Fusidic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A screening for reproductive/developmental toxicity of fusidic acid in male Sprague Dawley rats was performed in accordance to ICH testing guideline and following GLP.

Sodium fusidate administered by oral gavage to male Sprague Dawley rats for 28 days at dose level of 0, 100, 200 and 400 mg/kg bw. prior to mating with untreated females did not affect the mating performance or the spermatogenic cycle. Pregnancy outcome were similar in the four groups. No effects were observed on number of corpora lutea, implantations, early and late resorptions and litter size when compared to the vehicle control.

Based on these data, a NOAEL of 400 mg/kg bw/d could be established.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 January 1997- 16 March 1997

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: ICH test guidelines

Version / remarks:

Note for Guidance on reproductive Toxicology. Detection of toxicity to reproduction for medical products (CPMP/ICH//386/95, ICH TopicS5A)
and Note for Guidance on reproductive Toxicology. Toxicity on male fertility (CPMP/ICH/136/95, ICH Topic S5B)

Comparable to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

not specified

Principles of method if other than guideline:

The effect of sodium fusidate on the male fertility in rats was studied.
4 groups each containing 25 males and 25 females were examined.
Males were exposed to either 0 (vehicle), 100 ; 200 mg; or 400 mg/kg bw/day. Females were not exposed.
Males were exposed to sodium fusidate by oral gavage for four weeks.
Females were placed overnight (4p.m. to 8 a.m.) with the males and then returned to their home cage.
Mating procedure was repeated until mating occured or for at least 14 days.
Mortality, growth and fertility was studied following the oral exposure.

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Sodium fusidate
Batch no. C4532

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

(Mol: SPRD)
Age: 8 weeks
Weight: 200g (female) and 275g (male)
Møllegaard Breeding Center, Ejby, Denmark
Acclimatisation: 14 days
1 control and 3 treatment groups (25 males and 25 females)
Males: treated twice per day for 7 days/ week; Females: no treatment

Sex:

male/female

Details on test animals or test system and environmental conditions:

100 male and 100 female rats

Route of administration:

oral: gavage

Vehicle:

other: Disodium phosphate dihydrate (19.6 mg); citric acid monohydrate (1 mg/L); Disodium edetate (0.5 mg), Water (1 mL)

Details on exposure:

Males: treated twice per day for 7 days/ week
Females: no treatment
Duration 4 weeks

Details on mating procedure:

Mating ration: 1 female per male.
Females were placed overnight (4p.m. to 8 a.m.) with the males and then returned to their home cage.
Mating procedure was repeated until mating occured or for at least 14 days.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

NA

Duration of treatment / exposure:

4 weeks exposure followed by up to 2 weeks mating

Frequency of treatment:

twice/day

Details on study schedule:

NA

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

vehicle

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

administrated as 2*50 mg/kg bw/day

Dose / conc.:

200 mg/kg bw/day (nominal)

Remarks:

administrated as 2*100 mg/kg bw/day

Dose / conc.:

400 mg/kg bw/day (nominal)

Remarks:

administrated as 2*200 mg/kg bw/day

No. of animals per sex per dose:

25 males

Control animals:

yes, concurrent vehicle

Details on study design:

daily observations: health and behaviour

Positive control:

not included

Parental animals: Observations and examinations:

daily observations

Oestrous cyclicity (parental animals):

na

Sperm parameters (parental animals):

na

Litter observations:

Number of corpora lutea
Number of implantations
Number of viable and dead offspring
The litter size

Postmortem examinations (parental animals):

na

Postmortem examinations (offspring):

na

Statistics:

na

Reproductive indices:

na

Offspring viability indices:

na

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Regurgitation of the test substance followed aspiration into the lungs was observed in a proportion of the treated males. Clinical signs were dyspnea with gasping and wheezing respiration sound, red serous fluid from the nose. Reduced spontaneous activity and piloerection.These observations were treatment and dose related and not observed in the vehicle control.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

One female (group 1) was killed due to a growth at the front leg. 11 males (2 group 2 males; one group 3 male and 8 group 4 males) were found dead or prematurely killed for humane reasons due to aspiration of the sodium fusidate solution, which is very irritative.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No effects on growth observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Activity: Reduced spontaneous activity and piloerection.
Mating performance: No difference between the exposure and vehicle control groups

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related changes observed.

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

There was no difference in the mating performance in the vehicle and the sodium fusidate treated groups (copulation, fertility, and gestation indices). The time to successful mating (mating days) and the number of corpora lutea, implantations, early and late resorption, and litter size, were comparable in the vehicle control and the three groups where the males were treated with sodium fusidate prior to mating. The calculated pre-implantation loss varied widely in the four groups, but the difference was not treatment- or dose related. The post-implantation loss was comparable in the four groups of pregnant female rats.

Key result

Dose descriptor:

NOAEC

Effect level:

>= 400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

reproductive performance

Key result

Dose descriptor:

LOAEC

Effect level:

ca. 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

mortality

Remarks on result:

other: The death were attributed to regurgitation of the test substance by aspiration into the lungs. This is a known effect of sodium fusidate, which is locally very irritative. The incident of these deaths were clearly dose-related.

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

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

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Litter size were comparable in the vehicle control and the treated groups

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:

not examined

Histopathological findings:

not examined

Other effects:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

> 400 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

viability

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

> 400 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: number of corpera lutea, implantations, early and late resorptions and litter size

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

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:

not examined

Histopathological findings:

not examined

Other effects:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Reproductive effects observed:

no

Lowest effective dose / conc.:

400 mg/kg bw/day (actual dose received)

Treatment related:

no

Conclusions:

Sodium fusidate administered by oral gavage to male Sprague Dawley rats for 28 days at dose level of 0, 100, 200 and 400 mg/kg bw. prior to mating with untreated females did not affect the mating performance or the spermatogenic cycle. Pregnancy outcome were similar in the four groups. No effects were observed on number of corpora lutea, implantations, early and late resorptions and litter size when compared to the vehicle control.
A number of males were found dead or prematurely killed for humane reasons. The death that occurred in some of the males in the three treatment groups were attributed to regurgitation of the test substance by aspiration into the lungs. This is a known effect of sodium fusidate, which is locally very irritative. The incident of these deaths was clearly dose-related.

In conclusion, no effects were seen on the reproductive performance or fertility of the male rats at the maximum tolerable dose level. Based on these data, a NOAEL of 400 mg/kg bw/d could be established.

Executive summary:

A screening for reproductive / developmental toxicity of fusidic acid in male Sprague Dawley rats was performed in accordance to ICH testing guideline and following GLP.

Sodium fusidate administered by oral gavage to male Sprague Dawley rats for 28 days at dose level of 0, 100, 200 and 400 mg/kg bw. prior to mating with untreated females did not affect the mating performance or the spermatogenic cycle. Pregnancy outcome were similar in the four groups. No effects were observed on number of corpora lutea, implantations, early and late resorptions and litter size when compared to the vehicle control.

A number of males were found dead or prematurely killed for humane reasons. The death that occurred in some of the males in the three treatment groups were attributed to regurgitation of the test substance by aspiration into the lungs. This is a known effect of sodium fusidate, which is locally very irritative. The incident of these deaths was clearly dose-related.

In conclusion, no effects were seen on the reproductive performance or fertility of the male rats at the maximum tolerable dose level. Based on these data, a NOAEL of 400 mg/kg bw/d could be established.

 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

A screening for reproductive / developmental toxicity available (Key study - Klimich score 1).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

A key screening study for reproductive/developmental toxicity of fusidic acid in male Sprague Dawley rats was performed in accordance to ICH testing guideline and following GLP.

Sodium fusidate administered by oral gavage to male Sprague Dawley rats for 28 days at dose level of 0, 100, 200 and 400 mg/kg bw. prior to mating with untreated females did not affect the mating performance or the spermatogenic cycle. Pregnancy outcome were similar in the four groups. No effects were observed on number of corpora lutea, implantations, early and late resorptions and litter size when compared to the vehicle control. Based on these data, a NOAEL of 400 mg/kg bw/d could be established.

Supportive data available from a prenatal non-GLP developmental toxicity study performed in pregnant rats, mice and rabbits to examine the possible teratogenic effects of fusidin acid.

Rats and mice were dosed orally with 0, 20, 100, 200 mg/kg bw/d for 12 days (rats, day 3-15 of gestation) or 9 days (mice, day 6-15 of gestation). Rabbits were dosed orally with 0, 125 mg/kg bw/d for 12 days (day 6-18 of gestation). No test-item related toxicity and adverse effects observed. Thus, based on the results of this study using three species (mice/rats/rabbits), the dose level of 200 mg fusidin acid/kg/ bw/d can be considered as the No Observed Adverse Effect Level (NOAEL) for maternel toxicity as well as for developmental effects.

Supportive data available from a non-GLP developmental toxicity study was performed in rats using dose levels of 0 and 400 mg/kg bw/d. No test-item related toxicity and adverse effects observed. Thus, based on the results of this study using FDLR-rats, the dose level of 400 mg fusidin acid/kg/ bw/d can be considered as the No Observed Adverse Effect Level (NOAEL) for maternel toxicity as well as for developmental effects.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1965

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Rats:
Pregnant rats were devided into 3 groups of 29-31 animals and exposed from day 3-15 of gestation.
Dosing: 0, 20, 100, 200 mg/kg bw/day (control 59 pregnant rats, reciving water by oral tube)
On day 21 half the animals were killed and examined. Remaining animals were allowed to continue until term.
Endpoints examined: average number of foetus and average weight, average length of pregnancy, average number of young, average weight of young, average no. of mothers with dead foetus, number of dead foetus, number of still-born, no. ofyoung with subcutaneous haematomas at birth, average no. of weanlings, mortality during lactation period,average weight at weaning

Mice:
Pregnant mice were devided into 3 groups of 16-19 animals and exposed from day 6-15 of gestation.
Dosing: 0, 20, 100, 200 mg/kg bw/day (control 23 pregnant mice, reciving water by oral tube)
On day 18 half the animals were killed and examined. Remaining animals were allowed to continue until term.
Endpoints examined: average number of foetus and average weight, average no. of mothers with dead foetus, number of dead foetus, average length of pregnancy, average litter size, average weight, average number of weanlings,mortality during lactation period, average weight at weaning

Rabbits:
Pregnant rabbits were exposed from day 6-18 of gestation.
Dosing: 0, 125 mg/kg bw/day (control 11 pregnant rabbits, reciving placebo tablets)
On day 30 half the animals were killed and examined .Remaining animals were allowed to continue until term.
Endpoints examined: average number of foetus and average weight, average number of young and average weight of young

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

Sodium fusidate

Species:

other:

Strain:

other: albino rats; albino mice, rabbits (Danish white breed)

Route of administration:

other: Rats and mice: oral drinking water. Rabbits: tablets

Vehicle:

not specified

Details on exposure:

Rats:
Pregnant rats were devided into 3 groups of 29-31 animals and exposed from day 3-15 of gestation.
Dosing: 0, 20, 100, 200 mg/kg bw/day (control 59 pregnant rats, reciving water by oral tube)

Mice:
Pregnant mice were devided into 3 groups of 16-19 animals and exposed from day 6-15 of gestation.
Dosing: 0, 20, 100, 200 mg/kg bw/day (control 23 pregnant mice, reciving water by oral tube)


Rabbits:
Pregnant rabbits were exposed from day 6-18 of gestation.
Dosing: 0, 125 mg/kg bw/day (control 11 pregnant rabbits, reciving placebo tablets)

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

animals pregnant at initiation of the study

Duration of treatment / exposure:

rat: 12d (3-15 of gestation)
mice: 9d (day 6-15 of gestation.)
rabbits: 12d (day 6-18 of gestation)

Frequency of treatment:

daily dose of either 0, 20, 100 or 200 mg/kg bw.

Duration of test:

rat: 21d
mice: 18d
rabbits: 30d

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

20 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

only pregnant females were exposed:
rat: 29-31
mice: 16-19
rabbits: 18

Control animals:

yes, concurrent no treatment

Details on study design:

please refer to above section: principles of method if other than guideline

Maternal examinations:

duration of pregnancy (mice and rat)
number of mothers with dead foetuses/ number of dead foetus (mice and rat)
number of mothers with stillborn (rat)

Fetal examinations:

average number
average weight
subcutaneous haematomas

Statistics:

NA

Indices:

NA

Historical control data:

NA

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

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

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Number of abortions:

not examined

Pre- and post-implantation loss:

not examined

Total litter losses by resorption:

effects observed, non-treatment-related

Description (incidence and severity):

Mice: The rather large number of partially absorbed foetuses seen in all groups at autopsy, is probably due to mothers discomfort from the daily oral administration

Early or late resorptions:

not examined

Dead fetuses:

no effects observed

Description (incidence and severity):

rat: number of stillborn examined: No effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Rats: Number of stillborn
Mice, rabbit: Litter size
All: average number of young, distribution male/female

Details on maternal toxic effects:

no effects

Key result

Dose descriptor:

NOAEL

Remarks:

rat, mice and rabbit

Effect level:

>= 200 mg/kg bw/day (nominal)

Based on:

test mat.

Abnormalities:

not examined

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:

effects observed, treatment-related

Description (incidence and severity):

Rabbit: Litter size was rather low in the fusidin treatment group. Findings might be explained by the fact that intestinal disturbances (loose stool, decreased appetite) were encountered more often among mothers treated with the antibiotic and could be ascribed to an alternation in the intestinal flora.

Changes in postnatal survival:

effects observed, non-treatment-related

Description (incidence and severity):

Rats: rather high mortality is believed to be caused by manipulative procedures with mother and young

External malformations:

not examined

Skeletal malformations:

not examined

Visceral malformations:

not examined

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

>= 200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

changes in litter size and weights

changes in postnatal survival

Remarks on result:

other: Rats: high ratio of mortality in all groups during gestation and lactation period, not treatment related

Abnormalities:

not examined

Data show that 634 foetuses and young from 89 treated rats do not deviate from 447 foetuses and young from 59 control rats.

Data show that 352 foetuses and young from 52 treated mice do not deviate from 179 foetuses and young from 23 control mice.

Data show that 91 foetuses and young from 18 treated rabbits do not deviate from 86 foetuses and young from 11 control rabbits.

Conclusions:

A prenatal non-GLP developmental toxicity study was performed in pregnant rats, mice and rabbits to examine the possible teratogenic effects of fusidin acid.

No test-item related toxicity and adverse effects observed using dose levels of 0, 20, 100, 200 mg/kg bw/d (rats/mice) or 0, 125 mg/kg bw/d (rabbits). Thus, based on the results of this study using three species (mice/rats/rabbits), the dose level of 200 mg fusidin acid/kg/ bw/d can be considered as the No Observed Adverse Effect Level (NOAEL) for maternel toxicity as well as for developmental effects.

Executive summary:

A prenatal non-GLP developmental toxicity study was performed in pregnant rats, mice and rabbits to examine the possible teratogenic effects of fusidin acid.

Rats and mice were dosed orally with 0, 20, 100, 200 mg/kg bw/d for 12 days (rats, day 3-15 of gestation) or 9 days (mice, day 6-15 of gestation). Rabbits were dosed orally with 0, 125 mg/kg bw/d for 12 days

(day 6-18 of gestation).

No test-item related toxicity and adverse effects observed. Thus, based on the results of this study using three species (mice/rats/rabbits), the dose level of 200 mg fusidin acid/kg/ bw/d can be considered as the No Observed Adverse Effect Level (NOAEL) for maternel toxicity as well as for developmental effects.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1966

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

2 groups of 20 rats of each sex were exposed to sodium fusidate.
Average daily intake of 0 and 400 mg/kg bw. (14 days)
After 14 days one male and one female were grouped for mating.

One day 20 of gestation foetuses were taken by cacsarean section from 10 dams.
The uterus were examined. Implant sites were counted and compared to number of viable foetus, which were counted and weighed.
Foetal skeletal structures were examined under a disecting microscope. Internal organs were also examined for abnormalties.

Remaining 10 dams were permitted to cast their litter naturally. Pubs were counted and weighed.
Survivors were sacrified and organs examined at necropsy: liver, spleen, stomac, small and large intestines, pancreas, kidney, bladder, adrenals, gonads,adnexa, thyroids,pituitaries, thymus,salivary glands, lymph nodes, heart, aorta, lungs, sternum, skin,, spinal cord, brain and eyes.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

Sodium fusidate
SQ 16, 360 Batch no.13

Species:

rat

Strain:

other: FDRL

Details on test animals or test system and environmental conditions:

FDLR-rats of proven fertility

Route of administration:

oral: feed

Details on exposure:

Please refer to section "details on exposure if other than guideline"

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

NA

Details on mating procedure:

After 14 days of exposure, one male and one female were grouped for mating.

Duration of treatment / exposure:

14 days prior to mating

Frequency of treatment:

Daily exposure via food

Duration of test:

Following exposure: up to 20 days of gestation

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

400 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20 rats of each sex per dose

Control animals:

yes, concurrent no treatment

Details on study design:

Please refer to section "details on exposure if other than guideline"

Maternal examinations:

Females where foetuses were taken by cacsarean section were examined

Ovaries and uterine content:

Uterus examination
No of implant sites

Fetal examinations:

Dams where foetuses were taken by cacsarean section
- Number of viable foetus, were counted and weighed.
- Foetal skeletal structures were examined under a disecting microscope. Internal organs were also examined for abnormalties.

Pubs from remaining 10 dams which were permitted to cast their litter naturally.
- Pubs were counted and weighed.
- Survivors were sacrified and organs examined at necropsy: liver, spleen, stomac, small and large intestines, pancreas, kidney, bladder, adrenals, gonads,adnexa, thyroids,pituitaries, thymus,salivary glands, lymph nodes, heart, aorta, lungs, sternum, skin,, spinal cord, brain and eyes.

Statistics:

NA

Indices:

Fertility (percent of mating resulting inpregnacies)
Gestation (percent of pregnacies resulting in litters cast alive)
Viability (Percent of pubs cast alive that survived at 4 days)
Lactation (Percent of pubs alive at day 4 that survived to weaning at 21 days)

Historical control data:

NA

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

oral study

Mortality:

not specified

Description (incidence):

All females except one surved the study

Body weight and weight changes:

not specified

Description (incidence and severity):

Body weight reported. No information on weight changes

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Description (incidence and severity):

examination of uterus

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not specified

Description (incidence and severity):

Examination of uterus was conducted but not described

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Two control females had no pregnancies, however uterus examination indicated that there had been no implanted fetuses

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:

no effects observed

Key result

Dose descriptor:

NOEL

Effect level:

> 400 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

dead fetuses

early or late resorptions

number of abortions

pre and post implantation loss

total litter losses by resorption

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not examined

Changes in litter size and weights:

effects observed, treatment-related

Description (incidence and severity):

The body weight of the weanlings in the exposure group was significantly higher than the body weight of the control group

Changes in postnatal survival:

no effects observed

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Three fetuses in the control group had massive hematomas in the neck

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Approximately 4% of the pups in each group, had bone abnormalties

Visceral malformations:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

>= 400 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

changes in litter size and weights

changes in postnatal survival

external malformations

skeletal malformations

control                     test

Fertility (percent of mating resulting inpregnacies)                                                        100                     100

Gestation (percent of pregnacies resulting in litters cast alive)                                       100                     70*

Viability (Percent of pubs cast alive that survived at 4 days)                                        55.6                     89.3

Lactation (Percent of pubs alive at day 4 that survived to weaning at 21 days)             64.4                     89.3

*Two females in the exposure group destroyed their litters at birth. One female died in parturition.

Conclusions:

A non-GLP developmental toxicity study was performed in rats using dose levels of 0 and 400 mg/kg bw/d. No test-item related toxicity and adverse effects observed. Thus, based on the results of this study using FDLR-rats, the dose level of 400 mg fusidin acid/kg/ bw/d can be considered as the No Observed Adverse Effect Level (NOAEL) for maternel toxicity as well as for developmental effects.

Executive summary:

The effects of sodium fusidate on mating and in utero neonatal development was studied in FDLR-rats, which were exposed orally to 400 mg/kg bw/day for 14 days before mating.

No test-item related toxicity and adverse effects observed. Thus, based on the results of this study using FDLR-rats, the dose level of 400 mg fusidin acid/kg/ bw/d can be considered as the No Observed Adverse Effect Level (NOAEL) for maternel toxicity as well as for developmental effects.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

A screening for reproductive / developmental toxicity available (Key study - Klimich score 1) and two supporting developmental toxicity studies.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data, no classification for fusidic acid is proposed for reproduction (fertility and developmental toxicity).