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EC number: 204-524-2 | CAS number: 122-14-5
Neurotoxicity
Administrative data
Description of key information
An acute oral neurotoxicity study in the rat is available. A study of delayed neuropathy in the hen is available. A non-standard study of acute ocular toxicity is also available.
Key value for chemical safety assessment
Effect on neurotoxicity: via oral route
Link to relevant study records
- Endpoint:
- neurotoxicity: acute oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 2 March 1992 - 20 March 1992
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 81-8 (Neurotoxicity Screening Battery)
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 90617
Purity: 94.3% - Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Canada
- Age at study initiation: 49-52 days
- Weight at study initiation: 227-285 g (M), 162-202 g (F)
- Housing: Individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 30-70
- Air changes: 12-15/hour
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2 ~March 1992 To: 20 March 1992 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Groups of 12 or 13 male and 12 or 13 female Sprague-Dawley Crl:CD®(SD)BR rats received fenitrothion dissolved in corn oil, once by gavage at dose levels of 0, 12.5, 50 or 200 mg/kg bw for males and 0, 50, 200 or 800 mg/kg bw for females, at the dosage volume of 5 mL/kg bw.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Achieved concentrations, stability and homogeneith of the dosing solutions were verifed analytically
- Duration of treatment / exposure:
- Single gavage dose
- Frequency of treatment:
- Single gavage dose
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Vehicle control (corn oil): M, F
- Dose / conc.:
- 12.5 mg/kg bw/day
- Remarks:
- M
- Dose / conc.:
- 50 mg/kg bw/day
- Remarks:
- M, F
- Dose / conc.:
- 200 mg/kg bw/day
- Remarks:
- M, F
- Dose / conc.:
- 800 mg/kg bw/day
- Remarks:
- F
- No. of animals per sex per dose:
- 12 or 13
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The animals were evaluated using a functional observation battery (FOB) and motor activity test on prestudy, days 0 (day of treatment, at the time of peak effect), 7 and 14. At the completion of the study (day 15), 6 animals/sex/group were randomly selected for perfusion and those in the control and high dose groups underwent a neuropathological evaluation. The remaining animals in each group had their brains removed and then were subjected to necropsy. The brain of each of these rats in the control, low dose and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP) content.
- Observations and clinical examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 7, 14, 15 - Neurobehavioural examinations performed and frequency:
- The animals were evaluated using a functional observation battery (FOB) and motor activity test on prestudy, days 0 (day of treatment, at the time of peak effect), 7 and 14.
- Sacrifice and (histo)pathology:
- At the completion of the study (day 15), 6 animals/sex/group were randomly selected for perfusion and those in the control and high dose groups underwent a neuropathological evaluation. The remaining animals in each group had their brains removed and then were subjected to necropsy. The brain of each of these rats in the control, low dose and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP) content.
- Positive control:
- Not required
- Statistics:
- Diffferences between the control and treated groups were assessed using appropriate statistical methods
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- On the first few days following treatment, several abnormal clinical findings were observed such as wet fur staining along the ventral surface for the 200 and 800 mg/kg bw group rats and ocular discharge for the 200 mg/kg bw group males and one female from this same group, and for 800 mg/kg bw group females. For several male rats in the 200 mg/kg bw group, one female from this same group, and for most 800 mg/kg bw females, the tremors persisted for a few days post dosing. A few 800 mg/kg bw group females also appeared dehydrated or had a prominent backbone. Aside from some occasional dry fur staining, no abnormal findings were evident beyond Day 4.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One female in the 800 mg/kg bw group and one male in the 200 mg/kg bw group were found dead on Days 1 and 2, respectively.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The 200 mg/kg bw males had a significant decrease in body weights on all occasions following treatment compared to the control group
- 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):
- effects observed, treatment-related
- Description (incidence and severity):
- The FOB performed on Day 0 found several significant differences between control and fenitrothion-treated groups, including tremors, gait incapacity, reduced locomotor activity levels and arousal, decreased rearing and reduced body temperature for 50 and 200 mg/kg bw males and females and 800 mg/kg bw females. Autonomic signs such as myosis and salivation, together with a reduced response to pain perception (toe and tail pinch tests), abnormal visual placing response, and delays for the positional passivity test and failed air righting reflex were also observed for the 50 mg/kg bw males, 200 mg/kg bw males and females, and 800 mg/kg bw females. An abnormal home cage body position observed as lying down on ventral surface also occurred for males in the 50 mg/kg bw and 200 mg/kg bw groups and for females in the 800 mg/kg bw group. In addition, quantitative measurements of limb strength showed reductions in the forelimb for 50 and 200 mg/kg bw males and 800 mg/kg bw females, and decreases in the hindlimb for 200 mg/kg bw males and females and 800 mg/kg bw females .
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Glial fibrillary acidic protein content in the cerebral cortex of the 800 mg/kg group females was significantly elevated. The biological significance of this finding remains unclear given the variability of the data in both control and fenitrothion-treated groups, the increase in group mean was in part attributable to one rat with a high value, and that no structural changes in the nervous system were seen .
- Details on results:
- Measurements on Day 0 indicated significant reductions in total activity counts for 50 and 200 mg/kg bw males, and 50, 200 and 800 mg/kg bw females. The linear constructed variable was similarly affected for the females. In addition, trend analysis on female data found a significant linear and quadratic dose level effect for total activity counts and the linear constructed variable. No significant differences were detected between the control and 12.5 mg/kg bw males.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 12.5 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- behaviour (functional findings)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- behaviour (functional findings)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 50 mg/kg bw/day
- System:
- central nervous system
- Organ:
- brain
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- A NOAEL of 12.5 mg/kg bw was determined for males based on signs in the qualitative clinical and functional observation, reduction in grip strength, body temperature and motor activity at 50 mg/kg bw. A NOAEL was not demonstrated for females.
- Executive summary:
The acute oral neurotoxicity of fenitrothion was investigated in the rat. Groups of 12 or 13 male and 12 or 13 female Sprague-Dawley Crl:CD®(SD)BR rats received fenitrothion dissolved in corn oil, once by gavage at dose levels of 0, 12.5, 50 or 200 mg/kg bw for males and 0, 50, 200 or 800 mg/kg bw for females, at the dosage volume of 5 mL/kg bw. The animals were evaluated using a functional observation battery (FOB) and motor activity test on prestudy, days 0 (day of treatment, at the time of peak effect), 7 and 14. At the completion of the study (day 15), 6 animals/sex/group were randomly selected for perfusion and those in the control and high dose groups underwent a neuropathological evaluation. The remaining animals in each group had their brains removed and then were subjected to necropsy. The brain of each of these rats in the control, low dose and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP) content. One female in the 800 mg/kg bw group and one male in the 200 mg/kg bw group were found dead on Days 1 and 2, respectively. On the first few days following treatment, several abnormal clinical findings were observed such as wet fur staining along the ventral surface for the 200 and 800 mg/kg bw group rats and ocular discharge for the 200 mg/kg bw group males and one female from this same group, and for 800 mg/kg bw group females. For several male rats in the 200 mg/kg bw group, one female from this same group, and for most 800 mg/kg bw group females, the tremors persisted for a few days post dosing. A few 800 mg/kg bw group females also appeared dehydrated or had a prominent backbone. Aside from some occasional dry fur staining, no abnormal findings were evident beyond Day 4. The 200 mg/kg bw males had a significant decrease in body weights on all occasions following treatment compared to the control group. The FOB performed on Day 0 found several significant differences between control and fenitrothion-treated groups, including tremors, gait incapacity, reduced locomotor activity levels and arousal, decreased rearing and reduced body temperature for 50 and 200 mg/kg bw males and females and 800 mg/kg bw females. Autonomic signs such as myosis and salivation, together with a reduced response to pain perception (toe and tail pinch tests), abnormal visual placing response, and delays for the positional passivity test and failed air righting reflex were also observed for the 50 mg/kg bw males, 200 mg/kg bw males and females, and 800 mg/kg bw females. An abnormal home cage body position observed as lying down on ventral surface also occurred for males in the 50 mg/kg bw and 200 mg/kg bw groups and for females in the 800 mg/kg bw group. In addition, quantitative measurements of limb strength showed reductions in the forelimb for 50 and 200 mg/kg bw males and 800 mg/kg bw females, and decreases in the hindlimb for 200 mg/kg bw males and females and 800 mg/kg bw females. Measurements on Day 0 indicated significant reductions in total activity counts for 50 and 200 mg/kg bw males, and 50, 200 and 800 mg/kg bw females. The linear constructed variable was similarly affected for the females. In addition, trend analysis on female data found a significant linear and quadratic dose level effect for total activity counts and the linear constructed variable. No significant differences were detected between the control and 12.5 mg/kg bw males. Gross necropsy did not reveal any effects of treatment; there was no treatment-related neuropathology. Glial fibrillary acidic protein content in the cerebral cortex of the 800 mg/kg group females was significantly elevated. The biological significance of this finding remains unclear given the variability of the data in both control and fenitrothion-treated groups, the increase in group mean was in part attributable to one rat with a high value, and that no structural changes in the nervous system were seen. A NOAEL of 12.5 mg/kg bw was determined for males based on signs in the qualitative clinical and functional observation, reduction in grip strength, body temperature and motor activity at 50 mg/kg bw. A NOAEL was not demonstrated for females.
- Endpoint:
- neurotoxicity: acute oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 26 May 26 1988 - 26 August 1988
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- Assessment of ocular toxicity following a single oral dose
- GLP compliance:
- no
- Limit test:
- no
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 60553
Purity: 94.5% - Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crj:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Japan
- Age at study initiation: 6-7 weeks
- Weight at study initiation: 162-213 g (M), 131-210 g (F)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14-21 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-27
- Humidity (%): 52-77
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 10/14
IN-LIFE DATES: From: 26 May 1988 To: 26 August 1988 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Groups of 25 male or 25 female Crj:CD(SD) rats received fenitrothion by single gastric intubation at the dose levels of 0, 20, 200 mg/kg bw for males and 0, 40, 400 mg/kg bw for females, dissolved in corn oil at a dose volume of 5 ml/kg bw.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Single gavage dose
- Frequency of treatment:
- Single gavage dose
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Vehicle (corn oil) control; M, F
- Dose / conc.:
- 20 mg/kg bw/day
- Remarks:
- M
- Dose / conc.:
- 40 mg/kg bw/day
- Remarks:
- F
- Dose / conc.:
- 200 mg/kg bw/day
- Remarks:
- M
- Dose / conc.:
- 400 mg/kg bw/day
- Remarks:
- F
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Clinical signs and body weights were recorded for all animals. Ophthalmology and ERG examination, and autopsy on the eyes and their accessory organs were performed at 4, 7, 14, 28 and 91 days after dosing (5 animals/sex/group). Measurement of cholinesterase activity was performed on the next day of the ERG examination.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased incidences of cholinergic symptoms such as muscular fibrillation, eye discharge, and salivation were observed in the high dose treatment groups of both sexes (200 mg/kg bw in males; 400 mg/kg bw in females). Increased incidences of muscular fibrillation were also noted in males at 20 mg/kg bw and females at 40 mg/kg bw.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One male dose with 200 mg/kg bw died on hour following dosing.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- A significant, but transient, decrease in body weight was observed after the dosing in the high dose treatment groups of both sexes.
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no significant differences between the treated groups and the control.
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Inhibition of cholinesterase activity in erythrocytes were observed in all treatment groups and marked inhibitions were noted in the high dose groups of both sexes from 5-15 days after dosing. Significant inhibition of cholinesterase activity in plasma was seen in females of the high dose group at 5 days after dosing. Enzyme activities gradually recovered thereafter and had fully recovered at 13 weeks after the dosing
- 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 examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- ERG examination showed some significant changes mainly in the high dose treatment groups. However, these changes were considered to be incidental, since their values were within normal range.
- Key result
- Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 20 mg/kg bw/day
- System:
- peripheral nervous system
- Organ:
- neurons
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- No acute ocular toxicity was detected in the rats given sub-lethal doses of fenitrothion which induced a remarkable inhibition of the cholinesterase activity and toxic signs.
- Executive summary:
A non-standard study was performed to investigate the ocular toxicity of fenitrothion. Groups of SD rats (25/sex) were administered a single gavage dose of fenitrothion (in corn oil) at dose levels of 0, 20 or 200 mg/kg bw (males); 0, 40 or 400 mg/kg bw (females) and observed for up to 90 days. Signs of toxicity were observed and bodyweights measured. Opthalmology, histopathology of the eyes and ERG were performed at 4, 7, 14, 28 and 91 days after dosing. Cholinesterase activity was also measured. One mortality occurred in high dose males one hour following dosing. Signs of toxicity consistent with cholinesterase inhibition were observed in all treated groups. Inhibition of erythrocyte cholinesterase activity was shown in all treated groups. No acute ocular toxicity was detected in the rats given sub-lethal doses of fenitrothion which induced a remarkable inhibition of the cholinesterase activity and toxic signs.
- Endpoint:
- neurotoxicity: short-term oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 10 November 10 - 20 August 1976
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Assessment of delayed neurotoxicity in the hen follwoing single and repeated dosing
- GLP compliance:
- no
- Limit test:
- no
- Species:
- hen
- Strain:
- other: White Leghorn
- Sex:
- not specified
- Route of administration:
- oral: gavage
- Vehicle:
- other: 10% Tween 80 or Sorpol emulsifier
- Details on exposure:
- One group of 16 adult White Leghorn hens received fenitrothion dissolved in emulsifier (Sorpol 355), twice at the interval of 3-week at the dose level of 500 mg/kg, and then were kept under observation for 3 weeks after the second administration. Groups of 8 adult White Leghorn hens received fenitrothion suspended in 10% Tween 80 aqueous solution, by oral gavage for consecutive 4 weeks at the dose levels of 16.7 and 33.4 mg/kg, and then were kept under observation for 3 weeks after the 4-week administration period. As a positive control group, 3 adult White Leghorn hens received singly 500 mg/kg of tri-ortho-cresyl phosphate (TOCP), and were kept under observation for 4 weeks.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- One group of hens was administered two single doses of fenitrothion at a three week interval. Another group of hens was administered fenitrothion daily for 28 days.
- Frequency of treatment:
- One group of hens was administered two single doses of fenitrothion at a three week interval. Another group of hens was administered fenitrothion daily for 28 days.
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- Two doses at a 3-week interval
- Dose / conc.:
- 16.7 mg/kg bw/day
- Remarks:
- Daily for 28 days
- Dose / conc.:
- 33.4 mg/kg bw/day
- Remarks:
- Daily for 28 days
- No. of animals per sex per dose:
- 16 (single dose); 8 (repeated dose)
- Control animals:
- not specified
- Details on study design:
- As a positive control group, 3 adult White Leghorn hens received singly 500 mg/kg of tri-ortho-cresyl phosphate (TOCP), and were kept under observation for 4 weeks. Paralysis in legs was checked daily, using a scoring system. Body weights were measured weekly. All surviving hens were sacrificed and sciatic nerves and spinal cords were dissected out and examined histopathologically.
- Neurobehavioural examinations performed and frequency:
- Paralysis in legs was checked daily, using a scoring system.
- Sacrifice and (histo)pathology:
- All surviving hens were sacrificed and sciatic nerves and spinal cords were dissected out and examined histopathologically.
- Positive control:
- TOCP (500 mg/kg bw), single dose
- Statistics:
- No details
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In the acute study, signs including leg weakness, lack of leg coordination, loss of balance, decrease of spontaneous motor activity and irregular respiration were observed. The symptoms of acute intoxication disappeared 5-7 days post-treatment and no further noteworthy changes were observed.
In the repeated dose study, signs included decreased spontaneous motor activity, tremor and leg weakness as well as loss of appetite; signs gradually resolved. Paralysis in the legs was not observed. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- In the acute study, five out of sixteen hens died after 24-48 hours, regardless of atropine and 2-PAM treatment.
In the repeated dose study, one hen died on Day 5. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the acute study, bodyweights were lower at 1 week after administration and recovered slowly.
In the repeated dose study, mean body weights showed a slight decrease seven days after initiation of the administration and remained depressed during the administration period. Body weights recovered slowly on termination of administration. - 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):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- In the acute study, Schwann’s sheath, Schwann’s cell and axon in sciatic nerve were essentially normal and no remarkable changes on nerve fiber, ganglionic cells and nissle granules in spinal cord.
In the repeated dose study, no abnormalities were found in the sciatic nerves and spinal cord. - Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Details on results:
- In the positive control group, leg weakness, lack of leg coordination and loss of balance appeared on Days 12-14 and all hens showed well-developed leg paralysis in legs on Day 18. Histpathologically, degeneration of sciatic nerve fiber were observed.
- Key result
- Dose descriptor:
- other:
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- There was no evidence of delayed neuropathy in this study
- Key result
- Critical effects observed:
- no
- Conclusions:
- No evidence of delayed neuropathy was seen under the conditions of this study.
- Executive summary:
In a study of delayed neuropathy, groups of hens were adminstered single (500 mg/kg bw) or 28 repeated daily doses (16.7 or 33.4 mg/kg bw) fenitrothion. Hens were observed for 3 weeks after cessation of treatment and assessed histopathologically. Acute or sub-acute treatment with fenitrothion did not result in any symptoms of paralysis or neuropathology consistent with delayed neuropathy. Typical responses with the positive control compound TOCP confimed the sensitivity of the assay.
Referenceopen allclose all
Summary of bodyweights
Dose level (mg/kg bw) |
M |
F |
||||||
0 |
12.5 |
50 |
200 |
0 |
50 |
200 |
800 |
|
Day 0 |
261.8 |
261.0 |
262.2 |
262.6 |
180.5 |
178.0 |
179.9 |
181.9 |
Day 7 |
307.5 |
309.4 |
297.3 |
282.9** |
200.4 |
190.4 |
194.2 |
189.2 |
Day 14 |
345.8 |
349.2 |
335.6 |
328.3* |
217.4 |
208.1 |
211.2 |
212.1 |
Day 15 |
310.9 |
312.9 |
300.5 |
293.9* |
195.1 |
187.0 |
187.9 |
189.3 |
*significantly different to controls (p<0.05); **<0.01
Clinical findings
Male |
|
|
|
|
Dose level |
0 mg/kg bw |
12.5 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
Number of animals examined |
13 |
13 |
13 |
12 |
Behavior - slight fine tremors |
0 |
0 |
0 |
6 |
Eyes - dry red discharge |
0 |
0 |
0 |
11 |
Fur - urogenital region - yellow staining |
0 |
0 |
3 |
12 |
Fur - abdominal region - yellow staining |
0 |
0 |
0 |
9 |
Female |
|
|
|
|
Dose level |
0 mg/kg |
50 mg/kg |
200 mg/kg |
800 mg/kg |
Number of animals examined |
13 |
12 |
12 |
12 |
Dehydrated/prominent backbone |
0 |
0 |
0 |
8 |
Behavior - slight fine tremors |
0 |
0 |
1 |
7 |
Eye - red discharge |
0 |
0 |
1 |
7 |
Fur - urogenital region - yellow staining |
0 |
0 |
4 |
11 |
Fur - abdominal region - yellow staining |
0 |
0 |
0 |
7 |
Summary of FOB (Day 0, M)
Dose level |
0 mg/kg bw |
12.5 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
Number of animals examined |
13 |
13 |
13 |
12 |
Body position (description) |
|
|
|
|
Lying down ventral surface |
0 |
0 |
6* |
10*** |
Sitting/standing |
10 |
12 |
7 |
2** |
Rearing |
3 |
1 |
0 |
0 |
Tremors (head, body and/or limbs) (description) |
|
|
|
|
None |
13 |
13 |
1*** |
0*** |
Slight fine |
0 |
0 |
1*** |
0*** |
Slight coarse |
0 |
0 |
7*** |
4*** |
Moderate coarse |
0 |
0 |
4*** |
7*** |
Severe coarse |
0 |
0 |
0*** |
1*** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Dose level |
0 mg/kg bw |
12.5 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
Number of animals examined |
13 |
13 |
13 |
12 |
Rearing (mean score) |
6.2 |
4.9 |
0.4*** |
0.0*** |
Ataxic gait (description) |
|
|
|
|
Not recorded |
0 |
0 |
4 |
11 |
None |
13 |
13 |
1*** |
0 |
Slight |
0 |
0 |
1*** |
0 |
Moderate |
0 |
0 |
5*** |
0 |
Severe |
0 |
0 |
2*** |
1 |
Overall gait incapacity (description) |
|
|
|
|
None |
13 |
13 |
1*** |
0*** |
Slight |
0 |
0 |
2*** |
0*** |
Moderate |
0 |
0 |
5*** |
0*** |
Severe |
0 |
0 |
1*** |
1*** |
Extreme |
0 |
0 |
4*** |
11*** |
Tremors (head, body and/or limbs) (description) |
|
|
|
|
None |
13 |
13 |
1*** |
0*** |
Slight fine |
0 |
0 |
1*** |
0*** |
Slight coarse |
0 |
0 |
7*** |
3*** |
Moderate coarse |
0 |
0 |
4*** |
8*** |
Severe coarse |
0 |
0 |
0*** |
1*** |
Locomotor activity level (description) |
|
|
|
|
None resting |
0 |
0 |
4*** |
11*** |
Slight movement |
1 |
1 |
9*** |
1*** |
Moderate movement |
12 |
12 |
0*** |
0*** |
Arousal (description) |
|
|
|
|
Severely decreased |
0 |
0 |
5*** |
11*** |
Moderately decreased |
0 |
0 |
7*** |
1*** |
Normal |
13 |
13 |
1*** |
0*** |
Defecation (mean score) |
1.3 |
1.8 |
0.4 |
0.1** |
Urination (description) |
|
|
|
|
None |
3 |
4 |
8 |
10** |
Slight |
10 |
9 |
5 |
2** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Dose level |
0 mg/kg bw |
12.5 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
Number of animals examined |
13 |
13 |
13 |
12 |
Pupil size (description) |
|
|
|
|
Pinpoint |
1 |
0 |
11*** |
12*** |
Pinhead |
12 |
13 |
2*** |
0*** |
Exophthalmos |
0 |
0 |
0 |
1 |
Salivation (description) |
|
|
|
|
None |
13 |
12 |
7* |
1*** |
Slight |
0 |
0 |
4* |
2*** |
Moderate |
0 |
0 |
2* |
6*** |
Severe |
0 |
0 |
0* |
3*** |
Red coloration |
0 |
0 |
2 |
4* |
Extensor thrust (description) |
|
|
|
|
Normal |
13 |
13 |
11 |
3*** |
Slight reduction |
0 |
0 |
2 |
8*** |
Moderate reduction |
0 |
0 |
0 |
1*** |
Pinna reflex (description) |
|
|
|
|
None |
0 |
0 |
2* |
5*** |
Slight brisk flick |
0 |
0 |
4* |
5*** |
Moderate brisk flick |
12 |
13 |
7* |
2*** |
Very brisk flick |
1 |
0 |
0* |
0*** |
Toe pinch (description) |
|
|
|
|
No response |
0 |
0 |
2** |
10*** |
Slight withdrawal |
1 |
0 |
8** |
2*** |
Moderate withdrawal |
10 |
13 |
3** |
0*** |
Rapid withdrawal |
2 |
0 |
0** |
0*** |
Tail pinch (description) |
|
|
|
|
No response |
0 |
0 |
5*** |
12*** |
Slight movement |
1 |
0 |
5*** |
0*** |
Moderate movement |
11 |
13 |
3*** |
0*** |
Rapid movement |
1 |
0 |
0*** |
0*** |
Visual placing (description) |
|
|
|
|
No response |
0 |
0 |
1*** |
8*** |
Nose touch |
0 |
0 |
4*** |
4*** |
Vibrissae touch |
0 |
0 |
6*** |
0*** |
Normal |
13 |
13 |
2*** |
0*** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Dose level |
0 mg/kg bw |
12.5 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
Number of animals examined |
13 |
13 |
13 |
12 |
Positional passivity (description) |
|
|
|
|
Normal |
13 |
13 |
5** |
0*** |
Slight delay |
0 |
0 |
4** |
1*** |
Moderate delay |
0 |
0 |
2** |
1*** |
Severe delay |
0 |
0 |
0** |
1*** |
Cataleptic |
0 |
0 |
2** |
9*** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Dose level |
0 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
800 mg/kg bw |
Number of animals examined |
13 |
12 |
12 |
12 |
Body position (description) |
|
|
|
|
Lying down ventral surface |
0 |
0 |
2 |
6** |
Sitting/standing |
13 |
12 |
10 |
6** |
Tremors (head, body and/or limbs) (description) |
|
|
|
|
None |
13 |
8* |
1*** |
0*** |
Slight fine |
0 |
4* |
6*** |
5*** |
Slight coarse |
0 |
0* |
5*** |
7*** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Summary of FOB findings (Day 0, F)
Dose level |
0 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
800 mg/kg bw |
Number of animals examined |
13 |
12 |
12 |
12 |
Rearing (mean score) |
10.9 |
3.1*** |
1.2*** |
0.6*** |
Ataxic gait (description) |
|
|
|
|
Not recorded |
0 |
0 |
0 |
4 |
None |
13 |
4*** |
1*** |
0*** |
Slight |
0 |
7*** |
2*** |
1*** |
Moderate |
0 |
1*** |
8*** |
6*** |
Severe |
0 |
0*** |
1*** |
1*** |
Overall gait incapacity (description) |
|
|
|
|
None |
13 |
4*** |
1*** |
0*** |
Slight |
0 |
8*** |
6*** |
2*** |
Moderate |
0 |
0*** |
4*** |
5*** |
Severe |
0 |
0*** |
1*** |
1*** |
Extreme |
0 |
0*** |
0*** |
4*** |
Tremors (head, body and/or limbs) (description) |
|
|
|
|
None |
13 |
8* |
1*** |
0*** |
Slight fine |
0 |
4* |
6*** |
5*** |
Slight coarse |
0 |
0* |
5*** |
7*** |
Locomotor activity level (description) |
|
|
|
|
None resting |
0 |
0** |
0*** |
4*** |
Slight movement |
0 |
6** |
11*** |
8*** |
Moderate movement |
13 |
6** |
1*** |
0*** |
Arousal (description) |
|
|
|
|
Severely decreased |
0 |
0* |
1*** |
6*** |
Moderately decreased |
0 |
4* |
10*** |
6*** |
Normal |
13 |
8* |
1*** |
0*** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Dose level |
0 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
800 mg/kg bw |
Number of animals examined |
13 |
12 |
12 |
12 |
Pupil size (description) |
|
|
|
|
Pinpoint |
0 |
1 |
4* |
5* |
Pinhead |
13 |
11 |
8* |
7* |
Salivation (description) |
|
|
|
|
Normal |
13 |
12 |
8* |
1*** |
Slight |
0 |
0 |
2* |
6*** |
Moderate |
0 |
0 |
2* |
3*** |
Severe |
0 |
0 |
0* |
2*** |
Pinna reflex (description) |
|
|
|
|
None |
0 |
0 |
0 |
2** |
Slight brisk flick |
0 |
0 |
2 |
4** |
Moderate brisk flick |
13 |
12 |
10 |
6** |
Toe pinch (description) |
|
|
|
|
No response |
0 |
0 |
2** |
3*** |
Slight withdrawal |
0 |
1 |
4** |
6*** |
Moderate withdrawal |
13 |
11 |
6** |
3*** |
Tail pinch (description) |
|
|
|
|
No response |
0 |
0 |
3** |
5*** |
Slight movement |
0 |
0 |
4** |
5*** |
Moderate movement |
13 |
12 |
5** |
2*** |
Visual placing (description) |
|
|
|
|
No response |
0 |
0 |
1** |
1*** |
Nose touch |
0 |
0 |
1** |
3*** |
Vibrissae touch |
0 |
0 |
4** |
4*** |
Normal |
13 |
12 |
6** |
4*** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Dose level |
0 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
800 mg/kg bw |
Number of animals examined |
13 |
12 |
12 |
12 |
Positional passivity (description) |
|
|
|
|
Normal |
13 |
12 |
8* |
5** |
Slight delay |
0 |
0 |
2* |
2** |
Moderate delay |
0 |
0 |
1* |
3** |
Severe delay |
0 |
0 |
1* |
0** |
Cataleptic |
0 |
0 |
0* |
2** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Dose level |
0 mg/kg bw |
50 mg/kg bw |
200 mg/kg bw |
800 mg/kg bw |
Number of animals examined |
13 |
12 |
12 |
12 |
Air righting reflex (description) |
|
|
|
|
Normal |
13 |
12 |
7* |
5** |
Fails lands on side |
0 |
0 |
3* |
6** |
Fails lands on back |
0 |
0 |
2* |
1** |
Grip strength (Day 0)
|
Male |
Female |
||||||
Dose level (mg/kg bw) |
0 |
12.5 |
50 |
200 |
0 |
50 |
200 |
800 |
Forelimb grip strength (g) |
830.0 |
763.5 |
714.6* |
428.3** |
734.6 |
741.3 |
667.5 |
620.4* |
Hindlimb grip strength (g) |
668.8 |
620.4 |
602.3 |
470.8** |
638.5 |
640.8 |
561.7* |
544.6** |
Body temperature (ºC) |
37.7 |
37.7 |
34.1** |
33.4** |
38.1 |
36.0** |
34.3** |
33.4** |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
Motor activity (Day 0)
|
Male |
Female |
||||||
Dose level (mg/kg bw) |
0 |
12.5 |
50 |
200 |
0 |
50 |
200 |
800 |
Day 0 |
176.3 |
176.1 |
28.4*** |
26.6*** |
355.5 |
99.8*** |
78.3*** |
46.3*** |
Day 7 |
213.7 |
208.4 |
236.0 |
259.2 |
349.1 |
362.2 |
320.9 |
275.5 |
Day 14 |
232.2 |
249.8 |
227.0 |
217.2 |
352.2 |
392.7 |
358.3 |
307.8 |
*significantly different to controls (p<0.05); **<0.01; ***p<0.001
GFAP in brain (relative to controls)
|
Male |
Female |
||
Dose level (mg/kg bw) |
12.5 |
200 |
50 |
800 |
Cerebellum |
95.5 |
108.2 |
107.5 |
101.3 |
Cerebral cortex |
87.3 |
96.3 |
110.6 |
119.4* |
Hippocampus |
96.0 |
109.3 |
108.3 |
106.8 |
Striatum |
103.5 |
110.1 |
92.7 |
104.9 |
Thalamus/hypothalamus |
99.4 |
99.0 |
103.0 |
93.2 |
Remaining brain |
97.3 |
106.0 |
100.3 |
100.8 |
*significantly different to controls (p<0.05)
Summary of clinical signs
|
Male |
Female |
||||
Dose level (mg/kg bw) |
0 |
20 |
200 |
0 |
40 |
400 |
Group A (observed for 4 days after the dosing) |
|
|
|
|
|
|
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
5 |
Muscular fibrillation |
0 |
3 |
4* |
0 |
0 |
5** |
Eye discharge |
0 |
0 |
4* |
0 |
0 |
2 |
Salivation |
0 |
0 |
3 |
0 |
0 |
2 |
Group B (observed for 7 days after the dosing) |
|
|
|
|
|
|
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
5 |
Muscular fibrillation |
0 |
5** |
5** |
0 |
1 |
5** |
Eye discharge |
0 |
2 |
5** |
0 |
0 |
0 |
Salivation |
0 |
0 |
3 |
0 |
0 |
0 |
Group C (observed for 14 days after the dosing) |
|
|
|
|
|
|
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
5 |
Muscular fibrillation |
0 |
5** |
5** |
0 |
2 |
5** |
Eye discharge |
0 |
1 |
5** |
0 |
0 |
1 |
Salivation |
0 |
0 |
0 |
0 |
0 |
1 |
Group D (observed for 28 days after the dosing) |
|
|
|
|
|
|
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
5 |
Muscular fibrillation |
0 |
5** |
5** |
0 |
2 |
5** |
Eye discharge |
0 |
0 |
5** |
0 |
0 |
4* |
Salivation |
0 |
0 |
4* |
0 |
0 |
2 |
Group E (observed for 91 days after the dosing) |
|
|
|
|
|
|
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
5 |
Muscular fibrillation |
0 |
4* |
5** |
0 |
0 |
5** |
Eye discharge |
0 |
0 |
5** |
0 |
0 |
4* |
Salivation |
0 |
0 |
5** |
0 |
0 |
1 |
*significantly different to controls (p<0.05), **p<0.01)
Summary of bodyweight effects
|
Male |
Female |
||||
Dose level (mg/kg bw) |
0 |
20 |
200 |
0 |
40 |
400 |
Group A (observed for 4 days after the dosing) |
|
|
|
|
||
Day 0 |
167 |
175* |
182** |
138 |
140 |
136 |
Day 4 |
219 |
228 |
204 |
171 |
168 |
153* |
Group B (observed for 7 days after the dosing) |
|
|
|
|
||
Day 0 |
198 |
202 |
201 |
182 |
182 |
174 |
Day 4 |
248 |
248 |
220** |
212 |
212 |
185* |
Day 7 |
274 |
276 |
251** |
219 |
226 |
200 |
Group C (observed for 14 days after the dosing) |
|
|
|
|
||
Day 0 |
194 |
198 |
197 |
175 |
168 |
172 |
Day 4 |
244 |
243 |
217** |
207 |
194 |
182** |
Day 7 |
272 |
272 |
249* |
217 |
204 |
198* |
Day 14 |
334 |
330 |
316 |
236 |
230 |
232 |
Group D (observed for 28 days after the dosing) |
|
|
|
|
||
Day 0 |
199 |
205 |
196 |
172 |
178 |
171 |
Day 4 |
247 |
254 |
213** |
201 |
211 |
185 |
Day 7 |
273 |
284 |
243** |
214 |
222 |
198 |
Day 14 |
330 |
344 |
307* |
240 |
255 |
227 |
Day 21 |
363 |
393* |
361 |
259 |
277 |
246 |
Day 28 |
402 |
439* |
409 |
279 |
298 |
267 |
Group E (observed for 91 days after the dosing) |
|
|
|
|
||
Day 0 |
191 |
184 |
187 |
164 |
162 |
154 |
Day 4 |
237 |
223 |
206** |
199 |
193 |
162** |
Day 7 |
266 |
249 |
238* |
213 |
211 |
186** |
Day 14 |
322 |
303 |
301 |
241 |
238 |
223 |
Day 21 |
370 |
350 |
357 |
262 |
263 |
256 |
Day 28 |
407 |
391 |
398 |
280 |
285 |
277 |
Day 35 |
442 |
420 |
426 |
299 |
300 |
300 |
Day 42 |
460 |
446 |
461 |
310 |
308 |
312 |
Day 49 |
486 |
468 |
487 |
321 |
317 |
325 |
Day 56 |
503 |
477 |
498 |
326 |
321 |
336 |
Day 63 |
516 |
494 |
517 |
336 |
328 |
345 |
Day 70 |
538 |
511 |
534 |
340 |
331 |
355 |
Day 77 |
549 |
521 |
544 |
347 |
343 |
364 |
Day 84 |
564 |
539 |
565 |
352 |
347 |
370 |
Day 91 |
579 |
549 |
581 |
358 |
354 |
380 |
*significantly different to controls (p<0.05), **p<0.01)
Summary of electroretinogram findings
|
Male |
Female |
||||
Dose level (mg/kg) |
0 |
20 |
200 |
0 |
40 |
400 |
Peak latency time of a-wave (msec) |
||||||
Day 4 |
17.7 |
16.3 |
16.6 |
16.5 |
17.8 |
17.3 |
Day 7 |
16.8 |
16.2 |
17.5 |
17.8 |
16.9 |
17.4 |
Day 14 |
17.4 |
18.0 |
16.4 |
15.2 |
16.3 |
15.3 |
Day 28 |
18.5 |
20.6 |
18.9 |
17.3 |
20.1** |
18.7 |
Day 91 |
15.7 |
17.4 |
17.8 |
18.1 |
16.6 |
16.8 |
Amplitude of a-wave (mV) |
||||||
Day 4 |
355 |
337 |
287 |
305 |
237 |
210 |
Day 7 |
240 |
242 |
327* |
215 |
245 |
255 |
Day 14 |
267 |
230 |
300 |
380 |
345 |
250 |
Day 28 |
243 |
235 |
240 |
255 |
182** |
245 |
Day 91 |
250 |
267 |
265 |
285 |
315 |
262 |
Peak latency time of b-wave (msec) |
||||||
Day 4 |
63.0 |
61.4 |
57.6 |
60.5 |
61.3 |
60.6 |
Day 7 |
63.3 |
62.3 |
60.6 |
64.2 |
63.0 |
58.6* |
Day 14 |
59.4 |
64.1 |
60.8 |
57.6 |
64.2 |
59.6 |
Day 28 |
60.4 |
60.2 |
59.3 |
60.8 |
61.1 |
62.5 |
Day 91 |
55.8 |
58.0 |
58.6 |
55.0 |
54.9 |
58.6 |
Amplitude of b-wave (mV) |
||||||
Day 4 |
963 |
900 |
871 |
755 |
682 |
620 |
Day 7 |
712 |
640 |
860 |
620 |
652 |
710 |
Day 14 |
737 |
727 |
791 |
940 |
950 |
666 |
Day 28 |
537 |
735 |
755 |
742 |
627 |
727 |
Day 91 |
777 |
833 |
830 |
948 |
1031 |
887 |
1st peak latency time of oscillatory potentials (msec) |
||||||
Day 4 |
33.2 |
28.8 |
29.3 |
32.5 |
33.7 |
31.8 |
Day 7 |
35.1 |
35.8 |
33.6 |
34.0 |
32.1 |
31.9 |
Day 14 |
31.4 |
31.7 |
30.5 |
30.6 |
31.7 |
29.4 |
Day 28 |
31.0 |
30.1 |
30.6 |
33.5 |
32.2 |
32.3 |
Day 91 |
28.7 |
29.0 |
29.9 |
29.0 |
28.0 |
31.1* |
2nd peak latency time of oscillatory potentials (msec) |
||||||
Day 4 |
41.1 |
36.0 |
37.0 |
40.9 |
41.0 |
40.6 |
Day 7 |
45.0 |
44.3 |
41.8 |
43.3 |
40.8 |
40.2 |
Day 14 |
39.2 |
38.8 |
38.4 |
38.2 |
39.2 |
38.6 |
Day 28 |
39.0 |
37.7 |
37.8 |
42.2 |
40.7 |
40.9 |
Day 91 |
35.9 |
36.3 |
36.8 |
36.4 |
35.1 |
38.4 |
*significantly different to controls (p<0.05), **p<0.01)
Summary of cholinesterase activity
|
Male |
Female |
||||
Dose level (mg/kg) |
0 |
20 |
200 |
0 |
40 |
400 |
Plasma |
|
|
|
|
|
|
Day 5 |
0.20 |
0.17 |
0.18 |
0.90 |
0.64 |
0.40** |
Day 8 |
0.24 |
0.23 |
0.34 |
0.75 |
0.57 |
0.59 |
Day 15 |
0.23 |
0.19 |
0.24 |
0.98 |
0.99 |
0.79 |
Day 29 |
0.19 |
0.21 |
0.22 |
1.05 |
1.05 |
1.52 |
Day 92 |
0.14 |
0.20 |
0.19 |
1.67 |
1.58 |
1.44 |
Red blood cell |
|
|
|
|
|
|
Day 5 |
0.35 |
0.22* |
0.08** |
0.29 |
0.17** |
0.04** |
Day 8 |
0.33 |
0.24** |
0.09** |
0.27 |
0.14 |
0.10** |
Day 15 |
0.37 |
0.32 |
0.16** |
0.37 |
0.26** |
0.19** |
Day 29 |
0.47 |
0.49 |
0.36 |
0.46 |
0.41 |
0.35 |
Day 92 |
0.41 |
0.42 |
0.39 |
0.38 |
0.34 |
0.36 |
*significantly different to controls (p<0.05), **p<0.01)
Acute or sub-acute treatment with fenitrothion did not result in any symptoms of paralysis or neuropathology consistent with delayed neuropathy.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 12.5 mg/kg bw/day
- Species:
- rat
- Quality of whole database:
- A guideline-comparable study of acute neurotoxicity is available in the rat.
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
Additional information
Acute oral neurotoxicity
The acute oral neurotoxicity of fenitrothion was investigated in the rat. Groups of 12 or 13 male and 12 or 13 female Sprague-Dawley Crl:CD®(SD)BR rats received fenitrothion dissolved in corn oil, once by gavage at dose levels of 0, 12.5, 50 or 200 mg/kg bw for males and 0, 50, 200 or 800 mg/kg bw for females, at the dosage volume of 5 mL/kg bw. The animals were evaluated using a functional observation battery (FOB) and motor activity test on prestudy, days 0 (day of treatment, at the time of peak effect), 7 and 14. At the completion of the study (day 15), 6 animals/sex/group were randomly selected for perfusion and those in the control and high dose groups underwent a neuropathological evaluation. The remaining animals in each group had their brains removed and then were subjected to necropsy. The brain of each of these rats in the control, low dose and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP) content. One female in the 800 mg/kg bw group and one male in the 200 mg/kg bw group were found dead on Days 1 and 2, respectively. On the first few days following treatment, several abnormal clinical findings were observed such as wet fur staining along the ventral surface for the 200 and 800 mg/kg bw group rats and ocular discharge for the 200 mg/kg bw group males and one female from this same group, and for 800 mg/kg bw group females. For several male rats in the 200 mg/kg bw group, one female from this same group, and for most 800 mg/kg bw group females, the tremors persisted for a few days post dosing. A few 800 mg/kg bw group females also appeared dehydrated or had a prominent backbone. Aside from some occasional dry fur staining, no abnormal findings were evident beyond Day 4. The 200 mg/kg bw males had a significant decrease in body weights on all occasions following treatment compared to the control group. The FOB performed on Day 0 found several significant differences between control and fenitrothion-treated groups, including tremors, gait incapacity, reduced locomotor activity levels and arousal, decreased rearing and reduced body temperature for 50 and 200 mg/kg bw males and females and 800 mg/kg bw females. Autonomic signs such as myosis and salivation, together with a reduced response to pain perception (toe and tail pinch tests), abnormal visual placing response, and delays for the positional passivity test and failed air righting reflex were also observed for the 50 mg/kg bw males, 200 mg/kg bw males and females, and 800 mg/kg bw females. An abnormal home cage body position observed as lying down on ventral surface also occurred for males in the 50 mg/kg bw and 200 mg/kg bw groups and for females in the 800 mg/kg bw group. In addition, quantitative measurements of limb strength showed reductions in the forelimb for 50 and 200 mg/kg bw males and 800 mg/kg bw females, and decreases in the hindlimb for 200 mg/kg bw males and females and 800 mg/kg bw females. Measurements on Day 0 indicated significant reductions in total activity counts for 50 and 200 mg/kg bw males, and 50, 200 and 800 mg/kg bw females. The linear constructed variable was similarly affected for the females. In addition, trend analysis on female data found a significant linear and quadratic dose level effect for total activity counts and the linear constructed variable. No significant differences were detected between the control and 12.5 mg/kg bw males. Gross necropsy did not reveal any effects of treatment; there was no treatment-related neuropathology. Glial fibrillary acidic protein content in the cerebral cortex of the 800 mg/kg group females was significantly elevated. The biological significance of this finding remains unclear given the variability of the data in both control and fenitrothion-treated groups, the increase in group mean was in part attributable to one rat with a high value, and that no structural changes in the nervous system were seen. A NOAEL of 12.5 mg/kg bw was determined for males based on signs in the qualitative clinical and functional observation, reduction in grip strength, body temperature and motor activity at 50 mg/kg bw. A NOAEL was not demonstrated for females.
Delayed neuropathy
In a study of delayed neuropathy, groups of hens were adminstered single (500 mg/kg bw) or 28 repeated daily doses (16.7 or 33.4 mg/kg bw) fenitrothion. Hens were observed for 3 weeks after cessation of treatment and assessed histopathologically. Acute or sub-acute treatment with fenitrothion did not result in any symptoms of paralysis or neuropathology consistent with delayed neuropathy. Typical responses with the positive control compound TOCP confimed the sensitivity of the assay.
Acute ocular toxicity
A non-standard study was performed to investigate the ocular toxicity of fenitrothion. Groups of SD rats (25/sex) were administered a single gavage dose of fenitrothion (in corn oil) at dose levels of 0, 20 or 200 mg/kg bw (males); 0, 40 or 400 mg/kg bw (females) and observed for up to 90 days. Signs of toxicity were observed and bodyweights measured. Opthalmology, histopathology of the eyes and ERG were performed at 4, 7, 14, 28 and 91 days after dosing. Cholinesterase activity was also measured. One mortality occurred in high dose males one hour following dosing. Signs of toxicity consistent with cholinesterase inhibition were observed in all treated groups. Inhibition of erythrocyte cholinesterase activity was shown in all treated groups. No acute ocular toxicity was detected in the rats given sub-lethal doses of fenitrothion which induced a remarkable inhibition of the cholinesterase activity and toxic signs.
Justification for classification or non-classification
Classification of fenitrothion on the basis of neurotoxic effects (cholinesterase inhibition) is proposed (STOT SE1, STOT RE1). No additional effects (neuropathology, neuropathy, ocular toxicity) were identified in these specific investigations.
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