological, biochemical or histological evidence of a toxic effect on the hens receiving the test material in this study.
Executive summary:

No signs of neurotoxicity were observed during the in-life portion of the study in hens receiving test material. There was no haematological, biochemical or histological evidence of a toxic effect on the hens receiving the test material in this study. A NOEC of 50 mg/kg/day was therefore applied.

This information is provided as supporting study data only.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
hen
Quality of whole database:
K2-study not conducted to GLP or in compliance with agreed protocols.

Additional information

There are multiple studies for neurotoxicity on the substance, carried out over a number of years and using a variety of dose levels. On a weight of evidence basis, it appears that a neurotoxic response is only triggered for the substance at higher dose levels. Represented within the data set are a large number of acute oral toxicity studies that indicate that the substance only causes effects at high dose levels (range of > 2000 mg/kg to >20000 mg/kg).

For chronic neurotoxicity, there exists a subacute and subchronic test; the data for oral neurotoxicity has been taken from this study and is detailed at 20 mg/kg/day. Only one study for inhalation effects of neurotoxicity has been undertaken; this is an acute toxicity study, and as such, the results are questionable but are included for completeness purposes.

On the basis of the data available for review, it is deemed that neurotoxicity only takes place at higher dose levels. As such, no classification and labelling is applicable.

Justification for classification or non-classification

The above studies have all been ranked reliability 2 or 3 according to the Klimisch et al system. This ranking was deemed appropriate because the studies were not conducted to GLP or in compliance with agreed protocols. The reports do not detail a specific method; however it documents dose levels and responses in detail, so is deemed appropriate for use in the support of a formal registration. Sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds.

Justification for classification or non classification

The above results triggered no classification under the Dangerous Substance Directive (67/548/EEC) and the CLP Regulation (EC No 1272/2008). No classification for acute effects is therefore required.