Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1990

Materials and methods

Test guideline
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
Fenitrothion
Batch No.: 60553
Purity: 94.6%,

Test animals

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

Administration / exposure

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.
Doses / concentrationsopen allclose all
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

Examinations

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

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

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 / performance (P0)

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

Details on results (P0)

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.

Effect levels (P0)

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

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: P1 (second parental generation)

General toxicity (P1)

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 / performance (P1)

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.

Details on results (P1)

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.

Effect levels (P1)

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

Target system / organ toxicity (P1)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

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

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

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.

Effect levels (F1)

open allclose all
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

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Results: F2 generation

General toxicity (F2)

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

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Details on results (F2)

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.

Effect levels (F2)

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

Target system / organ toxicity (F2)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.