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Neurotoxicity

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Description of key information

All studies are included as supporting information and are not considered for the CSA.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2 May 1997 to 7 Aug 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 424 (Neurotoxicity Study in Rodents)
Version / remarks:
1997
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EPA FIFRA, 40 CR Part 158, Addendum 10, Series 81-8, 82-7, and 83-1
Deviations:
no
GLP compliance:
yes
Limit test:
no
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
Ophthalmological findings:
no effects observed
Behaviour (functional findings):
no effects observed
Neuropathological findings:
no effects observed
Dose descriptor:
NOEL
Effect level:
>= 1 500 ppm
Based on:
test mat.
Sex:
male
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
Dietary equivalent to 95.4 mg/kg bw/day
Dose descriptor:
NOEL
Effect level:
>= 3 000 ppm
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
Dietary equivalent to 216.4 mg/kg bw/day
Critical effects observed:
no

Achieved concentrations in food

Concentration analysis results: Routine concentration analyses indicated that all formulations were within 10% of target with the following exceptions: week 1 at 10 ppm (112% of target), week 1 at 1000 ppm (112%), week 3 at 10 ppm (117%) and week 13 at 30 ppm (88.6%).

Homogeneity results: The test substance was homogeneously mixed. At 3000 ppm the concentrations varied by approximately 3% and at 10 ppm by approximately 18%; however, this variability reflected a relatively high value for one of the duplicate samples from the bottom and when this value was excluded the concentrations varied by approximately 14%.

Stability results: The test substance was stable in rodent diet at room temperature over a period of 7 days.

Mortality: There were no mortalities.

 

Clinical observations: There were no treatment-related clinical signs of an adverse effect of treatment.

 

Body weight and weight gain: There were no treatment related effects on body weight.

 

Food consumption and compound intake: There were no treatment related effects on food consumption.

 

Dose rates (based on nominal dietary levels of the test substance) were calculated in terms of mg test substance/kg body weight. Mean values are shown below:

 

Table 1. Mean Dose Received (mg/kg/day)

test subst. (ppm)

10

30

500

1000

1500

3000

Males

0.7

1.9

31.8

 

95.4

 

Females

0.7

2.1

 

73.2

 

216.4

 

Ophthalmoscopy: There were no treatment-related findings.

 

Neurobehavioural assessment: There were no treatment related effects on any of the FOB parameters. There were no treatment related effects on performance measures, auditory startle response or locomotor activity.

 

Sacrifice and pathology

Macroscopic findings:There were no treatment-related effects.

 

Microscopic findings:There were no treatment related histopathological alterations. Any lesions present were of the type, incidence and severity expected in rats of this strain and age and were also present in controls.

Conclusions:
The no-observed-effect-level (NOEL) was >=1500 ppm (males) and >= 3000 ppm (females), equivalent to mean dose levels of >= 95.4 mg/kg bw/day (males) and >= 216.4 mg/kg bw/day (females), based on the absence of neurobehavioral and neurohistopathological effects at the highest dose levels employed.
Executive summary:

In this subchronic neurotoxicity study, performed according to OECD 424 under GLP, five groups of 10 male and 10 female Sprague-Dawley rats (Crl:CD®BR strain, approximately 6 weeks old) were administered the test substance orally, in the diet, at concentrations of 0, 10, 30, 500 and 1500 ppm (males) and 0, 10, 30, 1000 and 3000 ppm (females) for 13 weeks. Morbidity and mortality were recorded twice daily, clinical observations daily, and detailed physical examinations weekly. Body weights were recorded one day before treatment commenced and weekly thereafter. Food consumption was measured weekly. Ophthalmoscopic examinations were performed prior to treatment and during week 13. The animals were subjected to a battery of neurological function tests and observations (FOB) and assessmentof locomotor activity (LMA) prior to treatment, and during weeks 4, 8 and 13. After at least 13 weeks treatment, whole body perfusion was performed on the first 6 rats/sex/group. Central and peripheral nervous tissues, anterior tibialis and gastrocnemius skeletal muscles, kidneys and gross lesions were preserved. The central and peripheral nerve tissues from control and high dose animals were evaluated histologically. All remaining animals were necropsied and examined post mortem. Kidneys and gross lesions were preserved from non-perfused animals but all other tissues were discarded.

Overall mean dose levels achieved were 0, 0.7, 1.9, 31.8, and 95.4 mg/kg bw/day (males) and 0, 0.7, 2.1, 73.2, and 216.4 mg/kg bw/day (females).

There were no mortalities and no treatment-related clinical signs. Body weight development and food consumption were unaffected by treatment, at all dose levels. After 13 weeks of treatment, there was no evidence of ocular toxicity at any dose level. There were no treatment related neurotoxicity findings in the FOB or locomotor activity. There were no treatment-related gross pathology findings at any dose level. Microscopic examination of central and peripheral nerve tissues indicated no treatment-related histopathological alterations.

In conclusion, the no-observed-effect-level (NOEL) was >=1500 ppm (males) and >= 3000 ppm (females), equivalent to mean dose levels of >= 95.4 mg/kg bw/day (males) and >= 216.4 mg/kg bw/day (females), based on the absence of neurobehavioral and neurohistopathological effects at the highest dose levels employed.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Acute, subchronic and developmental neurotoxicity

An acute neurotoxicity study (Minnema 1997), a 13-week neurotoxicity study (Minnema 1998) and a developmental neurotoxicity study (Brammer 2003, supplemented with additional brain morphometry measurements on intermediate dose groups by Brammer 2007) were conducted in rats. A comprehensive set of neurotoxicity endpoints was investigated in these studies, including an evaluation of potential to induce neurobehavioral or neuromorphological changes. Acute administration of the test substance at dose levels approaching the MLD produces a range of effects mimicking neurobehavioral deficit. The effects are transient, insofar as they occur only at the time of peak systemic exposure, and are not associated with neurohistopathological alterations. Therefore, the evidence suggests the effects are not neurotoxic in origin but are an expression of acute pharmacological over-stimulation, often autonomically mediated. This contention is supported by the results of the subchronic study in which no neurobehavioral or neuromorphological effects occurred following 13 weeks exposure. No developmental neurotoxicity was seen at any dose level, including those causing maternal toxicity. It is concluded that the test substance does not exert a neurotoxic effect on either acute, subchronic or developmental exposure.

Public data

A published study (Rodrigues et al. 2010) examined the effect of thiamethoxam on the acetylcholinestrerase activity and high-affinity choline uptake in the brains of rats dosed by subcutaneous injection at 25, 50 and 100 mg/kg bw/day for 7 days. In the two highest dose groups an increase in anxiety behaviour was observed in conjunction with reduced alcholinestrerase activity and high-affinity choline uptake. No data examining body weight development or food consumption is provided in this publication and as such systemic toxicity due to test item administration cannot be evaluated. Systemic toxicity is a common confounding factor in the assessment of studies of this type and as such the omission of these data represents a serious flaw in the reporting of this study and prevents a thorough evaluation of the presented findings. Furthermore, the findings presented in this publication are not consistent with the GLP and OECD test guideline compliant neurotoxicity studies summarised above.

Justification for classification or non-classification

No neurotoxicity or neuropathological findings were observed in a sub-chronic neurotoxicity study according to OECD guideline and GLP up to the highest dose tested (1500/3000 ppm in males/females equivalent to 95 mg/kg bw/day and 216 mg/kg bw/day respectively). Classification is not triggered.