Registration Dossier

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

Referenceopen allclose all

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:
EPA OPP 83-1 (Chronic Toxicity)
Deviations:
no
Qualifier:
according to
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 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

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

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 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

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

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.

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
Reference
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:
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 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

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)

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.

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
Reference
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:
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 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

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)

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.

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.