Fenitrothion

Toxicity to reproduction

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

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

Test material information

Constituent 1

Reference substance name:

Fenitrothion

EC Number:

204-524-2

EC Name:

Fenitrothion

Cas Number:

122-14-5

Molecular formula:

C9H12NO5PS

IUPAC Name:

O,O-dimethyl O-3-methyl-4-nitrophenyl phosphorothioate

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 or test system 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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm

Remarks:

Control (basal diet)

Doses / concentrations 2

Dose / conc.:

10 ppm

Doses / concentrations 3

Dose / conc.:

40 ppm

Doses / concentrations 4

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 generation)

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

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)

1

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

2

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	19^a	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	28^a	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	14^b
No. of females delivering viable offspring	24	19	16^c	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	29^a	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	29^b	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	18^c	23	24	20^d
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	4/2^c	0/0	0/0	0/0	11/1
Bite wound	0/0	0/0	0/0	2/1	0/0	0/0	2/1^b	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.