Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Fusidic acid
EC Number:
230-256-0
EC Name:
Fusidic acid
Cas Number:
6990-06-3
Molecular formula:
C31H48O6
IUPAC Name:
2-[(1Z,2S,3aS,3bS,5aS,6S,7R,9aS,9bS,10R,11aR)-2-(acetyloxy)-7,10-dihydroxy-3a,3b,6,9a-tetramethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-ylidene]-6-methylhept-5-enoic acid
Test material form:
solid: crystalline
Details on test material:
Details are given for each individual study
Specific details on test material used for the study:
Sodium fusidate
Batch no. C4532

Test animals

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

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

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.

Effect levels (P0)

open allclose all
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.

Results: P1 (second parental generation)

General toxicity (P1)

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 / performance (P1)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Results: F1 generation

General toxicity (F1)

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

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

open allclose all
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

Results: F2 generation

General toxicity (F2)

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

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Overall reproductive toxicity

Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
400 mg/kg bw/day (actual dose received)
Treatment related:
no

Applicant's summary and conclusion

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.