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EC number: 217-968-7 | CAS number: 2022-85-7
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2004-06-29 to 2004-12-06
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 27 July 1995
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- Commission Directive 96/54/EC
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
Test material
- Reference substance name:
- Flucytosine
- EC Number:
- 217-968-7
- EC Name:
- Flucytosine
- Cas Number:
- 2022-85-7
- Molecular formula:
- C4H4FN3O
- IUPAC Name:
- flucytosine
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD® (SD) BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation:approximately 5 - 7 weeks
- Weight at study initiation: males: 131-177 g, females: 118-156 g
- Housing: animals were housed in groups of five by sex in polypropylene grid-floor cages suspended over trays lined with absorbent paper
- Diet (e.g. ad libitum): ad libitum, pelleted diet (Rodent 5LF2 (Certified) Diet, BCM IPS Limited, London, UK)
- Water (e.g. ad libitum): ad libitum, mains drinking water
- Acclimation period: 7 days
DETAILS OF FOOD AND WATER QUALITY:
The diet was analysed for contaminants. The diet and drinking water were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 1
- Humidity (%): 55 ± 15
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Remarks:
- BP
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: For the purpose of this study the test material was prepared at the appropriate concentrations as a suspension in Arachis oil BP. The formulations to be stable for at least fourteen days. Formulations were therefore prepared weekly and stored at approximately +4ºC in the dark.
VEHICLE
- Justification for use and choice of vehicle (if other than water): An aqueous formulation of the test material was not possible, therefore Arachis Oil BP was chosen for formulation
- Concentration in vehicle: 37.5, 100, 250 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg - Analytical verification of doses or concentrations:
- yes
- Remarks:
- HPLC
- Details on analytical verification of doses or concentrations:
- The stability and homogeneity of the test material formulations were determined by the testing facility. Results show that the formulations were stable for at least 14 days. Samples were taken of each test material formulation and were analysed for concentration of 5-fluorocytosine at the testing facility. HPLC was used for analysis of formulations and the results obtained indicate that the prepared formulations were within ± 8% of the nominal concentration.
The test material formulations were mixed thoroughly and samples were taken from the top, middle and bottom of the container, shaking between sampling. Sampling was performed in triplicate. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 400 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose selection was based on a preliminary dose range finding test.
- Rationale for animal assignment (if not random): The animals were randomly allocated to treatment groups using random letter tables and the group mean bodyweights were then determined to ensure similarity between the treatment groups.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Before dosing, 1 and 5 h after dosing during the working week. Before dosing and 1 h after dosing at weekends
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Before dosing, 1 and 5 h after dosing during the working week. Before dosing and 1 h after dosing at weekends
BODY WEIGHT: Yes
- Time schedule for examinations: Individual bodyweights were recorded on Day 0 (the day before the start of treatment) and on Days 7, 14, 21 and 28. Bodyweights were also recorded at terminal kill.
FOOD CONSUMPTION:
- Food consumption was recorded for each cage group at weekly intervals throughout the study.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: Yes
- Time schedule for examinations: Water intake was observed daily, for each cage group, by visual inspection of the water bottles for any overt changes.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At day 28 blood samples were obtained from the lateral tail vein or by cardiac puncture prior to necropsy on day 29.
- Anaesthetic used for blood collection: Not specified for days 28, for day 29 animals were sacrificed by an intravenous overdose of sodium pentobarbitone.
- Animals fasted: No
- How many animals: all
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:At day 28 blood samples were obtained from the lateral tail vein or by cardiac puncture prior to necropsy on day 29.
- Animals fasted: No
- How many animals: all
- Parameters checked in table [No.1] were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Prior to the start of treatment and on Days 5, 12, 19 and 26
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / behavioural assessments: Gait, Hyper/Hypothermia, Tremors, Skin colour, Twitches, Respiration, Convulsions, Palpebral closure, Bizarre/Abnormal/Stereotypic behaviour, Urination, Salivation, Defecation, Pilo-erection, Transfer arousal, Exophthalmia, Tail elevation, Lachrymation
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- Haematological, blood chemical, organ weight (absolute and relative to terminal bodyweight), weekly bodyweight gain and quantitative functional performance and sensory reactivity data were assessed for dose response relationships by linear regression analysis, followed by one way analysis of variance (ANOVA) incorporating Levene’s test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett’s test. Where Levene’s test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney ‘U’ test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 1000 mg/kg/day showed increased salivation up to ten minutes after dosing from Day 6 onwards and on one occasion, one female up to one hour after dosing on Day 21. Observations of this nature are often reported following oral administration of an unpalatable or slightly irritant test material formulation and, in isolation, are not indicative of systemic toxicity. Males treated with 1000 mg/kg/day showed generalised fur loss from Day 9 onwards. This finding is occasionally seen in laboratory maintained rats and in isolation can be regarded as incidental. One female treated with 1000 mg/kg/day had a damaged tail tip from Day 12 onwards. This was a physical injury and was considered unrelated to test material toxicity.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A reduction in bodyweight gain was detected for 1000 or 400 mg/kg/day males during weeks 1, 2 and 3 with statistical significance being achieved during weeks 1 and 2. Females treated with 1000 mg/kg/day showed a statistically significant reduction in bodyweight gain during week 1 only. Males treated with 150 mg/kg/day showed a statistically significant reduction in bodyweight gain during week 2 only. The dose response was unconvincing and in isolation, was considered of no toxicological importance.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 1000 mg/kg/day showed a reduction in food consumption during weeks 2 and 3 and also for females during week 4. Males treated with 400 mg/kg/day showed a reduction in food consumption during week 2 whilst females showed a reduction in food consumption during weeks 3 and 4.
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- Food efficiency (the ratio of bodyweight gain to dietary intake) for animals of either sex treated with 1000 mg/kg/day was slightly reduced during week 1 and also during weeks 2 and 3 for males.
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 1000 mg/kg/day showed evidence of a mild anaemia, which was haemolytic in nature, with statistically significant reductions for females in haemoglobin, haematocrit and erythrocyte count. Reductions were also evident for males but statistical significance was only achieved in erythrocyte count. Males from this treatment group also showed statistically significant increases in platelet count, mean corpuscular haemoglobin and mean corpuscular volume. The anaemic condition extended to the 400 mg/kg/day dose group with reductions in erythrocyte count, haemoglobin and haematocrit evident in females and increases in mean corpuscular haemoglobin and mean corpuscular volume evident in males.
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males treated with 1000 mg/kg/day showed a statistical significant increase in relative spleen weight compared with controls. No such effects were detected in 1000 mg/kg/day females or animals of either sex treated with 400 or 150 mg/kg/day. Animals of either sex from all treatment groups showed a statistically significant reduction in absolute heart weight. Males from all treatment groups showed a statistically significant reduction in liver weight whilst females from all treatment groups also showed a statistically significant reduction in absolute ovary and thymus weight. The dose response was unconvincing and in the absence of any histopathological correlates, the intergroup differences were considered to be of no toxicological importance. Animals of either sex treated with 1000 mg/kg/day and males treated with 400 mg/kg/day showed a statistically significant reduction in absolute kidney weight. In the absence of a similar effect for relative organ weights or any histopathological correlates, the intergroup differences were considered not to be toxicologically significant.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One female treated with 1000 mg/kg/day and one male treated with 150 mg/kg/day incurred damage to an eye upon removal at necropsy. This was a physical injury that occurred after termination and was considered unrelated to test material toxicity. Males treated with 1000 mg/kg/day showed fur loss at necropsy. This finding is occasionally seen in laboratory maintained rats and was considered unrelated to test material toxicity.
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- SPLEEN: Marginally higher grades of severity of extramedullary haemopoiesis were observed in the spleen of males treated with 1000 or 400 mg/kg/day. All remaining morphological changes were those commonly observed in laboratory maintained rats of the age and strain employed, and there were no differences in incidence or severity between control and treatment groups that were considered to be of toxicological significance.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 400 mg/kg bw/day (nominal)
- System:
- haematopoietic
- Organ:
- blood
- spleen
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Relevant for humans:
- yes
Any other information on results incl. tables
Table 2: Selected haematology, clinical chemistry and histopathological findings
Doses (mg/kg bw) |
0 |
150 |
400 |
1000 |
0 |
150 |
400 |
1000 |
male |
female |
|||||||
Number of animals/group |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Haematology(day 28) |
|
|
|
|
|
|
|
|
- Hb (g/dL) |
15.0 ± 0.6 |
15.1 ± 0.7 |
14.9 ± 0.5 |
14.2 ± 0.6 |
15 ± 0.4 |
14.1 ± 0.5 |
13.5** ± 0.7 |
13.8** ± 0.4 |
- RBC (TERA/L) |
7.33±0.29 |
7.16± 0.29 |
6.89± 0.49 |
6.42**± 0.44 |
7.41 ± 0.3 |
6.91* ± 0.35 |
6.45***± 0.25 |
6.72** ± 0.24 |
- HCT (L/L) |
42.3± 1.9 |
42.7± 1.5 |
42.0± 2.1 |
39.7± 1.7 |
42.1 ± 1.1 |
39.6 ± 1.6 |
37.4***± 1.7 |
38.8** ± 1.1 |
- MCH (pg) |
20.4± 0.2 |
21.1± 0.2 |
21.6*± 0.9 |
22.2**± 0.8 |
20.3 ± 0.5 |
20.4 ± 0.5 |
20.9 ± 0.5 |
20.6 ± 0.7 |
- MCV (FL) |
58± 1 |
60± 1 |
61**± 2 |
62***± 2 |
57 ± 2 |
58 ± 1 |
58 ± 1 |
58 ± 2 |
- MCHC (g/dL) |
35.4± 0.6 |
35.4± 0.4 |
35.4± 0.6 |
35.9± 0.6 |
35.7 ± 0.1 |
35.6 ± 0.3 |
36.1 ± 0.4 |
35.7 ± 0.2 |
- WBC (GIGA/L) |
10.2± 1.0 |
7.4± 1.7 |
7.9± 2.3 |
7.9± 1.4 |
9.2 ± 2.9 |
7.8 ± 2 |
7.5 ± 1.6 |
7.7 ± 3.8 |
- Retics |
5.5± 0.4 |
2.5± 1.4 |
5.6± 0.4 |
5.2± 0.9 |
5.1 ± 0.7 |
2.5 ± 1.1 |
2.5 ± 1.1 |
4.2 ± 0.9 |
- Neutr |
1.76 ± 0.78 |
1.13 ± 0.27 |
1.06 ± 0.35 |
1.09 ± 0.16 |
1.24 ± 0.54 |
1.22 ± 0.61 |
0.51 ± 0.24 |
0.64 ± 0.27 |
- Lymph |
8.38 ± 0.58 |
6.24 ± 1.50 |
6.83 ± 2.09 |
6.75 ± 1.36 |
7.88 ± 2.38 |
6.51 ± 1.49 |
6.96 ± 1.53 |
7.03 ± 3.79 |
- Mono |
0 ± 0 |
0 ± 0 |
0.02 ±0.04 |
0 ± 0 |
0 ± 0 |
0 ± 0 |
0.02 ±0.04 |
0 ± 0 |
- Eos |
0.04 ± 0.09 |
0.07 ± 0.07 |
0.04 ± 0.04 |
0.09 ± 0.09 |
0.04 ± 0.06 |
0.09 ± 0.06 |
0.07 ± 0.10 |
0.05 ± 0.07 |
- Bas |
0 ± 0 |
0 ± 0 |
0 ± 0 |
0 ± 0 |
0 ± 0 |
0 ± 0 |
0 ± 0 |
0 ± 0 |
- CT (secs) |
17.6± 0.6 |
17.9± 0.6 |
19± 0.6 |
18.4± 0.6 |
20.2 ± 1.5 |
19.2 ± 3.1 |
18.8 ± 2.3 |
19.1 ± 3.4 |
- PLT (GIGA/L) |
780± 0.6 |
879± 0.6 |
837± 0.6 |
1016*± 0.6 |
819 ± 83 |
900 ± 73 |
927 ± 102 |
883 ± 126 |
APTT (secs) |
13.5± 0.6 |
13.4± 0.6 |
12.7± 0.6 |
14.1± 0.6 |
13.9 ± 0.4 |
13.1 ± 1.5 |
14 ± 1.7 |
13.5 ± 1.8 |
Blood chemistry(day x) |
|
|
|
|
|
|
|
|
- sodium (MMOL/L) |
147 ± 1 |
146 ± 2 |
147 ± 2 |
146 ± 2 |
148 ± 2 |
148 ± 2 |
147 ± 2 |
148 ± 1 |
- potassium (MMOL/L) |
5.04 ± 0.19 |
4.81 ± 0.30 |
5.07 ± 0.13 |
5.17 ± 0.30 |
5.00 ± 0.44 |
4.92 ± 0.21 |
4.98 ± 0.24 |
4.97 ± 0.24 |
- chloride (MMOL/L) |
106 ± 1 |
105 ± 1 |
105 ± 1 |
105 ± 2 |
108 ± 2 |
110 ± 3 |
108 ± 1 |
108 ± 1 |
- Albumin (G/dL) |
4.42 ± 0.11 |
4.58 ± 0.27 |
4.48 ± 0.15 |
4.61 ± 0.25 |
4.56 ± 0.15 |
4.41 ± 0.26 |
4.34 ± 0.36 |
4.51 ± 0.25 |
- cholesterol (MMOL/L) |
61 ± 8 |
63 ± 8 |
64 ± 12 |
58 ± 9 |
62 ± 7 |
61 ± 8 |
69 ± 20 |
62 ± 12 |
- Bili (mg/dL) |
0.06 ± 0.02 |
0.09 ± 0.04 |
0.09 ± 0.01 |
0.08 ± 0.03 |
0.07 ± 0.02 |
0.07 ± 0.03 |
0.08 ± 0.02 |
0.11 ± 0.02 |
Histopathological findings |
|
|
|
|
|
|
|
|
Bone marrow |
|
|
|
|
|
|
|
|
- Adipose infiltration |
4/5 minimal, 1/5 slight |
5/5 no data |
5/5 no data |
5/5 minimal |
4/5 minimal, 1/5 slight |
5/5 no data |
5/5 no data |
5/5 minimal |
Heart |
|
|
|
|
|
|
|
|
- Focal myocarditis |
5/5 absent |
5/5 no data |
5/5 no data |
4/5 absent; 1/5 minimal |
4/5 absent, 1/5 minimal |
5/5 no data |
5/5 no data |
4/5 absent, 1/5 minimal |
Kidneys |
|
|
|
|
|
|
|
|
- Groups of basophilic tubules |
2/5 absent, 3/5 minimal |
5/5 no data |
5/5 no data |
4/5 absent, 1/5 minimal |
5/5 absent |
5/5 no data |
5/5 no data |
4/5 absent, 1/5 minimal |
- Hydronephrosis |
4/5 absent, 1/5 minimal |
5/5 no data |
5/5 no data |
5/5 minimal |
|
|
|
|
Spleen |
|
|
|
|
|
|
|
|
- Extramedullary haemopoiesis |
5/5 no data |
5/5 no data |
|
2/5 minimal, 2/5 slight, 1/5 moderate |
5/5 minimal |
5/5 minimal |
5/5 minimal |
5/5 minimal |
Statistics: Anova; Levene’s test or Mann-Whitney ‘U’ test
* = significantly different from control group p <0.05
** significantly different from control group p <0.01
*** significantly different from control group p <0.001
Applicant's summary and conclusion
- Conclusions:
- In the present study conducted according to OECD guideline 407 male and female Wistar rats were administered 0, 150, 400 and 1000 mg/kg bw 5-Fluorocytosine for 28 consecutive days. Adverse effects were observed for the 400 and 1000 mg/kg bw groups, consisting of haematological changes, changes in organ weights and histopathological changes of the spleen, thus the NOAEL was determined to be 150 mg/kg bw.
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