Furfuryl alcohol

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

09 December 2014 - 2016

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: JMAFFF, 12 Nousan No. 8147, 2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Furfuryl alcohol

EC Number:

202-626-1

EC Name:

Furfuryl alcohol

Cas Number:

98-00-0

Molecular formula:

C5H6O2

IUPAC Name:

(furan-2-yl)methanol

Test material form:

gas under pressure: refrigerated liquefied gas

Details on test material:

- Name of test material (as cited in study report): Furfuryl Alcohol
- Alternative names: 2-Furyl methanol, 2-Hydroymethyl furan
- Physical state: Liquid
- Analytical purity: 99.0%
- Lot/batch No.: 141223 A-unit
- Expiration date of the lot/batch: 23 March 2015
- Storage condition of test material: Refrigerated (2-8°C), stored in the dark
- Other: Boiling point: 171°C at 760 mmHg; Estimated saturated vapour concentration: 2.1 mg/L at 20°C

Test animals

Species:

rat

Strain:

other: RccHan:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan (UK) Ltd
- Age at study initiation: 9-10 weeks old
- Weight at study initiation: 257 - 381g (males), 176 - 214g (females)
- Fasting period before study: None
- Housing: 5 / cage (sexes separately).
- Diet: Harlan Teklad 2014C diet , ad libitum in the home cage.
- Water: potable water from the public supply, via water bottles, ad libitum in the home cage.
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 40-70%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: To: 08 January 2015 - 10 March 2015

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass vapouriser and flow-through snout-only exposure chamber
- Exposure chamber volume: not reported
- Method of holding animals in test chamber: Polycarbonate restraint tubes
- Source and rate of air: In-house compressed air system (breathing quality), 19 L/minute for Groups 1 and 2, 39 L/minute for Groups 3 and 4.
- Method of conditioning air:
- System of generating vapour: Glass vapouriser situated in a water-bath maintained at approximtaely 65-70°C.The test substance was supplied to the vaporiser, via a Polyethylene feed line, from a syringe (All Plastic) driven at a constant rate by a syringe pump (Harvard)
- Treatment of exhaust air: Filtered locally, drawn by in-house vacuum system
- Temperature, humidity, pressure in air chamber: Chamber temperature recorded every 30 minutes.

TEST ATMOSPHERE
- Brief description of analytical method used: Vapour samples collected using glass-sintered sampling traps followed by UPLC analysis.
- Samples taken from breathing zone: yes
- Nominal vapour concentration: Calculated from the test material usage, the duration of generation and the system airflow.
- Generation efficiencies: Calculated by nominal and achieved vapour concentrations

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Target vapour concentrations: 1.0 mg/L (preliminary test); 1.0, 1.2 or 1.5 mg/L (main study)
Achieved vapour concentrations: 1.19 mg/L (preliminary test); 0.842, 1.15 or 1.54 mg/L (main study)

No. of animals per sex per dose:

Preliminary test: 1/sex
Main study : 5/sex/group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Day 1 - immediately before the start of exposure, at hourly intervals during exposure, immediately after exposure and at 1-2 hours after exposure. Days 2-14 - twice daily and on day 15.
- Frequency of weighing: Day 1 (prior to exposure), days 2, 4, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: Macroscopic examination of the cranial, thoracic and abdominal cavities, tissues were discarded.

Statistics:

Analysis was by logistic regression on log dose.
Confidence intervals were calculated using the profile likelihood method

Results and discussion

Preliminary study:

At the mean achieved vapour concentration of 1.19 mg/L there were no mortalities. Clinical observations after exposure included wet rales in both animals and unsteady gait, partially closed eyelids and laboured breathing in the female. Both animals improved and survived until termination on day 8.

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1.35 mg/L air (analytical)

Based on:

test mat.

95% CL:

1.18 - 1.64

Exp. duration:

4 h

Effect levels 2

Sex:

male

Dose descriptor:

LC50

Effect level:

1.18 mg/L air (analytical)

Based on:

test mat.

95% CL:

0.943 - 1.52

Exp. duration:

4 h

Effect levels 3

Sex:

female

Dose descriptor:

LC50

Effect level:

1.48 mg/L air (analytical)

Based on:

test mat.

95% CL:

1.32 - 1.99

Exp. duration:

4 h

Mortality:

1.54 mg/L: Seven out of ten animals died or were killed (due to the severity of clinical signs) on day 1 immediately after exposure or within 1 hour after exposure (4/5 males and 3/5 females).
1.15 mg/L: Three out of ten animals (3/5 males) were killed (due to the severity of clinical signs) on day 9 .

Clinical signs:

other: 1.54 mg/L: During exposure, shallow breathing was observed in 1 female. Immediately after exposure, 3 males died and one female was unresponsive, abnormally cold to touch with a flattened, prostrate posture, reduced body tone and respiratory signs (wet r

Body weight:

1.54 mg/L: Surviving animals (1 male and 2 females) lost weight on days 2 and 4 and overall body weight gain (days 1-15) was reduced by 10g for the male.
1.15 mg/L: Body weight losses were observed in surviving males and all females until day 9. Although animals gained weight thereafter, overall body weight gain (days 1-15) remained below the day 1 weights in males and females.
0.842 mg/L: Body weight losses were observed up to day 4 for all animals. After day 4, all animals gained weight although overall body weight gain (days 1-15) remained below the day 1 weights for males.

Gross pathology:

1.54 mg/L: Distended GI tract, dark areas in the lungs or urinary bladder, were observed in some animals which died or were killed due to clinical signs. Distension in the GI tract was observed in 1 female killed on day 15.
1.15 mg/L : Thin appearance, dark areas in the skin or subcutis, skeletal muscle, were observed in animals which died or were killed due to clinical signs. Dark, dry and scabby tails were observed in the majority of males killed due to clinical signs. Scabs on the tail or hindpaws were noted in 2 males killed on day 15.
0.842 mg/L: no macroscopic abnormalities.

Any other information on results incl. tables

Table 1: Chamber Atmosphere Concentrations

Group	Phase	Vapour Concentration (mg/L)
		Target	Mean
1	Preliminary	1.0	1.19
2	Main	1.5	1.54
3		1.0	0.842
4		1.2	1.15

Applicant's summary and conclusion

Executive summary:

In an acute inhalation toxicity study in rats, three groups of 5 males and 5 females were exposed for a single 4-hour period to mean achieved vapour concentrations of 1.54, 1.15 or 0.842 mg/L furfuryl alcohol, followed by a 14-day observation period. A preliminary 4- hour exposure to a mean achieved vapour concentration of 1.19 mg/L furfuryl alcohol was conducted in 1 male and 1 female followed by a 7 day observation period. 

At 1.54 mg/L, there were 7/10 mortalities. Shallow breathing was observed in 1 female during exposure. Immediately after exposure, 3 males died and one female was unresponsive, abnormally cold to touch with a flattened, prostrate posture, reduced body tone and respiratory signs (wet rales, slow breathing and gasping). This female died approximately 1 hour after exposure. One other male and two females showed similar clinical signs and were killed for welfare reasons. The remaining 3 animals showed similar, though less severe, clinical signs but they improved over the 14 day observations period, although dry rales persisted until day 15.

At 1.15 mg/L, there were 3/10 mortalities. Slow breathing were seen in all animals during exposure. After exposure, all animals had an elevated posture, wet rales and slow breathing. In females, slow breathing persisted until day 8 and wet or dry rales continued until day 15. For males, slow breathing and wet or dry rales persisted from day 1. From day 7, the clinical condition of males declined and 3 males were killed, due to clinical signs, on day 9. The remaining two males improved slightly from days 9 to 15.

At 0.842 mg/L, there were no mortalities. Clinical signs after exposure were of dry or wet rales, irregular breathing, decreased activity, hunched posture, piloerection. Some animals were gasping on day 2. Clinical signs improved thereafter and all animals were clinically normal from day 12. At necropsy, treatment related changes were present in the lungs (dark areas) and gastro-intestinal tract (distension) of animals which died or were killed due to clinical signs. 

Distension of the GI tract was observed in 1 female at 1.54 mg/L which survived to scheduled termination, otherwise there were no macroscopic abnormalities in animals at the end of the 14-day observation period.

From the distribution of treatment related mortalities, the 4- hour acute inhalation LC50 was calculated to be 1.35 mg/L furfuryl alcohol, with confidence intervals of 1.18 to 1.64 mg/L (combined sexes).