Registration Dossier

Administrative data

Endpoint:
neurotoxicity: acute oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1980
Report Date:
1980

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 418 (Delayed Neurotoxicity of Organophosphorus Substances Following Acute Exposure)
Version / remarks:
adopted 1984
Deviations:
yes
Remarks:
only 4 animals used; no detailed report about pathology;
Principles of method if other than guideline:
Combined with acute toxicity test.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Weston 1452
- Physical state: white solid
- Analytical purity: 99.5%
- Lot/batch No.: PP-356
- Storage condition of test material: Room temperature
Specific details on test material used for the study:
- Name of test material (as cited in study report): Weston 1452
- Analytical purity: 99.5%

Test animals

Species:
hen
Strain:
other: White Leghorn Pullet hens, Hyline H-36
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kerr Hatcheries, Flemington, New Jersey, USA
- Age at study initiation: 12 months, from a commercial egg producing facility
- Weight at study initiation: 1.4 to 1.9 kg
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least two weeks

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test material was dissolved in corn oil and administered at a volume of 10.0 mL/kg using a K-9 stomach tube, Kaslow, size 12 french (levin type) fitted to a 20cc syringe.
All the Weston 1452 hens had received the same dosage 21 days before the doses reported in this report (see aucte hen study chapter 7.2.1)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
single treatment
Frequency of treatment:
once
Doses / concentrationsopen allclose all
Dose / conc.:
1 800 mg/kg bw/day (actual dose received)
Dose / conc.:
2 700 mg/kg bw/day (actual dose received)
Dose / conc.:
4 050 mg/kg bw/day (actual dose received)
Dose / conc.:
6 080 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
4
Control animals:
no

Examinations

Observations and clinical examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All hens were examined for signs of ill-health er reaction to treatment before dosing, hourly four hours after dosing and daily thereafter.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
Body weights were recorded on Days 21 (day of dosing) 22, 25, 28, 32, 35, 39, 42 and 45 for Groups III-VI which ci-incided with days 0, 1, 4, 7, 11, 14, 18, 21 and 24 for Groups VII and VIII.
Neurobehavioural examinations performed and frequency:
Three times per week each hen was removed from the cage, acclimated to "Astroturf" for 20 minutes and then "force-exercised". Each hen was then observed and scored for signs of neuromuscular impairment. The scoring system was as follows:
Symptom free: 0
Doubtful or minor signs (slight leg weakness): 1
Positive signs of neurological impairment (unsteady or altered gait, leg weakness): 2
Moderate neurological impairment (marked leg weakness, tendency to fall back on hocks, inability to land when dropped from approximately four feet, use of wings to maintain balance, loss of toe grip): 3
Extreme neurological impairment (hypertension of limbs, inability to walk, ataxia, prostration, morbidity): 4

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The majority of hens showed green and yellow discoloration of the feces (occasionally orange) on the day of dosing or the next day, this reflects the use of corn oil vehicle and is not considered to reflect a response to treatment.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The hens remained normal in respect of body weight throughout the observation period.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were no signs of toxicity and the hens remained normal in respect of appearance, mood and locomotor function throughout the observation period.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
At necropsy of hens in groups I and III, there were occasional findings of discoloration of liver (F 102 and 152), spleen (#126) and kidneys (#103); these are common pathological entities in hens of this age and are not considered to reflect any delayed or residual response to treatment.
Histopathological findings: neoplastic:
not examined

Any other information on results incl. tables

Hens that received TOCP showed no acute effects. Progressive leg weakness, incoordination, ataxia and paralysis commenced after 12 -14 days and culminated in sacrifice in extremis 24 or 28 days after dosing. None of the Weston 1452 or vehicle dosed hens showed any signs related to treatment and were symptom-free at all neurological examinations.

Applicant's summary and conclusion

Conclusions:
Hens given single oral dosages of 800-6080 g/kg did not show any evidence of acute, delayed or residual toxicity.