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Toxicological information

Neurotoxicity

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Administrative data

Endpoint:
neurotoxicity: acute oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Principles of method if other than guideline:
The study was designed to determine the neurotoxic effects following subcutaneous dosing of Triphenyl Phosphite (TPP) to adult hens.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name: triphenyl phosphite
- Lot/batch No.: TPPX-018-04291A

Test animals

Species:
other: chicken
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Mr. Odlin, Graygable Poultry Service, Bury St. Edmunds, Suffolk
- Age at study initiation: over 14 months
- Weight at study initiation: 2010 - 2920 g
- Housing: floor pens
- Diet: standard HRC laying bird ration in pellet form
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 (mean; range 17-30)
- Humidity (%): 73 (mean)
- Photoperiod (7 hrs dark /17 hrs light):

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
single administration, followed by a 21 day observation period
Doses / concentrationsopen allclose all
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
375 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Group 6 (control) : 5 hens
Group 7 (0.5 g/kg): 10 hens
Group 8 (0.375 g/kg): 10 hens
Group 9 (0.25 g/kg: 10 hens
Group 10 (0.125 g/kg): 10 hens
Control animals:
other: treated with water at the maximum dose volume of this study
Details on study design:
- Dose selection rationale: based on a range finder

Examinations

Observations and clinical examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days -14, -7, 0 (immediately prior to dosing), 4, 7, 11, 14 and 21.

FOOD CONSUMPTION
group msan food consumption was recorded over weekly intervals throughout the study.

ATAXIA ASSESSMENT
daily
Neurobehavioural examinations performed and frequency:
The movements of each bird were examined daily to assess muscle coordination. The degree of ataxia was scored on a point award system similar to that described by Cavanagh et al (1961). The scale ranges from 0 to 8, increasing scale number indicating increasing degree of ataxia.
Sacrifice and (histo)pathology:
All birds were subjected to gross post mortem examination. Tissues for histological examination were taken only from birds showing Grade 3 ataxia and upwards at termination of the study. The brain, spinal cord and sciatic nerve from each bird were fixed in 10% neutral buffered formalin, and sections of these tissues ware stained with haematoxylin and eosin.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Immediately prior to dosing, one bird in group 7 was sacrificed and replaced as it had shown a severe weight loss.
One bird In Group 7 and two birds in Croup 8 were found dead within 24 hours following dosing. These birds showed signs of unsteadiness or inability to stand prior to death, but no signs of toxicity were observed in any other birds shortly after dosing. Twelve birds developed ataxia following dosing, and on Day 20 one bird in Group 7 was sacrificed as it had Grade 8 ataxia. On Day 15 one bird in Group 10 was also sacrificed as it had been bullied by other birds. No signs of ill health were observed in any other birds.
Mortality:
mortality observed, treatment-related
Description (incidence):
Immediately prior to dosing, one bird in group 7 was sacrificed and replaced as it had shown a severe weight loss.
One bird In Group 7 and two birds in Croup 8 were found dead within 24 hours following dosing. These birds showed signs of unsteadiness or inability to stand prior to death, but no signs of toxicity were observed in any other birds shortly after dosing. Twelve birds developed ataxia following dosing, and on Day 20 one bird in Group 7 was sacrificed as it had Grade 8 ataxia. On Day 15 one bird in Group 10 was also sacrificed as it had been bullied by other birds. No signs of ill health were observed in any other birds.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Over Days -7 to 0, all groups showed mean bodyweight losses. Over Days 0 to 7 following dosing, all groups with the exception of the control group showed mean bodyweight increases which were smaller in Groups 7 and 8 than in Groups 9 and 10. During the remainder of the study, birds in Groups 7 and 8 tended to decrease in weight, particularly over Days 14 to 21.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption results were variable, partly because of spillage which was impossible to measure. Over Days 15 to 21 in Groups 7 and 8, food consumption showed a noticeable decrease. Otherwise, food consumption figures were considered to be within normal limits.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In a small number of birds the liver had an abnormal appearance. However, no abnormalities were detected in the majority of birds.
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
Birds showing Grade 3 ataxia and upwards were examined with the exception of one bird, the tissues of which were lost during processing, and all showed morphological evidence of neurotoxicity. The neuropathological changes observed were reasonably consistent with the clinical ataxia gradings, and indicated a treatment-related effect.
Details on results:
ATAXIA ASSESSMENT
Seven birds in Group 7 developed signs of neurotoxicity. The number of affected birds decreased with decreasing dose level, and no birds showed ataxia in Group 10. The first positive signs of ataxia (Grade 2 and upwards) were observed on Day 11 in a Group 7 bird, which was sacrificed on Day 20 as it had developed Grade 8 ataxia. At termination of the study, the grades of ataxia in surviving birds ranged from 3 to 7.

Applicant's summary and conclusion

Conclusions:
Under the conditions of this test, subcutaneous administration of Triphenyl Phosphite at dosage levels of 0.25 to 0.50 g/kg produced clinical signs of neurotoxicity in adult hens. This was confirmed by the results of the histopathologicol examination. No signs of neurotoxicity were observed in any birds dosed at 0.125 g/kg.