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EC number: 230-256-0 | CAS number: 6990-06-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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Toxicity to reproduction
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:
- 1 997
- 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
- 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
Constituent 1
- 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.
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