Flucytosine

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2004-08-03 to 2004-10-18

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

May 1981

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

1993

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

yes

Test material

Test material information

Constituent 1

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

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8-12 weeks
- Weight at study initiation: 200 g - 350 g
- Fasting period before study: no
- Housing: in group of five animals by sex in solid-floor polypropyleene cages with stainless steel lids, furnished with softwood flakes (Datesand Ltd., Cheshire, UK) and cardboard "fun tunnels" (Datesand ltd., Cheshire, UK)
- Diet (e.g. ad libitum): ad libitum, except for exposure time (EU Rodent Diet 5LF2, BCM IPS Limited, London, UK)
- Water (e.g. ad libitum): ad libitum, except for exposure time
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

clean air

Mass median aerodynamic diameter (MMAD):

5.5 µm

Geometric standard deviation (GSD):

2.79

Remark on MMAD/GSD:

Inhalable fraction [% < 4 µm]: 37.7

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposure chamber (ADG Developments Ltd, Hitchin, Herts, UK)
- Exposure chamber volume: 30 L
- Method of holding animals in test chamber: individually, in a tapered, polycarbonate restraining tube fitted onto a tier of the exposure chamber and sealed by means of a rubber ‘O’ ring. Only the nose of each animal was exposed to the test atmosphere.
- System of generating particulates/aerosols: SAG 419 Solid Aerosol Generator
- Method of particle size determination: Samples were collected from the chamber, the samples and the back up filter were weighed before and after sampling and the weight of the sample was determined by calculating the difference. The mean amount for each stage was used to determine the cumulative amount below each cut-off point size. In this way, the proportion (%) of aerosol less than 9.3, 6.2, 3.2, 1.6, 1.00 and 0.33 µm was calculated. The resulting values were converted to probits and plotted against Log10 cut-point size.
- Treatment of exhaust air: extracts passed through a "scrubber" trap which is connected with a high efficiency filter to a metered exhaust system.
- Temperature, humidity, pressure in air chamber: 19°C, 31-65%, pressure not specified

TEST ATMOSPHERE
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: see table 1
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 5.50/2.79

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: The concentration used is the maximum attainable.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The test atmosphere was sampled at approximately fifteen minute intervals during the exposure period and the actual concentration of the test material calculated.

Duration of exposure:

4 h

Concentrations:

Nominal concentration: 20.4 mg/L
Mean analytical concentration: 5.17 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: on day of exposure and on day 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: incidence and severity of all abnormalities including behavioural and clinical observations, necropsy findings, bodyweight changes, mortality and any other toxicological effects.

Statistics:

Probit analysis of particle size

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.17 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

not observed

Clinical signs:

other: hunched posture, piloerection, wet fur, increased respiratory rate were commonly seen in animals for short periods on removal from the chamber following 4h inhalation studies. These observations are considered to be associated with the restraint procedure

Body weight:

Variations in bodyweight gain are frequently seen for female animals of this strain and age during this type of study and, in isolation, are considered not to be significant.
One male showed reduced bodyweight gain during week 1 but recovered to show normal development during week 2. Normal development was noted for all other animals.

Gross pathology:

Apart from one instance of dark patches on the lungs, no macroscopic abnormalities were detected amongst animals at necropsy.

Any other information on results incl. tables

Table 1: Particle size distribution             

Impactor Stage number	Cut point (µm)	Mean Amount collected (mg)	Mean cumulative Amount less than cut point [%]
3	9.3	0.78	77.9
4	6.2	0.93	51.6
5	3.2	0.99	23.5
6	1.6	0.57	7.37
7	1.00	0.13	3.68
8	0.33	0.10	0.85
Backup filter	< 0.33	0.03

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

In the present study conducted according to OECD guideline 403 (1981) 5 female and 5 male rats of the Crl:SD strain were exposed to 5.17 mg/L using a nose-only apparatus for 4h. There were no signs of toxicity and thus, 5-fluorocytosine does not need to be classified according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) with regard to acute inhalation toxicity.