Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A 2 -generation reproductive toxicity study is available for fenitrothion

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 April 1989 - 15 September 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no
Justification for study design:
Standard study design according to OECD TG416
Specific details on test material used for the study:
Fenitrothion
Batch No.: 60553
Purity: 94.6%,
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl: CD® (SD)BR
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: Charles River, NC, USA
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Weight at study initiation: 199-257 g (M), 151-197 g (F)
- Fasting period before study: no
- Housing: group housed during the premating period, co-habitation during the mating period (1:1), indvidual during gestation and lactation (F)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 16 days
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Groups of 30 male and 30 female Crl: CD® (SD)BR rats each received fenitrothion in basal diet at concentrations of 0, 10, 40 and 120 ppm for 82-day (P1) or minimum of 88-day (F1a) pre-mating period, up to 21 days mating period, gestation and 28-day (F1a and F2) or 21-day (F1b) lactation period.
Details on mating procedure:
Rats were cohoused (1:1) for a maximum of 21 days; the day of mating (evidence of sperm in vaginal smear or presence of copulatory plug) was designated GD0.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Achieved concentrations, stability and homogeneity of the test material in the diet were analysed.
Duration of treatment / exposure:
Groups of rats were administered fenitrothion in the diet for 82-day (P1) or minimum of 88-day (F1a) pre-mating period, up to 21 days mating period, gestation and 28-day (F1a and F2) or 21-day (F1b) lactation period.
Frequency of treatment:
Daily / continuous in the diet
Details on study schedule:
The day on which evidence of mating was observed was designated as Day 0 of gestation. The day on which parturition was completed was designated as Day 1 of lactation. On Day 4 of lactation, the number of F1 pups was reduced to a maximum number of 8 per litter (4 males and 4 females, when possible). Offspring from the first mating (F1a) were maintained through weaning, then 30 animals/sex/group were selected as parental animals for the second generation.
Dose / conc.:
0 ppm
Remarks:
Control (basal diet)
Dose / conc.:
10 ppm
Dose / conc.:
40 ppm
Dose / conc.:
120 ppm
No. of animals per sex per dose:
30
Control animals:
yes, plain diet
Details on study design:
Animals were assigned randomly to dose groups on the basis of bodyweight
Positive control:
Not required
Parental animals: Observations and examinations:
Body weights and food consumption values for the parental animals were recorded throughout the study.
Litter observations:
Litter size and individual pup body weights were recorded during the lactation period.
Postmortem examinations (parental animals):
Complete gross necropsies were performed on all parental rats. All gross lesions and vagina, uterus/cervix, ovaries, mammary gland, pituitary gland, testis, epididymides, seminal vesicles, prostate, coagulating gland, pituitary gland and liver of each rat were examined for histopathology.
Postmortem examinations (offspring):
The F1a pups not selected as the second generation, F1b and F2 pups were sacrificed with carbon dioxide and examined for gross lesions at weaning.
Statistics:
Differences in parameters between the control and test groups were assessed using appropriate statistical techniques.
Reproductive indices:
Mating, fertility amd gestation indices were measured for both generations
Offspring viability indices:
Viability and lactation indices were measured for both generations
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs occurred for the male or female rats in the P1 generation as the result of exposure to diets containing the test substance.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Dosage-dependent, statistically significant effects on body weight gains, body weights and absolute and relative feed consumption values occurred for male and female rats given the test substance in the diet at a concentration of 120 ppm. Body weights and body weight gains were significantly affected by the 40 ppm in the F0 generation female rats during lactation.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Dosage-dependent, statistically significant effects on absolute and relative feed consumption values occurred for male and female rats given the test substance in the diet at a concentration of 120 ppm.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross lesions revealed at necropsy were considered as effects of the test substance
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related microscopic changes were observed in any of the tissues specified for evaluation from male and female F0 rats
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no test substance related effects on reproductive performance
There was no treatment-related mortality or clinical signs. Bodyweights and food consumption were reduced at 40 and 120 ppm. Fertility and reproductive parameters were unaffected by treatment. Gross necropsy did not reveal any treatment-related effects.
Key result
Dose descriptor:
NOAEL
Effect level:
10 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Key result
Critical effects observed:
no
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
During gestation, there tended to be an increase in the number of 120 ppm group F1 female rats with soft or liquid faeces and chromorrhinorrhea. During lactation, there tended to be an increase in the number of 120 ppm group F1 generation female rats with soft or liquid feces and statistically significant increases in the number of 120 ppm group F1 generation female rats with tremors occurred during lactation
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No deaths and moribund sacrifices occurred as the results of effects of the test substance.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Dosage-dependent, statistically significant effects on body weight gains and body weights occurred for male and female rats given the test substance in the diet at a concentration of 120 ppm. Body weights and body weight gains were significantly affected by the 40 ppm F1 generation male rats during the postcohabitation period.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Dosage-dependent, statistically significant effects on absolute and relative feed consumption values occurred for male and female rats given the test substance in the diet at a concentration of 120 ppm. Absolute feed consumption values were significantly affected by the 40 ppm concentration of the test substance in the F1 generation female rats.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross lesions revealed at necropsy were considered as effects of the test substance
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related microscopic changes were observed in any of the tissues specified for evaluation from male and female F1 generation rats
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
There was no treatment-related mortality or clinical signs. Bodyweights and food consumption were reduced at 40 and 120 ppm. Fertility and reproductive parameters were unaffected by treatment. Gross necropsy did not reveal any treatmnet-related effects.
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no test substance related effects on reproductive performance.
There was no treatment-related mortality or clinical signs. Bodyweights and food consumption were reduced at 40 and 120 ppm. Fertility and reproductive parameters were unaffected by treatment. Gross necropsy did not reveal any treatmnet-related effects.
Key result
Dose descriptor:
NOAEL
Effect level:
10 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Key result
Critical effects observed:
no
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The number of pups with observations related to morbidity/mortality (e.g. cold to touch, not nursing, weak) was increased at a concentration of 120 ppm
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
The 120 ppm concentration of the test substance was associated with significant increases in mortality.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The 120 ppm concentration of the test substance tended to reduce or significantly reduced pup body weights
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
no effects observed
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
The 120 ppm concentration of the test substance tended to reduce or significantly reduced pup body weights in litters of both generations and was associated with significant increases in mortality in F1a and F1b litters. There were no adverse effects on sex ratios or morphology of the offspring. The number of pups with observations related to morbidity/mortality (e.g. cold to touch, not nursing, weak) was increased for F1a litters and F1a at 120 ppm.
Key result
Dose descriptor:
NOAEL
Generation:
F1a
Effect level:
40 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Generation:
F1b
Effect level:
40 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Key result
Critical effects observed:
no
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The number of pups with observations related to morbidity/mortality (e.g. cold to touch, not nursing, weak) was increased in the F2 litters at a concentration of 120 ppm
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
The 120 ppm concentration of the test substance was associated with significant increases in mortality.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The 120 ppm concentration of the test substance tended to reduce or significantly reduced pup body weights.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Gross pathology findings for the offspring were considered incidental in nature and showed no relation to compound administration
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
The 120 ppm concentration of the test substance tended to reduce or significantly reduced pup body weights was associated with significant increases in mortality in the F2 litters. There were no adverse effects on sex ratios or morphology of the offspring. The number of pups with observations related to morbidity/mortality (e.g. cold to touch, not nursing, weak) was increased for the F2 generation litters at a concentration of 120ppm. Gross pathology findings for the offspring were considered incidental in nature and showed no relation to compound administration.
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
40 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no

Mean intakes (mg/kg bw/d)

Animal

Dosage group (ppm)

10

40

120

Male

Female

Male

Female

Male

Female

F0 (Premating)

0.5 - 1.0 (0.7)

0.6 - 1.1 (0.7)

2.2 - 4.3 (2.7)

2.5 - 4.3 (3.1)

6.6 - 12.8 (8.0)

7.8 - 13.5 (9.7)a

Gestation (F1a)

 

0.6

 

2.7

 

7.8

Lactation(F1a)

 

1.3

 

5.4

 

15.2

Gestation (F1b)

 

0.6

 

2.3

 

7.4

Lactation (F1b)

 

1.1

 

4.5

 

12.0

F1a (Premating)

0.7

0.8

2.8

3.3

8.8

11.1

Gestation

 

0.7

 

2.7

 

8.6

Lactation

 

1.3

 

4.8

 

14.1

Clinical signs (F1 parental females)

0 ppm

10 ppm

40 ppm

120 ppm

Gestation period

 

 

 

 

Soft or liquid faeces

0/ 0

7/ 1

1/ 1

18/ 4

Chromorhinorrhoea

1/ 1

2/ 2

2/ 2

6/ 4

Lactation period

 

 

 

 

Tremors

0/ 0

0/ 0

0/ 0

43/ 6*

Soft or liquid faeces

25/ 4

52/ 8

73/ 6

65/ 10

*significantly different to controls (p<0.05)

Summary of pre-mating bodyweights (g) in parental animals

 

Male

Female

0 ppm

10 ppm

40 ppm

120 ppm

0 ppm

10 ppm

40 ppm

120 ppm

F0

 

 

 

 

 

 

 

 

Day 1

231.3

229.2

231.2

229.6

178.0

175.1

173.8

174.8

Day 8

299.0

219.6

295.0

288.0**

209.4

206.8

208.1

201.9

Day 15

338.0

331.1

340.0

330.0

233.7

230.1

230.2

221.2**

Day 22

379.0

370.9

378.1

367.7

254.1

249.4

248.7

240.9

Day 29

414.5

405.8

415.5

400.5

273.9

267.5

267.1

256.8**

Day 36

443.7

431.2

443.5

429.9

287.2

280.7

281.8

271.1

Day 43

474.8

457.8

468.4

455.3

298.0

289.3

290.8

281.7

Day 50

506.8

486.0*

499.7

482.2*

308.3

299.3

300.7

291.5

Day 57

523.6

504.7

517.3

499.4

320.0

310.4

311.5

301.6

Day 64

544.3

523.7

532.1

516.0**

328.6

319.1

317.1

305.5**

Day 71

561.1

538.4*

552.5

533.7*

332.7

322.7

325.1

311.8

Day 78

577.3

556.2

567.5

547.2*

334.5

324.6

327.2

315.7

Day 82

583.8

562.2

572.7

556.1

341.5

331.9

332.4

319.4

Termination

718.3

698.2

700.9

685.9

-

-

-

-

F1

 

 

 

 

 

 

 

 

Day 1

95.9

96.2

94.2

78.6**

87.5

88.6

88.0

73.0**

Day 8

160.8

157.3

156.9

125.0**

136.7

135.1

135.9

109.5**

Day 15

225.4

222.8

224.5

181.5**

176.1

171.8

176.8

146.9**

Day 22

293.3

287.4

288.9

244.0**

205.7

198.9

205.0

176.0**

Day 29

350.4

348.3

346.2

299.2**

229.7

222.5

231.1

198.1**

Day 36

408.5

402.6

400.9

350.9**

256.8

247.7

254.2

223.1**

Day 43

453.2

447.4

444.4

393.7**

275.2

264.5

275.1

240.3**

Day 50

489.2

483.5

476.9

427.9**

290.5

277.4

289.0

255.0**

Day 57

520.4

513.8

505.7

454.7**

302.4

289.0

299.5

266.2**

Day 64

548.2

538.3

529.3

477.9**

312.8

298.6

309.4

275.2**

Day 71

574.4

563.4

553.8

500.0**

322.3

305.3*

318.2

281.9**

Day 78

600.2

584.7

577.0

518.1**

329.6

313.7

324.5

288.7**

Day 85

620.1

602.8

593.1

533.6**

337.6

321.1

331.4

295.3**

Termination

800.6

762.9

744.5*

666.1**

-

-

-

-

*significantly different to controls (p<0.05); **p<0.01

Summary of female bodyweights during gestation and lactation

Dose level

0 ppm

10 ppm

40 ppm

120 ppm

F0 - First gestation

Day 0

338.9

329.8

322.8

314.6

Day 6

366.2

352.6

353.3

334.6

Day 12

397.6

386.2

381.8

364.1**

Day 15

399.0

393.4

389.6

372.9

Day 20

464.3

453.9

448.0

417.6**

F0 - Second gestation

Day 0

377.6

367.7

372.9

347.0

Day 6

401.2

392.3

397.4

374.2

Day 12

426.7

418.8

421.6

400.4

Day 15

443.6

433.9

431.9

412.5

Day 20

508.3

502.2

493.2

469.6

F1 - gestation

Day 0

346.6

339.5

338.1

306.1**

Day 6

370.1

363.9

359.8

322.4**

Day 12

393.1

389.1

385.1

347.4**

Day 15

407.6

403.0

401.0

361.0**

Day 20

475.0

472.5

466.3

416.9**

Dose level

0 ppm

10 ppm

40 ppm

120 ppm

F0 – first lactation

Day 1

365.7

362.6

357.0

343.4

Day 4

365.7

357.3

355.5

329.9

Day 7

366.6

363.2

356.9

326.9**

Day 10

384.3

377.0

368.7

334.2**

Day 14

378.9

370.4

367.3

342.8**

Day 16

388.3

380.0

368.4*

346.4**

Day 18

378.1

366.3

361.4

340.4**

Day 21

368.2

351.9

349.5*

329.1**

Day 28

351.8

344.8

338.5

325.3

F0 – second lactation

Day 1

408.6

402.5

406.0

386.1

Day 4

409.0

403.6

398.2

378.0

Day 7

402.8

389.4

392.6

369.5

Day 10

410.6

400.6

405.1

371.7

Day 14

410.8

400.0

399.1

368.4**

Day 16

411.6

411.3

402.6

373.7

Day 18

406.7

405.3

389.8

368.1**

Day 21

391.4

385.8

379.6

367.0

F1 – lactation

Day 1

387.5

372.7

374.4

333.0**

Day 4

390.2

367.0

370.6

320.4**

Day 7

388.0

369.3

372.0

319.1**

Day 10

398.9

376.9

375.4*

325.9**

Day 14

402.3

382.0

376.1*

329.2**

Day 16

405.7

389.6

383.7

339.0**

Day 18

396.9

386.2

380.0

339.2**

Day 21

394.4

373.5*

370.7*

340.1**

Day 28

370.0

348.9*

358.7

328.8**

*significantly different to controls (p<0.05); **p<0.01

Summary of pre-mating food consumption

 

Male

Female

0 ppm

10 ppm

40 ppm

120 ppm

0 ppm

10 ppm

40 ppm

120 ppm

F0

Day 1-8

27.0

26.2

28.4

27.6

22.4

20.4**

20.5**

20.5**

Day 8-15

29.3

29.8

29.8

29.1

24.0

22.9

23.0

23.7

Day 15-22

26.6

26.0

26.9

25.7

21.3

20.2

21.3

22.2

Day 22-29

27.6

27.1

27.4

26.5

22.0

20.8

21.1

20.8

Day 29-36

28.2

26.5

27.8

27.2

22.0

21.3

21.5

21.6

Day 36-43

28.0

27.2

27.6

27.2

21.8

20.2

20.6

21.1

Day 43-50

28.0

26.7

27.6

26.7

21.4

19.9

20.3

20.6

Day 50-57

28.0

27.4

27.8

27.2

21.0

19.5

20.0

19.7

Day 57-64

28.6

27.8

28.7

28.2

21.1

20.0

20.7

20.4

Day 64-71

28.8

28.4

29.1

27.7

21.8

20.3

21.0

20.0

Day 71-78

29.6

28.8

29.4

28.6

22.1

20.7

21.3

20.7

Day 78-82

31.5

31.0

31.3

30.2

22.2

20.3

20.8

20.6*

F1

Day 1-8

17.7

17.2

17.6

15.1**

15.5

15.0

15.7

13.9*

Day 8-15

24.6

24.2

25.1

21.5**

19.8

19.0

20.1

18.6

Day 15-22

28.0

27.8

28.3

25.4*

20.8

19.5*

20.6

20.8

Day 22-29

30.4

30.3

31.1

28.1*

21.8

20.5

22.1

22.1

Day 29-36

32.4

31.6

32.4

29.9**

23.0

22.0

22.1

22.0

Day 36-43

32.4

32.3

32.6

29.8**

23.2

21.7

23.1

22.4

Day 43-50

32.4

32.4

32.3

29.7**

23.2

22.0

22.7

22.6

Day 50-57

32.1

32.0

32.0

29.3**

23.4

21.4*

21.8*

22.1

Day 57-64

32.6

32.2

32.1

29.0**

23.3

21.6

22.2

21.5

Day 64-71

32.3

31.8

31.3

28.7**

23.2

20.9**

21.5*

20.8*

Day 71-78

33.0

32.2

32.0

28.6**

22.8

21.4

21.1**

21.1

Day 78-85

34.2

33.1

33.8

30.1**

24.1

22.9

22.8

22.8

*significantly different to controls (p<0.05); **p<0.01

Summary of food consumption in females during gestation and lactation

Dose level

0 ppm

10 ppm

40 ppm

120 ppm

F0 – first gestation

Day 0-6

26.3

23.5*

25.6

22.7**

Day 6-12

27.9

26.7

26.9

26.0

Day 12-15

23.7

22.3

24.9

25.2

Day 15-20

26.7

26.1

25.8

23.1

F0 - second gestation

Day 0-6

24.5

24.1

23.2

24.0

Day 6-12

26.1

25.4

24.8

25.4

Day 12-15

26.9

25.9

24.6

25.8

Day 15-20

24.4

24.2

24.6

24.7

F1 - gestation

Day 0-6

25.8

25.6

24.4

22.7

Day 6-12

27.3

27.2

26.5

26.0

Day 12-15

28.6

29.2

28.4

26.5

Day 15-20

27.8

28.8

28.3

25.7

F0 f -first lactation

Day 1-4

34.3

38.0

35.3

32.0

Day 4-7

43.6

40.7

44.7

43.0

Day 7-10

54.8

53.8

54.6

41.9**

Day 10-14

62.4

61.0

60.1

53.6

F0 - second lactation

Day 1-4

30.0

28.2

31.3

24.7

Day 4-7

37.0

37.8

39.9

30.9**

Day 7-10

49.1

50.1

49.2

41.8**

Day 10-14

54.8

55.4

55.0

47.8

F1 - lactation

Day 1-4

30.2

28.9

28.1

23.6

Day 4-7

44.5

41.7

39.0

31.0**

Day 7-10

55.2

50.9

48.3**

39.6**

Day 10-14

65.4

61.7

56.8**

51.9**

*significantly different to controls (p<0.05); **p<0.01

Summary of reproductive parameters (F1a litters)

Dose level

0 ppm

10 ppm

40 ppm

120 ppm

Parental reproduction indices

Total No. of males placed with females

30

30

30

30

Total No. of males mated with females

27

27

26

25

Total No. of mated males resulting in pregnancy

25

19

17

19

Male mating index (%)

90.0

90.0

86.7

83.3

Male fertility index (%)

83.3

63.3

56.7

63.3

Total No. of females placed with males

30

30

30

30

Total No. of females showing evidence of mating

28

29

29

29

Total No. of females pregnant

26

20

19

21

Female mating index (%)

93.3

96.7

96.7

96.7

Pregnancy rate (%)

92.8

69.0

65.5

72.4

No. of females delivering offspring

26

19a

19

21

No. of females delivering viable offspring

26

19

19

21

Parturition index (%)

100

100

100

100

Offspring indices

Mean No. of live pups at parturition/litter

14.6

14.6

12.8

12.2

Mean No. of stillborn/litter

0.2

0.0

0.2

0.3

Viability index (%)

96.8

99.3

98.4

86.0**

Lactation index (%)

99.0

100.0

100.0

91.5**

Number of surviving pups/litter

Day 1

14.6

14.6

12.8

12.2

Day 4 (pre-cull)

14.1

14.5

12.6

10.5*

Day 4 (post-cull)

8.0

7.7

7.7

6.7*

Day 7

8.0

7.7

7.7

6.3*

Day 14

7.9

7.7

7.7

6.2*

Day 21

7.9

7.7

7.7

6.2*

Day 28

7.9

7.7

7.7

6.1**

Mean pup weight/litter (g)

Day 1

6.5

6.5

6.8

6.2

Day 4 (pre-cull)

9.8

9.5

10.0

8.8

Day 4 (post-cull)

9.8

9.5

10.2

8.9

Day 7

16.5

15.8

16.8

13.8

Day 14

35.2

34.9

35.4

28.7**

Day 21

55.0

54.3

54.1

45.9**

Percent male pups (%)

Day 1

45.5

51.0

49.2

53.9

Day 4 (pre-cull)

45.0

51.4

48.8

53.0

Day 4 (post-cull)

49.0

48.0

49.6

53.2

Day 7

49.3

48.0

49.6

53.0

Day 14

49.0

48.0

49.6

53.0

Day 21

49.0

48.0

49.6

53.0

Day 28

49.0

48.0

49.6

52.6

*significantly different to controls (p<0.05); **p<0.01

Summary of reproductive parameters (F1b litters)

Dose level

0 ppm

10 ppm

40 ppm

120 ppm

Parental reproduction indices

Total No. of males placed with females

30

28a

30

30

Total No. of males mated with females

25

23

23

17*

Total No. of mated males resulting in pregnancy

22

18

17

14

Male mating index (%)

83.3

82.1

76.7

56.7*

Male fertility index (%)

73.3

64.3

56.7

46.7

Total No. of females placed with males

30

28

30

30

Total No. of females showing evidence of mating

27

25

25

20

Total No. of females pregnant

24

19

18

16

Female mating index (%)

90.0

89.3

83.3

66.7

Pregnancy rate (%)

88.9

76.0

72.0

80.0

No. of females delivering offspring

24

19

17

14b

No. of females delivering viable offspring

24

19

16c

14

Parturition index (%)

100.0

100.0

94.1

100.0

Offspring indices

Mean No. of live pups at parturition/litter

14.4

15.1

12.7

12.3

Mean No. of stillborn/litter

0.1

0.4

0.3

0.0

Viability index (%)

96.8

98.6

98.0

97.7

Lactation index (%)

100.0

94.7**

100.0

96.3*

Number of surviving pups/litter

 

 

 

 

Day 1

14.4

15.1

12.7

12.3

Day 4 (precull)

14.0

14.9

12.4

12.0

Day 4 (postcull)

7.7

8.0

7.5

7.6

Day 7

7.7

8.0

7.5

7.5

Day 14

7.7

8.0

7.5

7.4

Day 21

7.7

8.0

7.5

7.4

Mean pup weight/litter (g)

Day 1

6.7

6.5

6.8

6.5

Day 4 (precull)

10.2

9.6

10.8

9.7

Day 4 (postcull)

10.3

9.6

10.9

9.8

Day 7

17.0

16.0

17.9

14.6

Day 14

36.6

34.8

37.9

29.6**

Day 21

56.2

55.3

57.9

47.6**

Percent male pups (%)

Day 1

51.1

48.1

47.3

47.1

Day 4 (precull)

52.1

48.2

46.3

47.9

Day 4 (postcull)

51.4

48.7

48.4

48.6

Day 7

51.4

48.7

48.4

48.6

Day 14

51.4

48.7

48.4

49.6

Day 21

51.4

48.6

48.4

49.6

*significantly different to controls (p<0.05); **p<0.01

Summary of reproductive parameters (F2 litters)

Dose level

0 ppm

10 ppm

40 ppm

120 ppm

Parental reproduction indices

Total No. of males placed with females

29a

30

30

30

Total No. of males mated with females

24

24

22

21

Total No. of mated males resulting in pregnancy

18

21

21

17

Male mating index (%)

82.8

80.0

73.3

70.0

Male fertility index (%)

62.1

70.0

70.0

56.7

Total No. of females placed with males

29b

30

30

30

Total No. of females showing evidence of mating

27

27

26

28

Total No. of females pregnant

19

23

24

21

Female mating index (%)

93.1

90.0

86.7

93.3

Pregnancy rate (%)

70.4

85.2

92.3

75.0

No. of females delivering offspring

18c

23

24

20d

No. of females delivering viable offspring

18

23

24

20

Parturition index (%)

100

100

100

100

Offspring indices

Mean No. of live pups at parturition/litter

13.6

13.7

13.0

12.4

Mean No. of stillborn/litter

0.2

0.2

0.1

0.2

Viability index (%)

99.6

99.0

99.7

85.5**

Lactation index (%)

100.0

100.0

99.4

89.8**

Number of surviving pups/litter

Day 1

13.6

13.7

13.0

12.4

Day 4 (precull)

13.6

13.6

13.0

10.6

Day 4 (postcull)

8.0

7.9

7.4

6.8

Day 7

8.0

7.9

7.4

6.6*

Day 14

8.0

7.9

7.4

6.2*

Day 21

8.0

7.9

7.4

6.2*

Day 28

8.0

7.9

7.4

6.2*

Mean pup weight/litter (g)

Day 1

6.8

6.7

6.6

6.5

Day 4 (precull)

10.4

9.9

9.6

8.4**

Day 4 (postcull)

10.4

10.0

9.6

8.4*

Day 7

17.0

16.5

15.8

12.1**

Day 14

36.4

35.0

34.0

26.8**

Day 21

58.2

56.2

54.4

44.0**

Percent male pups (%)

Day 1

46.5

49.2

50.0

56.4

Day 4 (precull)

46.7

49.3

50.0

57.2

Day 4 (postcull)

48.6

49.6

50.3

54.9

Day 7

48.6

49.6

50.3

54.2

Day 14

48.6

49.6

50.3

57.4

Day 21

48.6

49.6

50.6

57.4

Day 28

48.6

49.6

50.6

57.4

Summary of litter observations

 

F1a

F2

0 ppm

10 ppm

40 ppm

120 ppm

0 ppm

10 ppm

40 ppm

120 ppm

Litters examined (N)

26

19

19

21

18

23

24

20

Small and weak

2/2

0/0

0/0

14/5

0/0

0/0

0/0

0/0

Thin appearance

0/0

0/0

0/0

3/1

0/0

0/0

0/0

0/0

Weak

0/0

0/0

0/0

22/2

0/0

0/0

0/0

21/3

Cold to touch

0/0

2/1

17/2

61/4

0/0

0/0

5/2

56/4

Pup not nursing

1/1

0/0

0/0

14/3

0/0

0/0

0/0

53/3

Pale appearance

0/0

0/0

0/0

0/0

0/0

0/0

0/0

22/3

White substance surrounding umbilicus

0/0

0/0

0/0

0/0

0/0

0/0

0/0

1/1

Tremors

0/0

0/0

0/0

2/1

0/0

0/0

1/1

0/0

Urine-stained abdominal fur

0/0

0/0

0/0

1/1

0/0

0/0

0/0

0/0

Lesion

0/0

0/0

0/0

4/2c

0/0

0/0

0/0

11/1

Bite wound

0/0

0/0

0/0

2/1

0/0

0/0

2/1b

11/1

Right front leg and paw missing

0/0

0/0

0/0

3/1

0/0

0/0

0/0

0/0

Tail missing

0/0

0/0

29/2

3/1

0/0

0/0

4/1

25/1

Back discolored

0/0

0/0

0/0

2/1

0/0

0/0

0/0

0/0

Mouth discolored

2/1

0/0

0/0

2/1

0/0

0/0

0/0

0/0

Conclusions:
No effects on fertililty or reproductive capacity were seen in this study at dose levels sufficient to cause general toxicity in parental rats and offspring. In the absence of any effects, a reproductive NOAEL of 120 ppm (7.4-15.2 mg/kg bw/d) can be determined for this study. A parental NOAEL of 10 ppm (0.7 mg/kg bw/d) can be determined, based on bodyweight effects at higher dose levels. An offspring NOAEL of 40 ppm (2.3-5.4 mg/kg bw/d) can be determined for this study, based on increased mortality and bodyweight effects at the highest dose level.
Executive summary:

A two-generation reproductive toxicity study was performed in the rat uisng dietary concentrations of fenitrothion of 0, 10, 40 and 120 ppm. Successive generations of rats were exposed for at least 10 weeks prior to mating and throughout mating, gestation and lactation of the tresulting litters. The first generation was mated to produce two litters. Adminstration of the highest dose level resulted in clinical signs, reduced food consumption and bodyweight effects in parental animals. Bodyweight effects were also apparent in parental animals at 40 ppm. There were no effects on fertility in either generation. Increased pup mortality, clinical signs and reduced weight gain were seen in pups of both generations at 120 ppm. No effects on fertililty or reproductive capacity were seen in this study at dose levels sufficient to cause general toxicity in parental rats and offspring.  In the absence of any effects, a reproductive NOAEL of 120 ppm (7.4-15.2 mg/kg bw/d) can be determined for this study.  A parental NOAEL of 10 ppm (0.7 mg/kg bw/d) can be determined, based on bodyweight effects at higher dose levels.  An offspring NOAEL of 40 ppm (2.3-5.4 mg/kg bw/d) can be determined for this study, based on increased mortality and bodyweight effects at the highest dose level.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
8 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
A guideline-compliant 2-generation reproductive toxicity study is available for fenitrothion
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A two-generation reproductive toxicity study was performed in the rat uisng dietary concentrations of fenitrothion of 0, 10, 40 and 120 ppm. Successive generations of rats were exposed for at least 10 weeks prior to mating and throughout mating, gestation and lactation of the tresulting litters. The first generation was mated to produce two litters. Adminstration of the highest dose level resulted in clinical signs, reduced food consumption and bodyweight effects in parental animals. Bodyweight effects were also apparent in parental animals at 40 ppm. There were no effects on fertility in either generation. Increased pup mortality, clinical signs and reduced weight gain were seen in pups of both generations at 120 ppm. No effects on fertililty or reproductive capacity were seen in this study at dose levels sufficient to cause general toxicity in parental rats and offspring.  In the absence of any effects, a reproductive NOAEL of 120 ppm (7.4-15.2 mg/kg bw/d) can be determined for this study.  A parental NOAEL of 10 ppm (0.7 mg/kg bw/d) can be determined, based on bodyweight effects at higher dose levels.  An offspring NOAEL of 40 ppm (2.3-5.4 mg/kg bw/d) can be determined for this study, based on increased mortality and bodyweight effects at the highest dose level.

Effects on developmental toxicity

Description of key information

Studies of developmental toxicity in the rat and rabbit are available for fenitrothion.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
16 December 1985 - 17 January 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Fenitrothion
Batch No.: 41208
Purity: 96.6%
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton, Denver
- Age at study initiation: 4 months
- Weight at study initiation: 2.7-3.2 kg
- Housing: Individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 28 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-23
- Humidity (%): 15-64
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 December 1985 To: 17 January 1986
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Groups of 16 inseminated female HRA(NZW)SPF rabbits each received fenitrothion dissolved in corn oil, at dose levels of 0, 3, 10 and 30 mg/kg bw/d by oral gavage, daily from Days 7 to 19 of gestation at a dosage volume of 1.0 mL/kg bw.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Reserve samples of the dosing solutions were analysed for stability and achieved concentration.
Details on mating procedure:
Ovulation was induced in each females by iv injection of 250 IU HCG; females were inseminated with the sperm of males from the same strain on two occasions. The day of inseminatiom was designated GD0.
Duration of treatment / exposure:
GD7-19 (13 consecutive days).
Frequency of treatment:
Daily
Duration of test:
Dams were terminated on GD 29
Dose / conc.:
0 mg/kg bw/day
Remarks:
Vehicle control
Dose / conc.:
3 mg/kg bw/day
Dose / conc.:
10 mg/kg bw/day
Dose / conc.:
30 mg/kg bw/day
No. of animals per sex per dose:
16 inseminated females
Control animals:
yes, concurrent vehicle
Details on study design:
Doses were selcetd on the basis of range-finding studies in pregnant and non-pregnant rabbits. Animals were assigned to the treatment groups using a weight randomisation technique.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 7, 8, 9, 13, 16, 19, 20, 23, 26, 29

FOOD CONSUMPTION: Yes
- Time schedule for examinations: GD 0, 7, 8, 9, 13, 16, 19, 20, 23, 26, 29

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
Data were analysed and test groups compared to the controls using appropriate statistical techniques
Indices:
Not applicable
Historical control data:
Not required for this study
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors. These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8. Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8. All other mean food consumption values were statistically similar for all groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
The findings were considered to be incidental and not related to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
Three pregnant females at 30 mg/kg bw/d aborted or delivered prematurely (GD 22-29).
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
effects observed, treatment-related
Other effects:
no effects observed
Details on maternal toxic effects:
A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8. Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy). Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors. These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit. Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8. All other mean food consumption values were statistically similar for all groups. Gross necropsy diod not reveal any effects of treatment.
Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
effects observed, treatment-related
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
The mean number of implantations was lower in the high dose group, resulting in a lower litter size. Other parameters were unaffected by treatment. There was no dose-related increase in the incidence of any particular malformation or in the incidence of any type (i.e. external, visceral, or skeletal) of malformation. Although the litter incidence of skeletal malformations was slightly higher than controls in the 3 and 10 mg/kg bw/d groups, no malformations were noted in the seven litters of the 30 mg/kg bw/d group available for evaluation. Overt evidence of maternal toxicity was seen in animals receiving 30 mg/kg/ bwd but was not accompanied by adverse effects on fetal growth or development
Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
30 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
no

Summary of maternal findings

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

10 mg/kg bw/d

30 mg/kg bw/d

GD 7-19 (treatment period)

Number of animals observed

16

16

16

16

Found dead

1

0

1

6

Accidental death

0

2

0

0

Reduction in motor activity

0

0

1

14

Salivation

0

0

0

14

Dyspnoea

0

0

0

14

Tremors

0

0

0

14

GD 20-29 (post-treatment period)

Number of animals observed

15

14

15

10

Premature delivery/abortion

0

0

0

3

Reduction in motor activity

0

0

0

1

Food consumption (g)

GD 0-7

1124

1137

1161

1183

GD 7-8

126

102

108

91

GD 8-9

138

112

134

104

GD 9-13

548

441*

531

465

GD 13-16

329

316

307

296

GD 16-19

364

221

307

294

GD 19-20

95

101

107

83

GD 20-23

385

372

372

403

GD 23-26

333

352

314

387

GD 26-29

278

396

307

457*

Bodyweight change (g)

GD 0-7

169

149

166

148

GD 7-8

-31

-42

-47

-48

GD 7-9

-10

-38

-18

-68

GD 7-13

51

-2

29

-62*

GD 7-16

45

33

61

-83

GD 7-19

92

-25

27

-73

GD 7-20

85

-9

35

-104

GD 7-23

168

63

87

4

GD 7-26

192

114

141

50

GD 7-29

228

203

192

141

*significantly different to controls (p<0.05)

Summary of litter parameters

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

10 mg/kg bw/d

30 mg/kg bw/d

Number of females inseminated

16

16

16

16

Pregnancy rate (%)

87.5

93.8

100.0

100.0

No. of pregnant females

13

13

15

8

Number of litters with live foetuses

13

13

13

7

Mean number of corpora lutea

11.7

11.4

11.0

10.1

Mean number of implantations

8.3

7.6

8.3

5.7

Mean implantation efficiency (%)

72.5

67.9

76.8

61.5

Mean number of resorptions

1.7

1.2

1.3

1.1

Mean incidence of resorptions (%)

18.4

15.0

22.4

21.1

Mean incidence of foetal viability (%)

81.6

84.0

77.6

78.9

Mean number of live foetuses per litter

6.6

6.4

6.9

4.6

Mean number of dead foetuses per litter

0.0

0.1

0.0

0.0

Mean percent of males per litter

60.0

40.0

48.4

66.9

Mean fetal weight (g)

 

 

 

 

 Male

44.6

43.6

41.1

48.0

 Female

42.9

42.6

40.5

45.0

Summary of foetal findings

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

10 mg/kg bw/d

30 mg/kg bw/d

Number of foetuses (fetal incidence %)

Total number of foetuses examined

86

83

104

32

External malformations

1 (1.2)

0 (0.0)

3 (2.9)

0 (0.0)

External variations

0 (0.0)

0 (0.0)

1 (1.0)

0 (0.0)

Visceral malformations

0 (0.0)

2 (2.4)

0 (0.0)

0 (0.0)

Visceral variations

4 (4.7)

1 (1.2)

5 (4.8)

1 (3.1)

Skeletal malformations

2 (2.3)

6 (7.2)

4 (3.8)

0 (0.0)

Skeletal variations

67 (78)

64 (77)

79 (76)

25 (78)

Number of litter (litter incidence %)

Total number of litters examined

13

13

13

7

External malformations

1 (7.7)

0 (0.0)

2 (15)

0 (0.0)

External variations

0 (0.0)

0 (0.0)

1 (7.7)

0 (0.0)

Visceral malformations

0 (0.0)

2 (15)

0 (0.0)

0 (0.0)

Visceral variations

3 (23)

1 (7.7)

4 (31)

1 (14)

Skeletal malformations

1 (7.7)

2 (15)

3 (23)

0 (0.0)

Skeletal variations

13 (100)

13 (100)

13 (100)

7 (100)

Conclusions:
Maternal and developmental NOAELs of 10 mg/kg bw/d can be determined for this study, based on maternal toxicity (mortality, clinical signs, bodyweight effects) and reduced litter size at the highest dose level.
Executive summary:

In a developmental toxicity study, groups of 16 inseminated female HRA(NZW)SPF rabbits each received fenitrothion dissolved in corn oil, at dose levels of 0, 3, 10 and 30 mg/kg bw/d by oral gavage, daily from Days 7 to 19 of gestation at the dosage volume of 1.0 mL/kg bw. Clinical observations, body weights and food consumption were recorded for all females. On day 29 of gestation, all surviving pregnant females were sacrificed and a cesarean section performed. All live fetuses were evaluated for external findings, visceral findings (Staples' technique) and for skeletal findings following staining with Alizarin Red S. A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8.  Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy). Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors.  These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit.  Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8.  All other mean food consumption values were statistically similar for all groups.  Gross necropsy did not reveal any effects of treatment. The mean number of implantations was lower in the high dose group, resulting in a lower litter size.  Other parameters were unaffected by treatment.  There was no dose-related increase in the incidence of any particular malformation or in the incidence of any type (i.e. external, visceral, or skeletal) of malformation. Although the litter incidence of skeletal malformations was slightly higher than controls in the 3 and 10 mg/kg bw/d groups, no malformations were noted in the seven litters of the 30 mg/kg bw/d group available for evaluation. Overt evidence of maternal toxicity was seen in animals receiving 30 mg/kg/ bwd but was not accompanied by adverse effects on foetal growth or development. Maternal and developmental NOAELs of 10 mg/kg bw/d can be determined for this study, based on maternal toxicity (mortality, clinical signs, bodyweight effects) and reduced litter size at the highest dose level.

The highest dose level in this study was sufficient to cause maternal toxicity (including mortality) and was associated with a slight reduction in implantations and litter size. Findings are considered to be secondary to maternal effects.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
8 April 1986 - 2 May 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Fenitrothion
Batch No.: 41208
Purity: 96.6%
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD®(SD)BR
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, NY
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 199.8-259.1 g
- Housing: Individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-26
- Humidity (%): 30-70
- Air changes (per hr): 18.2
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 8 April 1986 To: 2 May 1986
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Groups of 24 time-mated female Sprague-Dawley Crl:CD®(SD)BR rats were gavaged with fenitrothion (dissolved in corn oil) at dose levels of 0, 3, 8 and 25 mg/kg bw/d from Gestation Days 6-15 of gestation, using a dose volume of 5 mL/kg bw.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Achieved concentration and stability were assessed
Details on mating procedure:
Rats were mated (1:1) with males of the same strain and source until mating was confirmed and for a maximum of 4 days. The day of mating (as indicated by copulatory plug or vaginal sperm) was designated Gestation Day (GD) 0.
Duration of treatment / exposure:
10 days (GD 6-15)
Frequency of treatment:
Daily
Duration of test:
Dams were terminated on GD20
Dose / conc.:
0 mg/kg bw/day
Remarks:
Vehicle (corn oil) control
Dose / conc.:
3 mg/kg bw/day
Dose / conc.:
8 mg/kg bw/day
Dose / conc.:
25 mg/kg bw/day
No. of animals per sex per dose:
24 time-mated females
Control animals:
yes, concurrent vehicle
Details on study design:
Mated females were randomly assigned to the dose groups
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: GD0, 6-19, 20

FOOD CONSUMPTION: Yes
- Time schedule for examinations: GD6-19, 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD20
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Statistics:
Differences between the control and treated groups were assessed using appropriate statistical tests.
Indices:
Not applicable
Historical control data:
Not required
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Signs of toxicity noted at 25 mg/kg bw/d during the treatment and post-treatment intervals included tremors, rough hair, thin appearance, rhinorrhoea and urine staining.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
All females survived until the scheduled sacrifice.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a significant decrease in the mean maternal body weights each day on GD11-19 at 25 mg/kg bw/d. The mean terminal (GD20) bodyweight in the 25 mg/kg bw/d group was slightly, but not significantly, less than the control value. However, the mean corrected terminal body weight was significantly less in the 25 mg/kg bw/d group when compared to controls. The mean maternal body weight gain values were significantly lower in the 25 mg/kg bw/d group during the treatment period compared to the control group. The mean body weight gain values in the 3 and 8 mg/kg/ bw/d groups were significantly above the control values for the post-treatment period.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption values were comparable between the control and treated groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Mean gravid uterine weights were significantly higher for the 3 and 8 mg/kg bw/d groups when compared to the control value. Mean gravid uterine weight at 25 mg/kg bw/d was similar to the controls.
Details on results:
All females survived until the scheduled sacrifice. Signs of toxicity noted at 25 mg/kg bw/d during the treatment and post-treatment intervals included tremors, rough hair, thin appearance, rhinorrhoea and urine staining. There was a significant decrease in the mean maternal body weights each day on GD11-19 at 25 mg/kg bw/d. The mean terminal (GD20) bodyweight in the 25 mg/kg bw/d group was slightly, but not significantly, less than the control value. However, the mean corrected terminal body weight was significantly less in the 25 mg/kg bw/d group when compared to controls. The mean maternal body weight gain values were significantly lower in the 25 mg/kg bw/d group during the treatment period compared to the control group. The mean body weight gain values in the 3 and 8 mg/kg/day groups were significantly above the control values for the post-treatment period. Food consumption values were comparable between the control and treated groups. Gross necropsy did not reveal any effects of treatment. Mean gravid uterine weights were significantly higher for the 3 and 8 mg/kg bw/d groups when compared to the control value. Mean gravid uterine weight at 25 mg/kg bw/d was similar to the controls.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Other effects:
no effects observed
Details on maternal toxic effects:
Parameters were comparable in all groups and were unaffected by treatment.
Key result
Dose descriptor:
NOAEL
Effect level:
8 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
body weight and weight gain
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
There were no differences between groups in the pregnancy rates, mean implantation efficiency, foetal viability, foetal sex ratio, or mean foetal body weights. Neither the frequency nor the distribution of foetal malformations indicated a teratogenic response in any group in this study.
Key result
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Summary of clinical signs

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

8 mg/kg bw/d

25 mg/kg bw/d

GD6-16 (treatment period)

Number of animals observed

24

24

24

24

Thin

1

3

1

7

Tremors

0

0

0

9

Rhinorrhea

0

1

0

6

Rough haircoat

0

0

0

7

Urine stains

0

1

0

10

GD17-20 (post-treatment period)

Number of animals observed

24

24

24

24

Thin

0

1

0

3

Tremors

0

0

0

5

Rhinorrhea

0

0

0

5

Rough haircoat

0

0

0

5

Urine stains

0

0

0

2

Summary of bodyweight effects

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

8 mg/kg bw/d

25 mg/kg bw/d

Mean body weight (g)

GD 0

238

241

237

237

GD 6

268

270

264

262

GD 7

266

266

263

261

GD 8

267

269

265

261

GD 9

270

275

269

262

GD 10

277

280

274

265

GD 11

283

286

280

269*

GD 12

287

290

284

273*

GD 13

289

295

286

276*

GD 14

294

301

293

278*

GD 15

301

309

300

281*

GD 16

310

319

311

286*

GD 17

323

332

325

301*

GD 18

337

347

339

315*

GD 19

349

362

356

331*

GD 20

362

378

370

347

Body weight change (g)

GD 0-6

30

29

27

26

GD 6-7

-2

-3

-2

-1

GD 6-8

-1

-1

1

-1

GD 6-9

2

5

4

-0.2

GD 6-10

9

11

9

3*

GD 6-11

15

17

15

7*

GD 6-12

19

21

19

10*

GD 6-13

21

26

22

13*

GD 6-14

26

31

28

15*

GD 6-15

33

39

36

19*

GD 6-16

42

49*

47

24*

GD 6-17

55

63

61

38*

GD 6-18

69

77

75

52*

GD 6-19

81

92*

91

68

GD 6-20

94

108*

106*

84

GD 16-20

52

59*

59*

60*

GD 0-20

124

137*

133

110

*significantly different to controls (p<0.05)

Uterus weights

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

8 mg/kg bw/d

25 mg/kg bw/d

Mean terminal body weight (g)

361.7

377.5

370.2

346.7

Mean gravid uterine weight (g)

71.8

81.4*

82.2*

73.4

Mean corrected terminal body weight (g)

289.9

296.1

288.1

273.3*

*significantly different to controls (p<0.05)

Litter parameters

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

8 mg/kg bw/d

25 mg/kg bw/d

Number of females mated

24

24

24

24

Number of litters with live fetuses

24

22

20

20

Mean number of corpora lutea

16.0

16.8

18.0

16.0

Mean number of implantations

14.0

15.3

15.8

14.1

Mean implantation efficiency (%)

88

92

89

87

Mean number of resorptions

0.9

0.5

1.0

0.8

Mean incidence of resorptions (%)

6

3

6

7

Mean incidence of fetal viability (%)

94

97

94

93

Mean number of live fetuses per litter

13.1

14.7

14.8

13.3

Mean number of dead fetuses per litter

0

0

0

0

Mean percent of males per litter

49

51

48

50

Mean fetal weight (g)

 

 

 

 

Male

3.5

3.5

3.6

3.5

Female

3.3

3.4

3.3

3.3

Foetal parameters

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

8 mg/kg bw/d

25 mg/kg bw/d

Number of fetuses (fetal incidence %)

Total number of fetuses examined

314

324

295

265

External malformations

0 (0.0)

0 (0.0)

1 (0.3)

1 (0.4)

External variations

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

Total number of fetuses examined

158

164

146

135

Visceral malformations

1 (0.6)

0 (0.0)

1 (0.7)

0 (0.0)

Visceral variations

35 (22)

38 (23)

33 (23)

22 (16)

Total number of fetuses examined

156

160

149

130

Skeletal malformations

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.8)

Skeletal variations

71 (46)

95 (59)

78 (52)

72 (55)

Number of litter (litter incidence %)

Total number of litters examined

24

22

20

20

External malformations

0 (0.0)

0 (0.0)

1 (5.0)

1 (5.0)

External variations

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

Total number of litters examined

24

22

20

20

Visceral malformations

1 (4.2)

0 (0.0)

1 (5.0)

0 (0.0)

Visceral variations

18 (75)

16 (73)

15 (75)

9 (45)

Total number of litters examined

24

22

20

20

Skeletal malformations

0 (0.0)

0 (0.0)

0 (0.0)

1 (5.0)

Skeletal variations

21 (88)

20 (91)

20 (100)

19 (95)

Conclusions:
A maternal NOAEL of 8 mg/kg bw/d can be determined for this study, based on clinical signs and bodyweight effects at the highest dose level of 25 mg/kg bw/d. A developmental NOAEL of 25 mg/kg bw/d can be determined in the absence of any effects at the highest dose level.
Executive summary:

In a developmental toxicity study, groups of 24 time-mated female Sprague-Dawley Crl:CD®(SD)BR rats were gavaged with fenitrothion (dissolved in corn oil) at dose levels of 0, 3, 8 and 25 mg/kg bw/d from Gestation Days 6-15 of gestation, using a dose volume of 5 mL/kg bw. Dams were sacrificed on GD20 and the uterine contents examined. All foetuses were assessed for extranal findings. Approximately one half of the foetuses in each litter were preserved in Bouin's and assessed for visceral findings using Wilson's technique; the remaining foetuses were assessed for skeletal findings following staining with Alizarin Red S. All females survived until the scheduled sacrifice.  Signs of toxicity noted at 25 mg/kg bw/d during the treatment and post-treatment intervals included tremors, rough hair, thin appearance, rhinorrhoea and urine staining.  There was a significant decrease in the mean maternal body weights each day on GD11-19 at 25 mg/kg bw/d.  The mean terminal (GD20) bodyweight in the 25 mg/kg bw/d group was slightly, but not significantly, less than the control value.  However, the mean corrected terminal body weight was significantly less in the 25 mg/kg bw/d group when compared to controls.  The mean maternal body weight gain values were significantly lower in the 25 mg/kg bw/d group during the treatment period compared to the control group.  The mean body weight gain values in the 3 and 8 mg/kg bw/d groups were significantly above the control values for the post-treatment period. Food consumption values were comparable between the control and treated groups.  Gross necropsy did not reveal any effects of treatment.  Mean gravid uterine weights were significantly higher for the 3 and 8 mg/kg bw/d groups when compared to the control value.  Mean gravid uterine weight at 25 mg/kg bw/d was similar to the controls. There were no differences between groups in the pregnancy rates, mean implantation efficiency, foetal viability, foetal sex ratio, or mean foetal body weights.  Neither the frequency nor the distribution of foetal malformations indicated a teratogenic response in any group in this study. There was no evidence of teratogenicity or developmental toxicity in this study at dose levels sufficient to result in mild maternal toxicity. A maternal NOAEL of 8 mg/kg bw/d can be determined for this study, based on clinical signs and bodyweight effects at the highest dose level of 25 mg/kg bw/d.  A developmental NOAEL of 25 mg/kg bw/d can be determined in the absence of any effects at the highest dose level.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Guideline-compliant studies of prenatal developmental toxicity in the rat and rabbit are available for fenitrothion.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Toxicity to reproduction: other studies

Additional information

In a developmental toxicity study, groups of 24 time-mated female Sprague-Dawley Crl:CD®(SD)BR rats were gavaged with fenitrothion (dissolved in corn oil) at dose levels of 0, 3, 8 and 25 mg/kg bw/d from Gestation Days 6-15 of gestation, using a dose volume of 5 mL/kg bw. Dams were sacrificed on GD20 and the uterine contents examined. All foetuses were assessed for extranal findings. Approximately one half of the foetuses in each litter were preserved in Bouin's and assessed for visceral findings using Wilson's technique; the remaining foetuses were assessed for skeletal findings following staining with Alizarin Red S. All females survived until the scheduled sacrifice.  Signs of toxicity noted at 25 mg/kg bw/d during the treatment and post-treatment intervals included tremors, rough hair, thin appearance, rhinorrhoea and urine staining.  There was a significant decrease in the mean maternal body weights each day on GD11-19 at 25 mg/kg bw/d.  The mean terminal (GD20) bodyweight in the 25 mg/kg bw/d group was slightly, but not significantly, less than the control value.  However, the mean corrected terminal body weight was significantly less in the 25 mg/kg bw/d group when compared to controls.  The mean maternal body weight gain values were significantly lower in the 25 mg/kg bw/d group during the treatment period compared to the control group.  The mean body weight gain values in the 3 and 8 mg/kg bw/d groups were significantly above the control values for the post-treatment period. Food consumption values were comparable between the control and treated groups.  Gross necropsy did not reveal any effects of treatment.  Mean gravid uterine weights were significantly higher for the 3 and 8 mg/kg bw/d groups when compared to the control value.  Mean gravid uterine weight at 25 mg/kg bw/d was similar to the controls. There were no differences between groups in the pregnancy rates, mean implantation efficiency, foetal viability, foetal sex ratio, or mean foetal body weights.  Neither the frequency nor the distribution of foetal malformations indicated a teratogenic response in any group in this study. There was no evidence of teratogenicity or developmental toxicity in this study at dose levels sufficient to result in mild maternal toxicity. A maternal NOAEL of 8 mg/kg bw/d can be determined for this study, based on clinical signs and bodyweight effects at the highest dose level of 25 mg/kg bw/d.  A developmental NOAEL of 25 mg/kg bw/d can be determined in the absence of any effects at the highest dose level.

In a developmental toxicity study, groups of 16 inseminated female HRA(NZW)SPF rabbits each received fenitrothion dissolved in corn oil, at dose levels of 0, 3, 10 and 30 mg/kg bw/d by oral gavage, daily from Days 7 to 19 of gestation at the dosage volume of 1.0 mL/kg bw. Clinical observations, body weights and food consumption were recorded for all females. On day 29 of gestation, all surviving pregnant females were sacrificed and a cesarean section performed. All live fetuses were evaluated for external findings, visceral findings (Staples' technique) and for skeletal findings following staining with Alizarin Red S.A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8.  Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy). Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors.  These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit.  Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8.  All other mean food consumption values were statistically similar for all groups.  Gross necropsy did not reveal any effects of treatment. The mean number of implantations was lower in the high dose group, resulting in a lower litter size.  Other parameters were unaffected by treatment.  There was no dose-related increase in the incidence of any particular malformation or in the incidence of any type (i.e. external, visceral, or skeletal) of malformation. Although the litter incidence of skeletal malformations was slightly higher than controls in the 3 and 10 mg/kg bw/d groups, no malformations were noted in the seven litters of the 30 mg/kg bw/d group available for evaluation. Overt evidence of maternal toxicity was seen in animals receiving 30 mg/kg/ bwd but was not accompanied by adverse effects on foetal growth or development. Maternal and developmental NOAELs of 10 mg/kg bw/d can be determined for this study, based on maternal toxicity (mortality, clinical signs, bodyweight effects) and reduced litter size at the highest dose level.

Justification for classification or non-classification

Fenitrothion has a harmonised classification but is not classified for reproductive toxicity. In the absence of relevant findings in the available studies, no change to this classification is proposed. There was no evidence of any effects of treatment on fertility or reproductive capacity in the two-generation study. No developmental toxicity was obserfved in the rat study at maternally toxic dose levels. Effects in the rabbit study were limited to reduced numbers of implantations and litter size at the highest dose level. Effects were associated with maternal toxicity inlcuding mortality, and are therefore considered to be secondary and non-specific and are not relevant for the purposes of classification.