2-furaldehyde

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented publication, comparable to guideline study with acceptable restrictions.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2004

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

yes

Remarks:

microscopic examination of kidneys, liver, lungs, spleen, thymus, nose, larynx and trachea only; no measurement of MCV, MCH, MCHC, reticulocytes, globulin.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Furfural (2-furaldehyde)

IUPAC Name:

Furfural (2-furaldehyde)

Constituent 2

Reference substance name:

2-furaldehyde

EC Number:

202-627-7

EC Name:

2-furaldehyde

Cas Number:

98-01-1

Molecular formula:

C5H4O2

IUPAC Name:

2-furaldehyde

Details on test material:

- Name of test material (as cited in study report): furfural
- Physical state: colourless oily liquid with a pungent aromatic odour
- Analytical purity: >=99%
- Other: obtained from Sigma/Aldrich (Brussels, Belgium)

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: young adults
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5/sex/cage in macrolon cages with sterilized bedding (during exposure: individually restrained in Batelle tubes for nose-only exposure)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70%
- Air changes (per hr): 10 changes per hour
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: From: no data To: no data

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

other: nitrogen gas diluted with humidified air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Batelle tubes
- Method of holding animals in test chamber: individually restrained in Batelle tubes, nose-only exposure
- Source and rate of air: 18-34 changes per hour.
- Method of conditioning air: Air was humidified using water kept at 39°C.
- System of generating particulates/aerosols: Nitrogen gas was bubbled through all glass evaporators filled wih furfural and held at 23°C. In the inhalation unit containing the Batelle tubes, this test atmosphere was diluted with humidified compressed air.
- Temperature, humidity, pressure in air chamber: daily mean temperature in range 22.1-22.8°C, standard deviation 0.4°C; daily mean humidity in range 43-44%, standard deviation 2-4%;
- Air flow rate: 15-28 L/min
- Air change rate: 18-34 air changes per hour.
- Method of particle size determination: not relevant
- Treatment of exhaust air: no data
TEST ATMOSPHERE
- Brief description of analytical method used: Furfural concentrations in the test atmosphere were semi-continuously determined by infrared analysis at 9.8 µm using two monitors. Prior to the first exposure, the infrared analysers were calibrated, one for the high levels in the range of 30-1500 mg/m3, the other for the lower concentrations in the range of 30-200 mg/m3 (correlation coefficients >0.996). One day after the last exposure, the integrity of the calibration was approved again.
- Samples taken from breathing zone: no data
VEHICLE (if applicable)
- Justification for use and choice of vehicle: no data
- Composition of vehicle: nitrogen gas
- Type and concentration of dispersant aid (if powder): not relevant
- Concentration of test material in vehicle: no data (not relevant)
- Lot/batch no. of vehicle (if required): no data
- Purity of vehicle: no data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Furfural concentrations in the test atmosphere were semi-continuously determined by infrared analysis at 9.8 µm using two monitors. Prior to the first exposure, the infrared analysers were calibrated, one for the high levels in the range of 30-1500 mg/m3, the other for the lower concentrations in the range of 30-200 mg/m3 (correlation coefficients >0.996). One day after the last exposure, the integrity of the calibration was approved again.
The mean (standard deviation) measured concentrations of furfural were 20(1), 41(1), 80(3), 158(3), 316(8) mg/m3 for the 6-h exposure groups (target concentrations of 20, 40, 80, 160 and 320 mg/m3 respectively) and 157(4), 314(1) and 635(24) mg/m3 for the 3-h exposure groups (target concentrations of 160, 320 and 640 mg/m3 respectively).

Duration of treatment / exposure:

28 days

Frequency of treatment:

6 h/day (0, 20, 40, 80, 160, 320, 640 and 1280 mg/m3) or 3 h/day (160, 320, 640 and 1280 mg/m3).

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 20, 40, 80, 160, 320, 640 and 1280 mg/m3 (6 h/day exposure) or 160, 320, 640 and 1280 mg/m3 (3 h/day exposure)
Basis:
nominal conc.

No. of animals per sex per dose:

5 per sex per dose

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: once or twice weekly.
FOOD CONSUMPTION: weekly
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes (parameters according to OECD 412, exception: MCV, MCH, MCHC, reticulocytes not measured))
- Time schedule for collection of blood: sacrifice
- Anaesthetic used for blood collection: no data
- Animals fasted: Yes
- How many animals: all surviving animals
CLINICAL CHEMISTRY: yes (parameters according to OECD 412, exception: globulin not measured)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (weighing of liver, kidneys, adrenals, brain, heart, spleen, thymus, testes, lungs)
HISTOPATHOLOGY: Yes (from weighed organs and complete respiratory tract).

Statistics:

Body weight data using one way analysis of covariance using pre-exposure weights as covariate. Organ weights and haematological and clinico-chemical data using one way analysis of variance. If significant differences among the means were indicated, this was followed by Dunnett’s test. Relative differential WBC counts by Kruskall-Wallis ANOVA followed by Mann-Whitney U-test. Incidence of histopathological changes by Fisher’s exact test. All comparisons were two-tailed, significance was tested at the 5% level.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

See below under "Details on results".

Mortality:

mortality observed, treatment-related

Description (incidence):

See below under "Details on results".

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Statement only, no tabulated data shown.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Statement only, no tabulated data shown.

Food efficiency:

no effects observed

Description (incidence and severity):

Statement only, no tabulated data shown.

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

Statement only, no tabulated data shown.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Statement only, no tabulated data shown. Publication stated: except perhaps the small increase in organic phosphate in females exposed to 320 mg/m3 for 6 h/day.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

See below under "Details on results".

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

See below under "Details on results".

Histopathological findings: neoplastic:

no effects observed

Details on results:

Mortality: At the end of the first exposure day, all animals exposed to 1280 mg/m3 were found dead. Up to day 8, five animals of the 640 mg/m3 group (6 h/day exposure) were found dead, and exposure of this group was discontinued. No other mortalities occurred.

Clinical signs: during exposure breathing abnormalities (i.e. decreased breathing frequency) at 80 mg/m3 and higher. No other clinical signs were observed.

Organ weights: Increased absolute and relative liver weights (statistically significant) were observed in males at 80 mg/m3 for the 6-h/day exposure. Increased relative spleen weights (statistically significant) were observed in males at 80 mg/m3 for the 6-h/day exposure, and decreased relative spleen weights (statistically significant) in females at 320 mg/m3 for the 3-hour exposure. These changes are considered to be due to biological variation, in the absence of a dose-relationship and/or a relationship with the duration of exposure. Decreased absolute and relative liver weights were observed in females at 160, 320 and 640 mg/m3 for the 3 h/day exposure (statistically significant except for absolute liver weights at 320 mg/m3). No dose-relationship existed, however, in the range 160-640 mg/m3 for the 3 h/day exposure, and there were no changes in absolute and relative liver weights at 160 and 320 mg/m3 for the 6 h/day exposure. Therefore these changes are also considered to be fortuitous and unrelated to the treatment.

Histopathology: Microscopic examination of the preserved organs revealed treatment-related changes in the nasal passages only. The histopathological changes observed consisted of respiratory epithelial lesions such as squamous metaplasia and atypical hyperplasia, and olfactory epithelial changes characterised by epithelial disarrangement. The histopathological changes observed in the respiratory epithelium were seen in all 6 h/day exposure groups (at 20 mg/m3 and higher) whereas the olfactory epithelial disarrangement was seen at 80 mg/m3 and above. In addition, at the exposure concentrations of 20 and 40 mg/m3, the transitional epithelium located in the anterior part of the nose was affected in all exposed animals, whereas the lining epithelium more posterior in the nose was affected in one or two animals of these groups only. At 80 mg/m3 and above, exposure related changes of the lining epithelium more posterior in the nose were seen at a higher incidence and degree. Similar lesions were observed in animals exposed for 3 h/day, however at a lower incidence and degree when compared to animals exposed for 6 h/day at half the concentration.

Effect levels

1

Dose descriptor:

NOAEC

Remarks:

systemic (6 h/day exposure)

Effect level:

320 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: mortality at 640 mg/m3

2

Dose descriptor:

NOAEC

Remarks:

local effects

Effect level:

< 20 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: histopathological changes in the nasal passage.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

For the 6-h/day exposure, the only treatment-related systemic finding was mortality at 640 mg/m3 and above. The histopathological findings are considered to be local and not systemic effects. Based on this, the NOAEC for systemic effects for the 6 h/day exposure was 320 mg/m3 (LOAEC 640 mg/m3 based on mortality). The NOAEC for local effects for the 6 h/day exposure was <20 mg/m3 (LOAEC 20 mg/m3) based on metaplasia and atypical hyperplasia of the transitional respiratory epithelium in the anterior part of the nose, and epithelial disarrangement of the olfactory epithelium.
The systemic NOAEC for the 3 h/day exposure was 640 mg/m3 (LOAEC 1280 mg/m3). The endpoints from the 3 h/day exposure are not considered to be appropriate endpoints, since OECD 412 prescribes a 6 hour/day exposure.