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EC number: 204-524-2 | CAS number: 122-14-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
A 28 -day study is not available; however a 90 -day oral rat toxicity study is available for fenitrothion and is supported by a further (non-standard) 90 -day study of ocular toxicity. A 21 -day repeated dose dermal toxicity in the rabbit is also available for fenitrothion.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 30 June 1992 - 2 October 1992
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-1 (Chronic Toxicity)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPP 82-7
- Deviations:
- no
- 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
- Details on species / strain selection:
- Standar strain and species
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Canada
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 50-53 days
- Weight at study initiation: 237-289 g (males), 168-215 g (females )
- Fasting period before study: None
- Housing: Individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 15 days
DETAILS OF FOOD AND WATER QUALITY:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: 30 June 1992 - 2 October 1992 - Route of administration:
- oral: feed
- Details on route of administration:
- Dietary incorporation
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- Dietary concentrations were 0, 6, 20, 60 and 200 ppm; corresponding to 0, 0.40, 1.32, 3.99 and 13.8 mg/kg bw/d in males; 0, 0.46, 1.56, 4.85 and 17.6 mg/kg bw/d in females.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily (continuous)
- Dose / conc.:
- 0 ppm
- Remarks:
- Control (basal diet)
- Dose / conc.:
- 6 ppm
- Remarks:
- 0.40 and 0.46 mg/kg bw/d in males and females, respectively
- Dose / conc.:
- 20 ppm
- Remarks:
- 1.32 and 1.56 mg/kg bw/d in males and females, respectively
- Dose / conc.:
- 60 ppm
- Remarks:
- 3.99 and 4.85 mg/kg bw/d in males and females, respectively
- Dose / conc.:
- 200 ppm
- Remarks:
- 13.8 and 17.6 mg/kg bw/d in males and females, respectively
- No. of animals per sex per dose:
- 12/sex (main groups)
15/sex (cholinesterase activity assessment) - Control animals:
- yes, concurrent no treatment
- Details on study design:
- Groups of 12 male and 12 female Sprague-Dawley rats for the main study and groups of 15 male and 15 female Sprague-Dawley rats for cholinesterase assessment received fenitrothion, in powdered Certified PMI Rodent Chow at concentrations of 0, 6, 20, 60 and 200 ppm (corresponding to 0, 0.40, 1.32, 3.99 and 13.8 mg/kg bw/d in males; 0, 0.46, 1.56, 4.85 and 17.6 mg/kg bw/day in females) for 13 weeks.
- Positive control:
- Not required
- Observations and examinations performed and frequency:
- All animals were observed twice a day for their toxic signs and mortality. Body weight was recorded weekly and days of behavioural testing. Food consumption was recorded weekly for all animals.
Main study animals: Functional observational battery (FOB) and motor activity were tested at prestudy and 4th, 8th and 13th weeks of treatment.
Cholinesterase test animals: Erythrocyte, plasma and brain cholinesterase activities were determined on 5 rats/sex/group at 4, 8 and 13 weeks. - Sacrifice and pathology:
- At the completion of the study, 6 rats/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 (6/sex) had their brains removed and then were subjected to necropsy. The brain of each of non-perfused rats in the control and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP).
- Statistics:
- Study parameters were assessd and compared to controls using appropriate statistical analyses.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Four females in the 200 ppm group showed tremors on one or two days during the second week of treatment. The 200 ppm group females also showed a higher incidence of muzzle staining and brown staining along the tail during the study compared to the control group.
- Mortality:
- no mortality observed
- Description (incidence):
- No animals died and none were sacrificed prior to study completion
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Both males and females in the 200 ppm group and females in the 60 ppm group had significantly reduced body weights compared to the control group on Day 7. The 200 ppm group's body weight remained significantly lower on Day 14 and 21 for males and from Days 7 to 42 for females
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption by the 200 ppm group males and females were significantly lower than the control group from Days 0 to 7. Food consumption by the 200 ppm group females remained significantly reduced from Days 7 to 14 but then increased significantly from Days 28 to 56 and from 84 to 91.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Reductions in blood and brain cholinesterase levels were noted for males in the 60 and 200 ppm groups and females in the 20, 60 and 200 ppm groups.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant differences considered to be related to treatment were seen for the qualitative components of the FOB. Significantly lower values for the 200 ppm group females in forelimb grip strength during the 4th week and in hindlimb grip strength during the 8th week occurred. These differences were considered not to be indicative of neurotoxicity taking lower body weights for the 200 ppm group females. Body temperature values as well as motor activity levels were not significantly different between control and fenitrothion-treated groups.
- 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
- Description (incidence and severity):
- No gross pathological findings or neuropathological changes (including brain measurements) seen were attributed to treatment with fenitrothion. No significant increases in glial fibrillary acidic protein were detected between the control and high dose groups for either male or females.
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 20 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 60 ppm
- System:
- nervous system
- Organ:
- neurons
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- A NOAEL of 20 ppm (equivalent to 1.32 and 1.56 mg/kg bw/d in males and females respectively) can be determined for this study based on the inhibition of cholinesterase activity at higher dietary concentrations.
- Executive summary:
The neurotoxicity of fenitrothion was investigated in a 90 -day rat study. Groups of 12 male and 12 female Sprague-Dawley rats (main study) and groups of 15 male and 15 female rats (cholinesterase assessment) received fenitrothion in the diet at concentrations of 0, 6, 20, 60 and 200 ppm. Dietary concentrations were calculated to be equal to mean intakes of 0, 0.40, 1.32, 3.99 and 13.8 mg/kg bw/d in males; 0, 0.46, 1.56, 4.85 and 17.6 mg/kg bw/d in females) for 13 weeks. All animals were observed twice a day for their toxic signs and mortality. Body weight was recorded weekly and days of behavioral testing. Food consumption was recorded weekly for all animals. Functional observational battery (FOB) and motor activity assessments were performed pre-test and during Weeks 4, 8 and 13. At termination, 6 rats/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 (6/sex) had their brains removed and then were subjected to necropsy. The brain of each of non-perfused rats in the control and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP). Cholinesterase activities (erythrocyte, plasma, brain) were measured at 4, 8 and 13 weeks (5/sex). No animal died and none were sacrificed prior to scheduled termination. No treatment-related toxic signs were noted in male rats. Four females in the 200 ppm group showed tremors on one or two days during the second week of treatment. The 200 ppm group females also showed a higher incidence of muzzle staining and brown staining along the tail during the study compared to the control group. Both males and females in the 200 ppm group and females in the 60 ppm group had significantly reduced body weights compared to the control group on Day 7. The 200 ppm group's mean body weight remained significantly lower on Day 14 and 21 for males and from Days 7 to 42 for females. Food consumption for the 200 ppm group males and females were significantly lower than the control group from Days 0 to 7. Food consumption for the 200 ppm group females remained significantly reduced from Days 7 to 14 but then increased significantly from Days 28 to 56 and from 84 to 91. No significant differences considered to be related to treatment were seen for the qualitative components of the FOB. Significantly lower values for the 200 ppm group females in forelimb grip strength during the 4th week and in hindlimb grip strength during the 8th week occurred. These differences were considered not to be indicative of neurotoxicity taking lower body weights for the 200 ppm group females. Body temperature values as well as motor activity levels were not significantly different between control and fenitrothion-treated gropus. Reductions in blood and brain cholinesterase levels were noted for males in the 60 and 200 ppm groups and females in the 20, 60 and 200 ppm groups. No gross pathological findings or neuropathological changes (including brain measurements) seen were attributed to treatment with fenitrothion. No significant increases in glial fibrillary acidic protein were detected between the control and high dose groups for either male or females. A NOAEL of 20 ppm (equivalent to 1.32 and 1.56 mg/kg bw/d in males and females respectively) can be determined for this study based on the inhibition of cholinesterase activity at higher dietary concentrations.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 17 March 1988 - 30 June 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:
- 90-day study, specifically investigating ocular toxicity.
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 60553
Purity: 94.5%, - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Standard species/strain for use in regulatory studies
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Housing: individual
- Diet: ad llibitum
- Water: ad libitum
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 45-65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 10/14
IN-LIFE DATES: From: 17 March 1988 To: 30 June 1988 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- Groups of 12 male or 12 female Crj:CD(SD) rats received fenitrothion orally by admixture with the diet at the dose levels of 0, 2.5, 5, 10, 30 ppm for 13 weeks.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily (continuous)
- Dose / conc.:
- 0 ppm
- Remarks:
- Control (basal diet)
- Dose / conc.:
- 2.5 ppm
- Dose / conc.:
- 5 ppm
- Dose / conc.:
- 10 ppm
- Dose / conc.:
- 30 ppm
- No. of animals per sex per dose:
- 12/sex
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- The study was designed to specifically investigate ocular toxicity, but included assessment of cholinesterase activity.
- Positive control:
- None
- Observations and examinations performed and frequency:
- Clinical signs, body weights and food consumption were recorded for all animals. Ophthalmology and ERG examination, measurements of cholinesterase activity were performed for all animals
- Sacrifice and pathology:
- Gross pathological and histopathological examinatins on the eyes and their accessory organs were performed for all animals. Electron microscopy was performed on the eyes and their accessory organs from 2 males and 2 females of the control and high dose groups.
- Statistics:
- Experimental parameters were assessed and compared using appropriate statisitcal methods.
- 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
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- There were no distinct changes attributable to the feeding of fenitrothion in any of the treated groups.
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Cholinesterase activities in plasma and erythrocytes were distinctly inhibited in both sexes of the 30 ppm group; females of this group also showed an inhibition of cholinesterase activity in the brain. In addition, inhibition of plasma cholinesterase activity was seen in females of the 10 ppm group
- 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:
- no effects observed
- Description (incidence and severity):
- No toxic changes were found in the eye, musculus rectus medialis, and optic nerve from the animals of the treated groups examined.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No toxic changes were found in the eye, musculus rectus medialis, and optic nerve from the animals of the treated groups examined.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- Electroretinography did not reveal any changes attributable to the feeding of fenitrothion in any of the treated groups. Electron microscopy did not reveal any changes in the eye, musculus rectus medialis, and optic nerve from the animals of the treated groups examined
- Details on results:
- There was no mortality or signs of toxicity. Bodyweights and food consumption were unaffected by treatment. Ophthalmoscopy and electroretinography did not show any treatment-related changes. Cholinesterase activities in plasma and erythrocytes were distinctly inhibited in both sexes of the 30 ppm group; females of this group also showed an inhibition of cholinesterase activity in the brain. In addition, inhibition of plasma cholinesterase activity was seen in females of the 10 ppm group. No effects on the eye were detected at necropsy, following microscopy or electron microscopy.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 30 ppm
- System:
- nervous system
- Organ:
- brain
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- There was no evidence of ocular toxicity in this study at dose levels resulting in marked cholinesterase inhibition. A NOAEL of 10 ppm can be determined for effects on cholinesterase activity.
- Executive summary:
In a study designed to assess ocular toxicity, groups of 12 male or 12 female Crj:CD(SD) rats received fenitrothion orally by admixture with the diet at the dose levels of 0, 2.5, 5, 10, 30 ppm for 13 weeks. Clinical signs, body weights and food consumption were recorded for all animals. Ophthalmology and ERG examination, measurement of cholinesterase activity, gross pathological and histopathological examinatins on the eyes and their accessory organs were performed for all animals. Electron microscopy was performed on the eyes and their accessory organs from 2 males and 2 females of the control and high dose groups. There was no mortality or signs of toxicity. Bodyweights and food consumption were unaffected by treatment. Ophthalmoscopy and electroretinography did not show any treatment-related changes. Cholinesterase activities in plasma and erythrocytes were distinctly inhibited in both sexes of the 30 ppm group; females of this group also showed an inhibition of cholinesterase activity in the brain. In addition, inhibition of plasma cholinesterase activity was seen in females of the 10 ppm group. Electroretinography did not reveal any changes attributable to the feeding of fenitrothion in any of the treated groups. Electron microscopy did not reveal any changes in the eye, musculus rectus medialis, and optic nerve from the animals of the treated groups examined. There was no evidence of ocular toxicity in this study at dose levels resulting in marked cholinesterase inhibition. A NOAEL of 10 ppm can be determined for effects on cholinesterase activity.
Referenceopen allclose all
Summary of bodyweights (g)
Dose level |
0 ppm |
6 ppm |
20 ppm |
60 ppm |
200 ppm |
Males |
|
|
|
|
|
Day 0 |
264.2 |
262.7 |
265.3 |
266.0 |
263.6 |
Day 7 |
318.4 |
314.7 |
320.6 |
319.6 |
298.4** |
Day 14 |
359.4 |
355.1 |
364.3 |
362.5 |
336.8** |
Day 21 |
388.6 |
384.7 |
395.2 |
394.9 |
372.3* |
Day 26 |
413.1 |
410.9 |
421.6 |
417.7 |
393.1 |
Day 27 |
409.3 |
406.0 |
419.0 |
415.4 |
392.5 |
Day 28 |
414.0 |
409.8 |
423.8 |
421.1 |
401.7 |
Day 35 |
439.1 |
428.7 |
453.3 |
447.8 |
429.5 |
Day 42 |
465.2 |
454.5 |
475.0 |
473.5 |
456.8 |
Day 49 |
488.2 |
472.8 |
496.0 |
494.2 |
479.1 |
Day 54 |
503.2 |
495.3 |
511.1 |
509.7 |
484.4 |
Day 55 |
496.6 |
492.9 |
508.4 |
505.3 |
482.3 |
Day 56 |
502.2 |
488.3 |
512.1 |
506.4 |
497.4 |
Day 63 |
518.8 |
503.1 |
254.2 |
524.5 |
509.1 |
Day 70 |
536.7 |
520.4 |
539.1 |
541.2 |
525.5 |
Day 77 |
553.6 |
538.6 |
553.6 |
558.7 |
539.7 |
Day 84 |
563.4 |
549.3 |
564.8 |
570.6 |
552.3 |
Day 89 |
569.5 |
570.8 |
581.6 |
584.5 |
554.7 |
Day 90 |
563.2 |
564.4 |
573.0 |
579.3 |
551.2 |
Day 91 |
566.8 |
556.0 |
569.7 |
577.7 |
558.8 |
Females |
|
|
|
|
|
Day 0 |
189.2 |
188.9 |
186.8 |
185.6 |
186.5 |
Day 7 |
213.8 |
211.3 |
209.0 |
204.9* |
186.0** |
Day 14 |
226.8 |
226.4 |
225.4 |
219.9 |
190.2** |
Day 21 |
244.1 |
242.7 |
238.1 |
234.7 |
210.6** |
Day 26 |
249.7 |
251.4 |
246.6 |
243.4 |
216.2** |
Day 27 |
251.3 |
250.7 |
247.8 |
242.5 |
215.4** |
Day 28 |
255.9 |
253.2 |
248.1 |
246.5 |
226.4** |
Day 35 |
269.3 |
264.8 |
261.0 |
257.4 |
246.4** |
Day 42 |
280.8 |
276.5 |
270.5 |
268.6 |
216.8* |
Day 49 |
290.8 |
280.4 |
277.0 |
279.6 |
277.1 |
Day 54 |
288.6 |
283.3 |
279.3 |
284.3 |
271.2 |
Day 55 |
287.1 |
280.4 |
277.9 |
282.7 |
268.5 |
Day 56 |
295.8 |
286.1 |
279.1 |
284.9 |
282.2 |
Day 63 |
300.7 |
292.5 |
288.6 |
296.5 |
284.7 |
Day 70 |
307.0 |
300.6 |
291.4 |
304.2 |
291.6 |
Day 77 |
314.0 |
308.0 |
301.5 |
313.0 |
299.8 |
Day 84 |
319.0 |
313.6 |
306.3 |
315.8 |
305.3 |
Day 89 |
319.1 |
313.8 |
306.2 |
317.3 |
305.5 |
Day 90 |
316.5 |
311.0 |
302.9 |
312.3 |
302.8 |
Day 91 |
318.4 |
312.2 |
304.7 |
315.6 |
307.2 |
*significantly different to controls (p<0.05); **p<0.01
Summary of food consumption (g/day)
Dose level |
0 ppm |
6 ppm |
20 ppm |
60 ppm |
200 ppm |
Males |
|
|
|
|
|
Day 0 - 7 |
196.5 |
194.7 |
201.6 |
200.9 |
182.2** |
Day 7 - 14 |
203.2 |
197.2 |
208.9 |
207.7 |
194.8 |
Day 14 - 21 |
206.3 |
202.9 |
212.0 |
211.5 |
209.5 |
Day 21 - 28 |
202.2 |
199.0 |
204.5 |
204.8 |
211.2 |
Day 28 - 35 |
204.2 |
199.0 |
210.9 |
204.8 |
211.8 |
Day 35 - 42 |
213.2 |
199.4 |
204.1 |
209.8 |
214.8 |
Day 42 - 49 |
217.0 |
197.9** |
208.5 |
211.9 |
213.3 |
Day 49 - 56 |
208.8 |
197.0 |
205.3 |
206.0 |
213.3 |
Day 56 - 63 |
211.1 |
200.5 |
207.7 |
208.1 |
213.6 |
Day 63 - 70 |
215.3 |
203.1 |
205.5 |
207.0 |
210.1 |
Day 70 - 77 |
215.6 |
205.4 |
206.2 |
211.9 |
210.6 |
Day 77 - 84 |
208.9 |
204.3 |
207.5 |
214.9 |
215.3 |
Day 84 - 91 |
199.6 |
194.7 |
199.3 |
204.0 |
206.7 |
Females |
|
|
|
|
|
Day 0 - 7 |
139.3 |
137.1 |
137.5 |
135.7 |
119.3** |
Day 7 - 14 |
143.3 |
138.8 |
142.3 |
140.4 |
100.9** |
Day 14 - 21 |
151.1 |
149.9 |
145.7 |
148.1 |
145.2 |
Day 21 - 28 |
145.7 |
141.9 |
140.8 |
143.9 |
154.4 |
Day 28 - 35 |
149.6 |
141.0 |
141.9 |
151.2 |
167.4** |
Day 35 - 42 |
152.9 |
145.4 |
141.4 |
150.4 |
173.9** |
Day 42 - 49 |
151.6 |
143.1 |
146.8 |
153.9 |
180.7** |
Day 49 - 56 |
148.2 |
141.6 |
139.1 |
147.5 |
164.8** |
Day 56 - 63 |
150.4 |
147.3 |
145.1 |
159.1 |
165.8 |
Day 63 - 70 |
151.8 |
145.0 |
143.8 |
153.6 |
160.3 |
Day 70 - 77 |
152.0 |
145.9 |
146.2 |
153.0 |
163.2 |
Day 77 - 84 |
149.6 |
146.8 |
145.9 |
150.3 |
161.2 |
Day 84 - 91 |
142.9 |
139.8 |
135.6 |
145.8 |
159.9* |
*significantly different to controls (p<0.05); **p<0.01)
Summary of FOB
Dose level |
0 ppm |
6 ppm |
20 ppm |
60 ppm |
200 ppm |
Females |
|
|
|
|
|
Forelimb grip strength (g) |
|
|
|
||
Week 3 |
1120.4 |
1095.0 |
1100.0 |
1084.2 |
998.8** |
Week 7 |
1091.3 |
1111.3 |
1066.7 |
1102.5 |
1036.3 |
Week 12 |
1182.5 |
1157.1 |
1051.3 |
1036.7 |
971.7 |
Hindlimb grip strength (g) |
|
|
|
||
Week 3 |
773.3 |
797.1 |
760.0 |
765.8 |
737.5 |
Week 7 |
766.3 |
792.5 |
755.8 |
726.3 |
658.8** |
Week 12 |
908.3 |
982.1 |
915.0 |
884.6 |
808.8 |
*significantly different to controls (p<0.05); **p<0.01
Summary of cholinesterase activity
Dose level |
0 ppm |
6 ppm |
20 ppm |
60 ppm |
200 ppm |
Males |
|
|
|
|
|
Plasma cholinesterase (U/L) |
|
|
|
||
Week 4 |
349.0 |
350.4 |
292.2 |
220.0** |
181.4** |
Week 8 |
379.0 |
299.0 |
295.4 |
196.0* |
155.8** |
Week 13 |
359.5 |
299.8 |
313.0 |
231.2* |
216.6** |
Erythrocyte cholinesterase (U/L) |
|
|
|
||
Week 4 |
2255.0 |
2117.0 |
2131.4 |
1711.0* |
1206.4** |
Week 8 |
2106.0 |
2054.8 |
1839.8 |
1519.4** |
1205.8** |
Week 13 |
2186.5 |
1978.0 |
1978.8 |
1815.0 |
1299.2** |
Brain cholinesterase (U/L) |
|
|
|
||
Week 4 |
10.06 |
10.08 |
9.62 |
8.00** |
3.52** |
Week 8 |
8.30 |
7.60 |
8.66 |
7.19 |
3.49** |
Week 13 |
9.53 |
9.26 |
9.51 |
8.18** |
4.00** |
Females |
|
|
|
|
|
Plasma cholinesterase (U/L) |
|
|
|
||
Week 4 |
1533.0 |
1194.6 |
720.4 |
513.4* |
314.0*** |
Week 8 |
2159.4 |
1914.4 |
938.8** |
505.6** |
324.8** |
Week 13 |
2888.4 |
1396.0 |
976.2 |
661.8** |
376.8*** |
Erythrocyte cholinesterase (U/L) |
|
|
|
||
Week 4 |
2331.6 |
2218.6 |
1880.4* |
1499.6** |
1162.2** |
Week 8 |
1601.0 |
1589.8 |
1332.6 |
1175.8 |
822.5 |
Week 13 |
1650.0 |
1889.8 |
1668.2 |
1217.6 |
1021.8 |
Brain cholinesterase (U/L) |
|
|
|
||
Week 4 |
10.23 |
9.74 |
8.72* |
4.58** |
2.12** |
Week 8 |
9.13 |
8.74 |
8.08 |
3.89** |
2.01** |
Week 13 |
9.40 |
9.62 |
8.92 |
3.99** |
2.18** |
*significantly different to controls (p<0.05); **p<0.01; ***p<0.001
Summary of cholinesterase inhibition
Dose level |
0 ppm |
2.5 ppm |
5 ppm |
10 ppm |
30 ppm |
Male |
|
|
|
|
|
Number of animals examined |
10 |
9 |
10 |
10 |
10 |
Plasma |
0.22 |
0.17 |
0.21 |
0.17 |
0.13** |
Erythrocytes |
0.32 |
0.32 |
0.31 |
0.31 |
0.21** |
Brain |
0.43 |
0.48 |
0.50** |
0.48 |
0.45 |
Female |
|
|
|
|
|
Number of animals examined |
10 |
9 |
10 |
10 |
10 |
Plasma |
1.95 |
1.40 |
1.63 |
1.05* |
0.30** |
Erythrocytes |
0.27 |
0.27 |
0.25 |
0.25 |
0.13** |
Brain |
0.49 |
0.48 |
0.47 |
0.47 |
0.42** |
*significantly different to controls (p<0.05); **p<0.01
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 1.32 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- A modern 90 -day rat toxicity study is available for fenitrothion and is supported by a further (non-standard) 90 -day study
- System:
- peripheral nervous system
- Organ:
- neurons
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 15 November 1990 - 10 December 1990
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 90617
Purity: 93.7% - Species:
- rabbit
- Strain:
- New Zealand White
- Details on species / strain selection:
- Standard species/strain used for regulatory studies
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Kitayama Labs, Japan
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 10 weeks
- Weight at study initiation: 1944-2311 g (males), 1704-2026 g (females)
- Housing: individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: one week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 45-65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 15 November 1990 To: 10 December 1990 - Type of coverage:
- occlusive
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TEST SITE
- Area of exposure: 12x14 cm
- Type of wrap if used: occlusive
REMOVAL OF TEST SUBSTANCE
- Washing (if done): water and soap
- Time after start of exposure: 6 hours
VEHICLE
- Justification for use and choice of vehicle: undiluted
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 6 hours/day for 21 successive days
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- control (distilled water)
- Dose / conc.:
- 3 mg/kg bw/day
- Dose / conc.:
- 10 mg/kg bw/day
- Dose / conc.:
- 50 mg/kg bw/day
- Dose / conc.:
- 250 mg/kg bw/day
- No. of animals per sex per dose:
- 5/sex
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Fenitrothion was administered percutaneously to groups of 5 male and 5 female New Zealand White rabbits at the dose levels of 0, 3, 10, 50 and 250 mg/kg bw/d by the topical route for a period of 21 successive days. The test material, a brown oily substance, was administered undiluted. The control group received distilled water.
- Positive control:
- Not required
- Observations and examinations performed and frequency:
- Parameters evaluated were clinical observations (twice daily), dermal reactions (daily), body weights and food consumption (weekly), plasma and erythrocyte cholinesterase activity (one week before treatment, 2 and 24 hours after final dosing), haematology and biochemistry.
- Sacrifice and pathology:
- Brain cholinesterase activity, necropsy, organ weights and histopathology were assessed at study termination.
- Statistics:
- Parameters measured in this study were assessed and compared using appropriate statisitcal methods.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Signs observed in animals prior to death were hypoactivity, muscular hypotonia, tremor, bradypnoea, hypothermia, salivation, clonic convulsion, loose or mucous stool, diarrhea and soiled perineum. In the surviving three females at 250 mg/kg bw/d, one animal revealed loose stool and soiled perineum and the other two animals showed no abnormalities. No clinical signs were noted in animals of the control and 3, 10 and 50 mg/kg bw/d groups.
- Dermal irritation:
- effects observed, treatment-related
- Description (incidence and severity):
- Very slight or well defined erythema and very slight or slight oedema were observed at the application site in males and females of the 3, 10 and 50 mg/kg bw/d groups, and were classified as mild according to the Draize index. Males and females of the 250 mg/kg bw/d group showed slightly more severe irritation than other treated groups. The maximum mean irritation scores at 250 mg/kg bw/d were classified as moderate according to the Draize index. The other dermal reaction observed in all groups treated with fenitrothion was desquamation of the epidermis.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Five males and two females at 250 mg/kg bw/d showed deterioration of general condition and died during the administration period (two males and one female were killed in a moribund condition).
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Depression of body weight gain and decrease in body weights were observed in males and females at 250 mg/kg bw/d.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased WBC count and variable differential counts were observed in decedents at 250 mg/kg bw/d. No haematological effects were reported at lower dose levels.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased AST and ALT activity and blood urea nitrogen and a decrease in serum electrocytes were observed in some animals at 250 mg/kg bw/d. No effects on clinical chemistry parameters were reported at lower dose levels.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased adrenal weight was seen in some rabbits at 250 mg/kg bw/d.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- At 250 mg/kg bw/d, one male and one female revealed slight focal necrosis in the liver; histopathological changes in the digestive tract and kidney were considered to reflect a general deterioration of condition.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Erythrocyte cholinesterase activity decreased in males and females at 10, 50 and 250 mg/kg bw/d. Plasma and brain cholinesterase activities decreased in males at 50 and 250 mg/kg bw/d and in females at 10, 50 and 250 mg/kg bw/d. No significant changes in erythrocyte, plasma or brain cholinesterase activities were observed at 3 mg/kg bw/d.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- < 3 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Local dermal irritation
- Remarks on result:
- other: Local toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 3 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: cholinesterase activity
- Remarks on result:
- other: Systemic toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 10 mg/kg bw/day
- System:
- nervous system
- Organ:
- brain
- neurons
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- A NOAEL could not be determined for this study due to local dermal reactions at the application site in rabbits of all treated groups. A NOAEL for systemic toxicity of 3 mg/kg bw/d can be determined based on the significant inhibition of cholinesterase activity at higher dose levels.
- Executive summary:
The repeated dose dermal toxicity of fenitrothion was investigated in a 21 -day study in the rabbit. Fenitrothion was administered percutaneously to groups of 5 male and 5 female New Zealand White rabbits at the dose levels of 0, 3, 10, 50 and 250 mg/kg bw/d by the topical route for a period of 21 successive days. The test material, a brown oily substance, was administered undiluted. The control group received distilled water. Parameters evaluated included clinical observations (twice daily), dermal reactions (daily), body weights and food consumption (weekly), plasma and erythrocyte cholinesterase activity (one week before treatment, 2 and 24 hours after final dosing) and haematology, biochemistry, brain cholinesterase activity, necropsy, organ weights and histopathology at study termination. Five males and two females at 250 mg/kg bw/d showed deterioration of general condition and died during the administration period (two males and one female were killed in a moribund condition). Signs observed in animals prior to death were hypoactivity, muscular hypotonia, tremor, bradypnoea, hypothermia, salivation, clonic convulsion, loose or mucous stool, diarrhoea and soiled perineum. In the surviving three females at 250 mg/kg bw/d, one animal revealed loose stool and soiled perineum and the other two animals showed no abnormalities. No clinical signs were noted in animals of the control and 3, 10 and 50 mg/kg bw/d groups. Very slight or well defined erythema and very slight or slight oedema were observed at the application site in males and females of the 3, 10 and 50 mg/kg bw/d groups, and were classified as mild according to the Draize index. Males and females of the 250 mg/kg bw/d group showed slightly more severe irritation than other treated groups. The maximum mean irritation scores at 250 mg/kg bw/d were classified as moderate according to the Draize index. The other dermal reaction observed in all groups treated with fenitrothion was desquamation of the epidermis. Depression of body weight gain and decrease in body weights were observed in males and females at 250 mg/kg bw/d. Increased WBC count and variable differential counts were observed in decedents at 250 mg/kg bw/d. No haematological effects were reported at lower dose levels. Increased AST and ALT activity and blood urea nitrogen and a decrease in serum electrolytes were observed in some animals at 250 mg/kg bw/d. No effects on clinical chemistry parameters were reported at lower dose levels. Gross necropsy did not reveal any effects of treatment. Increased adrenal weight was seen in some rabbits at 250 mg/kg bw/d. At 250 mg/kg bw/d, one male and one female revealed slight focal necrosis in the liver; histopathological changes in the digestive tract and kidney were considered to reflect a general deterioration of condition. Erythrocyte cholinesterase activity decreased in males and females at 10, 50 and 250 mg/kg bw/d. Plasma and brain cholinesterase activities decreased in males at 50 and 250 mg/kg bw/d and in females at 10, 50 and 250 mg/kg bw/d. No significant changes in erythrocyte, plasma or brain cholinesterase activities were observed at 3 mg/kg bw/d. A NOAEL could not be determined for this study due to local dermal reactions at the application site in rabbits of all treated groups. A NOAEL for systemic toxicity of 3 mg/kg bw/d can be determined based on the significant inhibition of cholinesterase activity at higher dose levels.
Reference
Summary of dermal reactions (males)
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
|||||||||
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
|
Day 0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 4 |
0 |
0 |
0 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.20 |
0 |
0.20 |
Day 5 |
0 |
0 |
0 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.40 |
0 |
0.40 |
Day 6 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.40 |
0 |
0.40 |
0.60 |
0 |
0.60 |
Day 7 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
0.80 |
0 |
0.80 |
1.20 |
0.20 |
1.40 |
Day 8 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0.20 |
1.20 |
1.25 |
1.00 |
2.25 |
Day 9 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.20 |
0.20 |
1.40 |
1.33 |
1.33 |
2.66 |
Day 10 |
0.60 |
0 |
0.60 |
0.60 |
0 |
0.60 |
1.20 |
0.20 |
1.40 |
1.33 |
0.67 |
2.00 |
Day 11 |
0.60 |
0 |
0.60 |
0.40 |
0 |
0.40 |
0.80 |
0.20 |
1.00 |
1.00 |
0.33 |
1.33 |
Day 12 |
0.60 |
0 |
0.60 |
0.40 |
0 |
0.40 |
0.80 |
0.20 |
1.00 |
1.00 |
0 |
1.00 |
Day 13 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
0.80 |
0 |
0.80 |
1.00 |
0 |
1.00 |
Day 14 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 15 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 16 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 17 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 18 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 19 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Day 20 |
0.60 |
0 |
0.60 |
0.40 |
0.20 |
0.60 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
Termination |
0.80 |
0 |
0.80 |
0.40 |
0.40 |
0.80 |
0.60 |
0 |
0.60 |
- |
- |
- |
Summary of dermal reactions (females)
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
|||||||||
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
|
Day 0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
Day 5 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.20 |
0 |
0.20 |
1.00 |
0.20 |
1.20 |
Day 6 |
0 |
0 |
0 |
0.40 |
0 |
0.40 |
0.40 |
0.40 |
0.80 |
1.00 |
0.80 |
1.80 |
Day 7 |
0 |
0 |
0 |
0.40 |
0 |
0.40 |
0.60 |
0.40 |
1.00 |
1.40 |
1.00 |
2.40 |
Day 8 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.80 |
0.40 |
1.20 |
1.20 |
0.60 |
1.80 |
Day 9 |
0.20 |
0 |
0.20 |
0.20 |
0 |
0.20 |
0.60 |
0.40 |
1.00 |
1.00 |
0.40 |
1.40 |
Day 10 |
0.20 |
0 |
0.20 |
0.20 |
0 |
0.20 |
0.60 |
0.40 |
1.00 |
1.00 |
0.40 |
1.40 |
Day 11 |
0.20 |
0 |
0.20 |
0.40 |
0 |
0.40 |
0.60 |
0.40 |
1.00 |
1.20 |
0.20 |
1.40 |
Day 12 |
0.40 |
0 |
0.40 |
0.60 |
0 |
0.60 |
0.80 |
0.40 |
1.20 |
1.20 |
0.20 |
1.40 |
Day 13 |
0.80 |
0.20 |
1.00 |
1.00 |
0.60 |
1.60 |
0.80 |
0.40 |
1.20 |
1.20 |
0.20 |
1.40 |
Day 14 |
1.00 |
0.60 |
1.60 |
1.20 |
0.60 |
1.80 |
0.80 |
0.20 |
1.00 |
1.20 |
0.20 |
1.40 |
Day 15 |
0.80 |
0.60 |
1.40 |
1.20 |
0.60 |
1.80 |
0.80 |
0.20 |
1.00 |
1.00 |
0 |
1.00 |
Day 16 |
0.80 |
0 |
0.80 |
1.20 |
0.40 |
1.60 |
0.80 |
0 |
0.80 |
1.00 |
0 |
1.00 |
Day 17 |
0.60 |
0 |
0.60 |
1.20 |
0.20 |
1.40 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Day 18 |
0.60 |
0 |
0.60 |
1.00 |
0.20 |
1.20 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Day 19 |
0.60 |
0 |
0.60 |
1.00 |
0.20 |
1.20 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Day 20 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Termination |
0.40 |
0 |
0.40 |
0.80 |
0 |
0.80 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Bodyweights and weight gains
|
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
Males |
|||||
Day 0 |
(5) 2.482 |
(5) 2.471 |
(5) 2.503 |
(5) 2.439 |
(5) 2.448 |
Day 7 |
(5) 2.616 |
(5) 2.611 |
(5) 2.710 |
(5) 2.599 |
(5) 2.456 |
Day 14 |
(5) 2.783 |
(5) 2.744 |
(5) 2.810 |
(5) 2.695 |
(2) 2.493 |
Day 20 |
(5) 2.915 |
(5) 2.831 |
(5) 2.938 |
(5) 2.764 |
(2) 2.302 |
Body Weight Gains |
|||||
Day 7 |
(5) 0.134 |
(5) 0.140 |
(5) 0.208 |
(5) 0.160 |
(5) 0.007 |
Day 14 |
(5) 0.301 |
(5) 0.273 |
(5) 0.307 |
(5) 0.256 |
(2) 0.176 |
Day20 |
(5) 0.433 |
(5) 0.360 |
(5) 0.436 |
(5) 0.325 |
(2) -0.115* |
Females |
|||||
Day 0 |
(5) 2.522 |
(5) 2.482 |
(5) 2.583 |
(5) 2.437 |
(5) 2.531 |
Day 7 |
(5) 2.578 |
(5) 2.590 |
(5) 2.678 |
(5) 2.642 |
(5) 2.685 |
Day 14 |
(5) 2.773 |
(5) 2.744 |
(5) 2.787 |
(5) 2.808 |
(5) 2.623 |
Day 20 |
(5) 2.882 |
(5) 2.865 |
(5) 2.901 |
(5) 2.864 |
(3) 2.695 |
Body Weight Gains |
|||||
Day 7 |
(5) 0.056 |
(5) 0.108 |
(5) 0.095 |
(5) 0.204 |
(5) 0.154 |
Day 14 |
(5) 0.251 |
(5) 0.262 |
(5) 0.203 |
(5) 0.370 |
(5) 0.093 |
Day 20 |
(5) 0.360 |
(5) 0.383 |
(5) 0.317 |
(5) 0.427 |
(3) 0.200 |
*significantly differerent to controls (p<0.05)
Cholinesterase activity
|
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
|
Males |
||||||
Erythrocyte |
Before treatment |
916.28 |
811.80 |
993.39 |
954.04 |
891.61 |
2h after |
1274.98 |
1020.21 |
687.90** |
646.96** |
- |
|
24h after |
1198.76 |
829.02 |
1049.14 |
500.65** |
- |
|
Plasma |
Before treatment |
257.60 |
325.01 |
280.94 |
284.41 |
298.18 |
2h after |
355.72 |
357.27 |
317.66 |
218.58 |
- |
|
24h after |
385.30 |
386.07 |
323.55 |
232.73* |
- |
|
Brain |
|
11204.60 |
10057.80 |
8904.40 |
7127.60** |
- |
Females |
||||||
Erythrocyte |
Before treatment |
917.69 |
874.41 |
741.74 |
780.84 |
896.69 |
2h after |
1291.47 |
1349.59 |
630.33* |
377.49** |
222.36** |
|
24h after a) |
1135.52 |
1063.48 |
761.98 |
400.29** |
237.47** |
|
Plasma |
before treatment |
139.52 |
139.92 |
161.46 |
124.95 |
127.03 |
2h after |
360.55 |
309.10 |
259.03 |
95.36** |
38.05** |
|
24h after |
356.89 |
325.72 |
212.25** |
143.90** |
22.98** |
|
Brain |
|
12798.00 |
11736.20 |
10119.40* |
9010.20** |
2590.00** |
*significantly different to controls (p<0.05); **p<0.01
Adrenal weights
Week 4 |
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
Males |
|||||
Body weight (kg) |
2.788 |
2.765 |
2.814 |
2.667 |
- |
Adrenal absolute weight (g) |
0.21 |
0.25 |
0.24 |
0.20 |
- |
Adrenal relative weight (%) |
0.07 |
0.09 |
0.08 |
0.08 |
- |
Females |
|||||
Body weight (kg) |
2.808 |
2.681 |
2.817 |
2.768 |
2.641 |
Adrenal absolute weight (g) |
0.21 |
0.20 |
0.25 |
0.22 |
0.28* |
Adrenal relative weight (%) |
0.07 |
0.08 |
0.09 |
0.08 |
11 |
*significantly different to controls (p<0.05)
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 3 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rabbit
- Quality of whole database:
- A guideline-compliant 21-day rabbit study is available for fenitrothion
- System:
- central nervous system
- Organ:
- brain
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 15 November 1990 - 10 December 1990
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Fenitrothion
Batch No.: 90617
Purity: 93.7% - Species:
- rabbit
- Strain:
- New Zealand White
- Details on species / strain selection:
- Standard species/strain used for regulatory studies
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Kitayama Labs, Japan
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 10 weeks
- Weight at study initiation: 1944-2311 g (males), 1704-2026 g (females)
- Housing: individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: one week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 45-65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 15 November 1990 To: 10 December 1990 - Type of coverage:
- occlusive
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TEST SITE
- Area of exposure: 12x14 cm
- Type of wrap if used: occlusive
REMOVAL OF TEST SUBSTANCE
- Washing (if done): water and soap
- Time after start of exposure: 6 hours
VEHICLE
- Justification for use and choice of vehicle: undiluted
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 6 hours/day for 21 successive days
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- control (distilled water)
- Dose / conc.:
- 3 mg/kg bw/day
- Dose / conc.:
- 10 mg/kg bw/day
- Dose / conc.:
- 50 mg/kg bw/day
- Dose / conc.:
- 250 mg/kg bw/day
- No. of animals per sex per dose:
- 5/sex
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Fenitrothion was administered percutaneously to groups of 5 male and 5 female New Zealand White rabbits at the dose levels of 0, 3, 10, 50 and 250 mg/kg bw/d by the topical route for a period of 21 successive days. The test material, a brown oily substance, was administered undiluted. The control group received distilled water.
- Positive control:
- Not required
- Observations and examinations performed and frequency:
- Parameters evaluated were clinical observations (twice daily), dermal reactions (daily), body weights and food consumption (weekly), plasma and erythrocyte cholinesterase activity (one week before treatment, 2 and 24 hours after final dosing), haematology and biochemistry.
- Sacrifice and pathology:
- Brain cholinesterase activity, necropsy, organ weights and histopathology were assessed at study termination.
- Statistics:
- Parameters measured in this study were assessed and compared using appropriate statisitcal methods.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Signs observed in animals prior to death were hypoactivity, muscular hypotonia, tremor, bradypnoea, hypothermia, salivation, clonic convulsion, loose or mucous stool, diarrhea and soiled perineum. In the surviving three females at 250 mg/kg bw/d, one animal revealed loose stool and soiled perineum and the other two animals showed no abnormalities. No clinical signs were noted in animals of the control and 3, 10 and 50 mg/kg bw/d groups.
- Dermal irritation:
- effects observed, treatment-related
- Description (incidence and severity):
- Very slight or well defined erythema and very slight or slight oedema were observed at the application site in males and females of the 3, 10 and 50 mg/kg bw/d groups, and were classified as mild according to the Draize index. Males and females of the 250 mg/kg bw/d group showed slightly more severe irritation than other treated groups. The maximum mean irritation scores at 250 mg/kg bw/d were classified as moderate according to the Draize index. The other dermal reaction observed in all groups treated with fenitrothion was desquamation of the epidermis.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Five males and two females at 250 mg/kg bw/d showed deterioration of general condition and died during the administration period (two males and one female were killed in a moribund condition).
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Depression of body weight gain and decrease in body weights were observed in males and females at 250 mg/kg bw/d.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased WBC count and variable differential counts were observed in decedents at 250 mg/kg bw/d. No haematological effects were reported at lower dose levels.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased AST and ALT activity and blood urea nitrogen and a decrease in serum electrocytes were observed in some animals at 250 mg/kg bw/d. No effects on clinical chemistry parameters were reported at lower dose levels.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased adrenal weight was seen in some rabbits at 250 mg/kg bw/d.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- At 250 mg/kg bw/d, one male and one female revealed slight focal necrosis in the liver; histopathological changes in the digestive tract and kidney were considered to reflect a general deterioration of condition.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Erythrocyte cholinesterase activity decreased in males and females at 10, 50 and 250 mg/kg bw/d. Plasma and brain cholinesterase activities decreased in males at 50 and 250 mg/kg bw/d and in females at 10, 50 and 250 mg/kg bw/d. No significant changes in erythrocyte, plasma or brain cholinesterase activities were observed at 3 mg/kg bw/d.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- < 3 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Local dermal irritation
- Remarks on result:
- other: Local toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 3 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: cholinesterase activity
- Remarks on result:
- other: Systemic toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 10 mg/kg bw/day
- System:
- nervous system
- Organ:
- brain
- neurons
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- A NOAEL could not be determined for this study due to local dermal reactions at the application site in rabbits of all treated groups. A NOAEL for systemic toxicity of 3 mg/kg bw/d can be determined based on the significant inhibition of cholinesterase activity at higher dose levels.
- Executive summary:
The repeated dose dermal toxicity of fenitrothion was investigated in a 21 -day study in the rabbit. Fenitrothion was administered percutaneously to groups of 5 male and 5 female New Zealand White rabbits at the dose levels of 0, 3, 10, 50 and 250 mg/kg bw/d by the topical route for a period of 21 successive days. The test material, a brown oily substance, was administered undiluted. The control group received distilled water. Parameters evaluated included clinical observations (twice daily), dermal reactions (daily), body weights and food consumption (weekly), plasma and erythrocyte cholinesterase activity (one week before treatment, 2 and 24 hours after final dosing) and haematology, biochemistry, brain cholinesterase activity, necropsy, organ weights and histopathology at study termination. Five males and two females at 250 mg/kg bw/d showed deterioration of general condition and died during the administration period (two males and one female were killed in a moribund condition). Signs observed in animals prior to death were hypoactivity, muscular hypotonia, tremor, bradypnoea, hypothermia, salivation, clonic convulsion, loose or mucous stool, diarrhoea and soiled perineum. In the surviving three females at 250 mg/kg bw/d, one animal revealed loose stool and soiled perineum and the other two animals showed no abnormalities. No clinical signs were noted in animals of the control and 3, 10 and 50 mg/kg bw/d groups. Very slight or well defined erythema and very slight or slight oedema were observed at the application site in males and females of the 3, 10 and 50 mg/kg bw/d groups, and were classified as mild according to the Draize index. Males and females of the 250 mg/kg bw/d group showed slightly more severe irritation than other treated groups. The maximum mean irritation scores at 250 mg/kg bw/d were classified as moderate according to the Draize index. The other dermal reaction observed in all groups treated with fenitrothion was desquamation of the epidermis. Depression of body weight gain and decrease in body weights were observed in males and females at 250 mg/kg bw/d. Increased WBC count and variable differential counts were observed in decedents at 250 mg/kg bw/d. No haematological effects were reported at lower dose levels. Increased AST and ALT activity and blood urea nitrogen and a decrease in serum electrolytes were observed in some animals at 250 mg/kg bw/d. No effects on clinical chemistry parameters were reported at lower dose levels. Gross necropsy did not reveal any effects of treatment. Increased adrenal weight was seen in some rabbits at 250 mg/kg bw/d. At 250 mg/kg bw/d, one male and one female revealed slight focal necrosis in the liver; histopathological changes in the digestive tract and kidney were considered to reflect a general deterioration of condition. Erythrocyte cholinesterase activity decreased in males and females at 10, 50 and 250 mg/kg bw/d. Plasma and brain cholinesterase activities decreased in males at 50 and 250 mg/kg bw/d and in females at 10, 50 and 250 mg/kg bw/d. No significant changes in erythrocyte, plasma or brain cholinesterase activities were observed at 3 mg/kg bw/d. A NOAEL could not be determined for this study due to local dermal reactions at the application site in rabbits of all treated groups. A NOAEL for systemic toxicity of 3 mg/kg bw/d can be determined based on the significant inhibition of cholinesterase activity at higher dose levels.
Reference
Summary of dermal reactions (males)
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
|||||||||
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
|
Day 0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 4 |
0 |
0 |
0 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.20 |
0 |
0.20 |
Day 5 |
0 |
0 |
0 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.40 |
0 |
0.40 |
Day 6 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.40 |
0 |
0.40 |
0.60 |
0 |
0.60 |
Day 7 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
0.80 |
0 |
0.80 |
1.20 |
0.20 |
1.40 |
Day 8 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0.20 |
1.20 |
1.25 |
1.00 |
2.25 |
Day 9 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.20 |
0.20 |
1.40 |
1.33 |
1.33 |
2.66 |
Day 10 |
0.60 |
0 |
0.60 |
0.60 |
0 |
0.60 |
1.20 |
0.20 |
1.40 |
1.33 |
0.67 |
2.00 |
Day 11 |
0.60 |
0 |
0.60 |
0.40 |
0 |
0.40 |
0.80 |
0.20 |
1.00 |
1.00 |
0.33 |
1.33 |
Day 12 |
0.60 |
0 |
0.60 |
0.40 |
0 |
0.40 |
0.80 |
0.20 |
1.00 |
1.00 |
0 |
1.00 |
Day 13 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
0.80 |
0 |
0.80 |
1.00 |
0 |
1.00 |
Day 14 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 15 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 16 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 17 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 18 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
1.00 |
0 |
1.00 |
Day 19 |
0.40 |
0 |
0.40 |
0.40 |
0 |
0.40 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Day 20 |
0.60 |
0 |
0.60 |
0.40 |
0.20 |
0.60 |
0.40 |
0 |
0.40 |
1.00 |
0 |
1.00 |
Termination |
0.80 |
0 |
0.80 |
0.40 |
0.40 |
0.80 |
0.60 |
0 |
0.60 |
- |
- |
- |
Summary of dermal reactions (females)
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
|||||||||
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
Erythema |
Oedema |
Total |
|
Day 0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Day 4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
Day 5 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.20 |
0 |
0.20 |
1.00 |
0.20 |
1.20 |
Day 6 |
0 |
0 |
0 |
0.40 |
0 |
0.40 |
0.40 |
0.40 |
0.80 |
1.00 |
0.80 |
1.80 |
Day 7 |
0 |
0 |
0 |
0.40 |
0 |
0.40 |
0.60 |
0.40 |
1.00 |
1.40 |
1.00 |
2.40 |
Day 8 |
0 |
0 |
0 |
0.20 |
0 |
0.20 |
0.80 |
0.40 |
1.20 |
1.20 |
0.60 |
1.80 |
Day 9 |
0.20 |
0 |
0.20 |
0.20 |
0 |
0.20 |
0.60 |
0.40 |
1.00 |
1.00 |
0.40 |
1.40 |
Day 10 |
0.20 |
0 |
0.20 |
0.20 |
0 |
0.20 |
0.60 |
0.40 |
1.00 |
1.00 |
0.40 |
1.40 |
Day 11 |
0.20 |
0 |
0.20 |
0.40 |
0 |
0.40 |
0.60 |
0.40 |
1.00 |
1.20 |
0.20 |
1.40 |
Day 12 |
0.40 |
0 |
0.40 |
0.60 |
0 |
0.60 |
0.80 |
0.40 |
1.20 |
1.20 |
0.20 |
1.40 |
Day 13 |
0.80 |
0.20 |
1.00 |
1.00 |
0.60 |
1.60 |
0.80 |
0.40 |
1.20 |
1.20 |
0.20 |
1.40 |
Day 14 |
1.00 |
0.60 |
1.60 |
1.20 |
0.60 |
1.80 |
0.80 |
0.20 |
1.00 |
1.20 |
0.20 |
1.40 |
Day 15 |
0.80 |
0.60 |
1.40 |
1.20 |
0.60 |
1.80 |
0.80 |
0.20 |
1.00 |
1.00 |
0 |
1.00 |
Day 16 |
0.80 |
0 |
0.80 |
1.20 |
0.40 |
1.60 |
0.80 |
0 |
0.80 |
1.00 |
0 |
1.00 |
Day 17 |
0.60 |
0 |
0.60 |
1.20 |
0.20 |
1.40 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Day 18 |
0.60 |
0 |
0.60 |
1.00 |
0.20 |
1.20 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Day 19 |
0.60 |
0 |
0.60 |
1.00 |
0.20 |
1.20 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Day 20 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Termination |
0.40 |
0 |
0.40 |
0.80 |
0 |
0.80 |
0.60 |
0 |
0.60 |
1.00 |
0 |
1.00 |
Bodyweights and weight gains
|
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
Males |
|||||
Day 0 |
(5) 2.482 |
(5) 2.471 |
(5) 2.503 |
(5) 2.439 |
(5) 2.448 |
Day 7 |
(5) 2.616 |
(5) 2.611 |
(5) 2.710 |
(5) 2.599 |
(5) 2.456 |
Day 14 |
(5) 2.783 |
(5) 2.744 |
(5) 2.810 |
(5) 2.695 |
(2) 2.493 |
Day 20 |
(5) 2.915 |
(5) 2.831 |
(5) 2.938 |
(5) 2.764 |
(2) 2.302 |
Body Weight Gains |
|||||
Day 7 |
(5) 0.134 |
(5) 0.140 |
(5) 0.208 |
(5) 0.160 |
(5) 0.007 |
Day 14 |
(5) 0.301 |
(5) 0.273 |
(5) 0.307 |
(5) 0.256 |
(2) 0.176 |
Day20 |
(5) 0.433 |
(5) 0.360 |
(5) 0.436 |
(5) 0.325 |
(2) -0.115* |
Females |
|||||
Day 0 |
(5) 2.522 |
(5) 2.482 |
(5) 2.583 |
(5) 2.437 |
(5) 2.531 |
Day 7 |
(5) 2.578 |
(5) 2.590 |
(5) 2.678 |
(5) 2.642 |
(5) 2.685 |
Day 14 |
(5) 2.773 |
(5) 2.744 |
(5) 2.787 |
(5) 2.808 |
(5) 2.623 |
Day 20 |
(5) 2.882 |
(5) 2.865 |
(5) 2.901 |
(5) 2.864 |
(3) 2.695 |
Body Weight Gains |
|||||
Day 7 |
(5) 0.056 |
(5) 0.108 |
(5) 0.095 |
(5) 0.204 |
(5) 0.154 |
Day 14 |
(5) 0.251 |
(5) 0.262 |
(5) 0.203 |
(5) 0.370 |
(5) 0.093 |
Day 20 |
(5) 0.360 |
(5) 0.383 |
(5) 0.317 |
(5) 0.427 |
(3) 0.200 |
*significantly differerent to controls (p<0.05)
Cholinesterase activity
|
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
|
Males |
||||||
Erythrocyte |
Before treatment |
916.28 |
811.80 |
993.39 |
954.04 |
891.61 |
2h after |
1274.98 |
1020.21 |
687.90** |
646.96** |
- |
|
24h after |
1198.76 |
829.02 |
1049.14 |
500.65** |
- |
|
Plasma |
Before treatment |
257.60 |
325.01 |
280.94 |
284.41 |
298.18 |
2h after |
355.72 |
357.27 |
317.66 |
218.58 |
- |
|
24h after |
385.30 |
386.07 |
323.55 |
232.73* |
- |
|
Brain |
|
11204.60 |
10057.80 |
8904.40 |
7127.60** |
- |
Females |
||||||
Erythrocyte |
Before treatment |
917.69 |
874.41 |
741.74 |
780.84 |
896.69 |
2h after |
1291.47 |
1349.59 |
630.33* |
377.49** |
222.36** |
|
24h after a) |
1135.52 |
1063.48 |
761.98 |
400.29** |
237.47** |
|
Plasma |
before treatment |
139.52 |
139.92 |
161.46 |
124.95 |
127.03 |
2h after |
360.55 |
309.10 |
259.03 |
95.36** |
38.05** |
|
24h after |
356.89 |
325.72 |
212.25** |
143.90** |
22.98** |
|
Brain |
|
12798.00 |
11736.20 |
10119.40* |
9010.20** |
2590.00** |
*significantly different to controls (p<0.05); **p<0.01
Adrenal weights
Week 4 |
0 mg/kg bw/d |
3 mg/kg bw/d |
10 mg/kg bw/d |
50 mg/kg bw/d |
250 mg/kg bw/d |
Males |
|||||
Body weight (kg) |
2.788 |
2.765 |
2.814 |
2.667 |
- |
Adrenal absolute weight (g) |
0.21 |
0.25 |
0.24 |
0.20 |
- |
Adrenal relative weight (%) |
0.07 |
0.09 |
0.08 |
0.08 |
- |
Females |
|||||
Body weight (kg) |
2.808 |
2.681 |
2.817 |
2.768 |
2.641 |
Adrenal absolute weight (g) |
0.21 |
0.20 |
0.25 |
0.22 |
0.28* |
Adrenal relative weight (%) |
0.07 |
0.08 |
0.09 |
0.08 |
11 |
*significantly different to controls (p<0.05)
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEL
- 3 mg/cm²
- Study duration:
- subacute
- Species:
- rabbit
- Quality of whole database:
- A guideline-compliant 21-day rabbit study is available for fenitrothion
Additional information
Repeated dose oral toxicity
The neurotoxicity of fenitrothion was investigated in a 90 -day rat study. Groups of 12 male and 12 female Sprague-Dawley rats (main study) and groups of 15 male and 15 female rats (cholinesterase assessment) received fenitrothion in the diet at concentrations of 0, 6, 20, 60 and 200 ppm. Dietary concentrations were calculated to be equal to mean intakes of 0, 0.40, 1.32, 3.99 and 13.8 mg/kg bw/d in males; 0, 0.46, 1.56, 4.85 and 17.6 mg/kg bw/d in females) for 13 weeks. All animals were observed twice a day for their toxic signs and mortality. Body weight was recorded weekly and days of behavioral testing. Food consumption was recorded weekly for all animals. Functional observational battery (FOB) and motor activity assessments were performed pre-test and during Weeks 4, 8 and 13. At termination, 6 rats/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 (6/sex) had their brains removed and then were subjected to necropsy. The brain of each of non-perfused rats in the control and high dose groups was subsequently analyzed for glial fibrillary acidic protein (GFAP). Cholinesterase activities (erythrocyte, plasma, brain) were measured at 4, 8 and 13 weeks (5/sex). No animal died and none were sacrificed prior to scheduled termination. No treatment-related toxic signs were noted in male rats. Four females in the 200 ppm group showed tremors on one or two days during the second week of treatment. The 200 ppm group females also showed a higher incidence of muzzle staining and brown staining along the tail during the study compared to the control group. Both males and females in the 200 ppm group and females in the 60 ppm group had significantly reduced body weights compared to the control group on Day 7. The 200 ppm group's mean body weight remained significantly lower on Day 14 and 21 for males and from Days 7 to 42 for females. Food consumption for the 200 ppm group males and females were significantly lower than the control group from Days 0 to 7. Food consumption for the 200 ppm group females remained significantly reduced from Days 7 to 14 but then increased significantly from Days 28 to 56 and from 84 to 91. No significant differences considered to be related to treatment were seen for the qualitative components of the FOB. Significantly lower values for the 200 ppm group females in forelimb grip strength during the 4th week and in hindlimb grip strength during the 8th week occurred. These differences were considered not to be indicative of neurotoxicity taking lower body weights for the 200 ppm group females. Body temperature values as well as motor activity levels were not significantly different between control and fenitrothion-treated gropus. Reductions in blood and brain cholinesterase levels were noted for males in the 60 and 200 ppm groups and females in the 20, 60 and 200 ppm groups. No gross pathological findings or neuropathological changes (including brain measurements) seen were attributed to treatment with fenitrothion. No significant increases in glial fibrillary acidic protein were detected between the control and high dose groups for either male or females. A NOAEL of 20 ppm (equivalent to 1.32 and 1.56 mg/kg bw/d in males and females respectively) can be determined for this study based on the inhibition of cholinesterase activity at higher dietary concentrations.
In a non-standard study designed to assess ocular toxicity, groups of 12 male or 12 female Crj:CD(SD) rats received fenitrothion orally by admixture with the diet at the dose levels of 0, 2.5, 5, 10, 30 ppm for 13 weeks. Clinical signs, body weights and food consumption were recorded for all animals. Ophthalmology and ERG examination, measurement of cholinesterase activity, gross pathological and histopathological examinatins on the eyes and their accessory organs were performed for all animals. Electron microscopy was performed on the eyes and their accessory organs from 2 males and 2 females of the control and high dose groups. There was no mortality or signs of toxicity. Bodyweights and food consumption were unaffected by treatment. Ophthalmoscopy and electroretinography did not show any treatment-related changes. Cholinesterase activities in plasma and erythrocytes were distinctly inhibited in both sexes of the 30 ppm group; females of this group also showed an inhibition of cholinesterase activity in the brain. In addition, inhibition of plasma cholinesterase activity was seen in females of the 10 ppm group. Electroretinography did not reveal any changes attributable to the feeding of fenitrothion in any of the treated groups. Electron microscopy did not reveal any changes in the eye, musculus rectus medialis, and optic nerve from the animals of the treated groups examined. There was no evidence of ocular toxicity in this study at dose levels resulting in marked cholinesterase inhibition. A NOAEL of 10 ppm can be determined for effects on cholinesterase activity.
Repeated dose dermal toxicity
The repeated dose dermal toxicity of fenitrothion was investigated in a 21 -day study in the rabbit. Fenitrothion was administered percutaneously to groups of 5 male and 5 female New Zealand White rabbits at the dose levels of 0, 3, 10, 50 and 250 mg/kg bw/d by the topical route for a period of 21 successive days. The test material, a brown oily substance, was administered undiluted. The control group received distilled water. Parameters evaluated included clinical observations (twice daily), dermal reactions (daily), body weights and food consumption (weekly), plasma and erythrocyte cholinesterase activity (one week before treatment, 2 and 24 hours after final dosing) and haematology, biochemistry, brain cholinesterase activity, necropsy, organ weights and histopathology at study termination. Five males and two females at 250 mg/kg bw/d showed deterioration of general condition and died during the administration period (two males and one female were killed in a moribund condition). Signs observed in animals prior to death were hypoactivity, muscular hypotonia, tremor, bradypnoea, hypothermia, salivation, clonic convulsion, loose or mucous stool, diarrhoea and soiled perineum. In the surviving three females at 250 mg/kg bw/d, one animal revealed loose stool and soiled perineum and the other two animals showed no abnormalities. No clinical signs were noted in animals of the control and 3, 10 and 50 mg/kg bw/d groups. Very slight or well defined erythema and very slight or slight oedema were observed at the application site in males and females of the 3, 10 and 50 mg/kg bw/d groups, and were classified as mild according to the Draize index. Males and females of the 250 mg/kg bw/d group showed slightly more severe irritation than other treated groups. The maximum mean irritation scores at 250 mg/kg bw/d were classified as moderate according to the Draize index. The other dermal reaction observed in all groups treated with fenitrothion was desquamation of the epidermis. Depression of body weight gain and decrease in body weights were observed in males and females at 250 mg/kg bw/d. Increased WBC count and variable differential counts were observed in decedents at 250 mg/kg bw/d. No haematological effects were reported at lower dose levels. Increased AST and ALT activity and blood urea nitrogen and a decrease in serum electrolytes were observed in some animals at 250 mg/kg bw/d. No effects on clinical chemistry parameters were reported at lower dose levels. Gross necropsy did not reveal any effects of treatment. Increased adrenal weight was seen in some rabbits at 250 mg/kg bw/d. At 250 mg/kg bw/d, one male and one female revealed slight focal necrosis in the liver; histopathological changes in the digestive tract and kidney were considered to reflect a general deterioration of condition. Erythrocyte cholinesterase activity decreased in males and females at 10, 50 and 250 mg/kg bw/d. Plasma and brain cholinesterase activities decreased in males at 50 and 250 mg/kg bw/d and in females at 10, 50 and 250 mg/kg bw/d. No significant changes in erythrocyte, plasma or brain cholinesterase activities were observed at 3 mg/kg bw/d. A NOAEL could not be determined for this study due to local dermal reactions at the application site in rabbits of all treated groups. A NOAEL for systemic toxicity of 3 mg/kg bw/d can be determined based on the significant inhibition of cholinesterase activity at higher dose levels.
Justification for classification or non-classification
Classification with STOT-RE1 is appropriate for fenitrothion, based on the inhibition of cholinesterase activity seen at relevant dose levels in the 90 -day oral toxicity studies.
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