Fenamiphos

Neurotoxicity

Description of key information

Acute neurotoxicity:

NOAEL is 0.25 mg/kg bw, based on inhibition of erythrocyte ChE activity and clinical signs at 0.5 mg/kg bw in dogs.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: acute oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Qualifier:

no guideline available

Principles of method if other than guideline:

- Principle of test: Dogs were examined for cholinergic signs and symptoms in three individual trials with varying blood sampling time points after a single oral administration of the test item at different dose levels.

- Short description of test conditions: The test item was orally administered to groups of male and female Beagle dogs by gavage at single doses of 0, 0.063, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg bw. The test substance was applied as a solution in water / Cremophor EL (2 %). The application volume was 5 - 10 mL/kg bw.

- Parameters analysed: Food intake, clinical signs, body weight, plasma, erythrocyte and brain ChE activity

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

dog

Strain:

Beagle

Remarks:

HsdBor:BEAG for trail 1, HsdBor:DOBE for trail 2 and 3

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: water/ cremophor EL (2%)

Details on exposure:

VEHICLE
- Amount of vehicle: 5 - 10 mL/kg bw

Frequency of treatment:

Single application

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

0.063 mg/kg bw/day (nominal)

Dose / conc.:

0.125 mg/kg bw/day (nominal)

Dose / conc.:

0.25 mg/kg bw/day (nominal)

Dose / conc.:

0.5 mg/kg bw/day (nominal)

Dose / conc.:

1 mg/kg bw/day (nominal)

Dose / conc.:

2 mg/kg bw/day (nominal)

No. of animals per sex per dose:

2 animals per sex

Control animals:

yes, concurrent vehicle

Details on study design:

The study was divided into three trials:

In the first 4 dogs (2 males and 2 females) were treated with single doses of the test substance at 0.063, 0.125, 0.25 and 0.5 mg/kg bw, with a 3 week wash-out period between each dosing and starting with the highest dose; blood was taken for plasma and erythrocyte ChE activity at time 0, 20, 60, 90, 120, 180 and 360 min and 1, 7, 14 and 21 d, after administration of the test substance. Three weeks later the four dogs were treated with the test substance again at the highest dose used in trial 1, namely 0.5 mg/kg bw, and one hour later killed for brain ChE determination.

In the second trial was the test substance administered to groups of 4 dogs (2 males and two females) at a dose of 0.5 mg/kg bw or 2.0 mg/kg bw. Blood was taken for determination of plasma and erythrocyte ChE activity before administration of the test material and 1 and 2 h later. The animals were then killed and brain was taken for ChE activity estimation.

In the third trial, the test substance was administered at a dose of 1.0 mg/kg bw to 4 dogs (2 males and 2 females), blood being taken for estimation of plasma and erythrocyte ChE activity before administration of the test material and 1, 2, 4, and 24 h later. The dogs were then killed and brain taken for ChE estimation (i.e. 24 h after administration of the test substance). Throughout, plasma and erythrocyte ChE activity was expressed as a percentage of the activity at time 0 in the case of the plasma and erythrocyte (i.e. each dog was its own control).

In all 3 trials, the dogs were monitored for cholinergic signs and symptoms. Food intake was determined daily and body weight measured weekly. Eight control dogs from two other studies were used to establish “control” values of brain ChE activity.

Observations and clinical examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

Specific biochemical examinations:

CHOLINESTERASE ACTIVITY: Yes
- Time schedule for examinations: see "Details on study design"
- How many animals: all

Clinical signs:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food efficiency:

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

Trial 1 - Plasma and erythrocyte ChE activity
No clinical sign of cholinergic toxicity was seen up to 0.5 mg/kg bw in trial 1. Clinical signs of cholinergic toxicity were seen at 0.5 mg/kg bw and above, as was vomiting. Atropine was given to the 2.0 mg/kg bw group 30-60 minutes after dosing. No effect was seen on feed intake or on body weight.
In trial 1, at 0.125 mg/kg bw and above plasma ChE activity was consistently and significantly reduced, but had largely recovered by 24h, whereas at 0.063 mg/kg body weight, significant inhibition (20.6%) was only observed at one time point (2h after dosing). Recovery was nearly complete at all doses by 24h. In trial 1, at all doses, erythrocyte ChE activity was <20% reduced. Maximum effects were seen at 60 – 90 minutes after administration of the material.

Trial 2 - Plasma and erythrocyte ChE activity
In trial 2, considerable degrees of depression of plasma ChE activity were recorded at 0.5 mg/kg bw (almost 80% at 60 min), while virtually complete inhibition was observed at 2.0 mg/kg bw. In trial 2, inhibition of erythrocyte ChE activity was >20% in both 0.5 and 2.0 mg/kg bw during the whole experiment (2h).

Trial 3 - Plasma and erythrocyte ChE activity
In trial 3, erythrocyte ChE activity was most inhibited at 60 and 120 min after dosing, biologically significant inhibition of erythrocyte ChE activity was not seen at 24h (dose 1 mg/kg bw).

Brain ChE activity
Brain ChE activity was measured on the 4 dogs of trial 1, 1 h after administration of the test substance at a dose of 0.5 mg/kg and on the 4 dogs from trial 2 that had been administered the test substance at the same dose, but 2 hours after administration of the test substance: in both cases, the activity was greater than in the brains from the control animals. Brain ChE activity in dogs killed 2h after administration of the test substance, 2.0 mg/kg bw, was 6.05 U/g tissue (control values were 2.71 U/g); however in trial 3, where animals, administered the test substance at a dose of 1.0 mg/kg bw, were killed 24h after dosing brain ChE activity was 2.05 U/g, when the brain was taken immediately and frozen, and 2.15 U/g when brain was frozen 3h after sacrifice.

Key result

Dose descriptor:

NOAEL

Effect level:

0.25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

other: inhibition of erythrocyte ChE activity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

0.5 mg/kg bw/day (nominal)

System:

autonomic nervous system

Organ:

brain

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

The NOAEL is 0.25 mg/kg bw, based on inhibition of erythrocyte ChE activity and clinical signs at 0.5 mg/kg bw.

Executive summary:

The test item was orally administered to groups of male and female Beagle dogs by gavage at single doses of 0, 0.063, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg bw. The test substance was applied as a solution in water / Cremophor EL (2 %). The application volume was 5 - 10 mL/kg bw.

No treatment-related effects on feed intake or body weight development were observed. At > 0.5 mg/kg bw the animals showed slight cholinergic clinical signs. One animal vomited at 0.5 mg/kg bw. Further dose escalation lead to severe symptoms of intoxication like defecation, shivering, recumbancy, and finally cramps at 2.0 mg/kg bw.

A dose dependent decrease of plasma ChE activity was seen at > 0.125 mg/kg bw with a > 60 % inhibition at 0.5 mg/kg bw. The maximum inhibition occurred 60 to 90 minutes after administration. Determinations after 7, 14, and 21 days indicated full recovery. A dose of 0.5 mg/kg bw caused a slight decrease of ery ChE. Maximal inhibition was 60 to 90 minutes after administration. Recovery was complete after 24 hours. The determination of brain ChE yielded a time related increase. The increase was most pronounced 2 h after administration. At a dose level of 2.0 mg/kg bw brain ChE was not decreased. A single oral dose of 0.25 mg the test substance per kg bw to dogs was a NOAEL with regard to inhibition of erythrocyte ChE.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.25 mg/kg bw/day

Study duration:

subacute

Species:

dog

Quality of whole database:

The study was considered acceptable.

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The information provided below was taken from the original plant protection dossier on the active substance submitted in 2017 for inclusion of the test substance to Annex I of Directive 91/414/EEC and has been previously evaluated in the Draft Assessment Report (DAR) according to the Commission Regulation (EU) No 1107/2009 (2003) and subject to peer review by EFSA and Member States (2006). The summaries as published in the RAC opinion (2011) are given below.

 

Acute neurotoxicity

Detzer (2002): The test item was orally administered to groups of male and female Beagle dogs by gavage at single doses of 0, 0.063, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg bw. The test substance was applied as a solution in water / Cremophor EL (2 %). The application volume was 5 - 10 mL/kg bw.

No treatment-related effects on feed intake or body weight development were observed. At > 0.5 mg/kg bw the animals showed slight cholinergic clinical signs. One animal vomited at 0.5 mg/kg bw. Further dose escalation lead to severe symptoms of intoxication like defecation, shivering, recumbancy, and finally cramps at 2.0 mg/kg bw.

A dose dependent decrease of plasma ChE activity was seen at > 0.125 mg/kg bw with a > 60 % inhibition at 0.5 mg/kg bw. The maximum inhibition occurred 60 to 90 minutes after administration. Determinations after 7, 14, and 21 days indicated full recovery. A dose of 0.5 mg/kg bw caused a slight decrease of ery ChE. Maximal inhibition was 60 to 90 minutes after administration. Recovery was complete after 24 hours.

The determination of brain ChE yielded a time related increase. The increase was most pronounced 2 h after administration. At a dose level of 2.0 mg/kg bw brain ChE was not decreased.

A single oral dose of 0.25 mg test substance per kg bw to dogs was a NOAEL with regard to inhibition of erythrocyte ChE.