Furfuryl alcohol

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19/20 december 1988- 20/21 march 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Near guideline, GLP study, minor restrictions in study design and/or reporting.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1999

Report date:

1999

Reference 2

Reference Type:

other: cited in NTP (1999)

Title:

Unnamed

Year:

1997

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)

Deviations:

yes

GLP compliance:

yes

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

Details on test material:

- Name of test material (as cited in study report): Furfuryl alcohol
- Physical state: a clear yellow liquid
- Analytical purity: greater than 98%
- Supplier: QO Chemicals, Inc.(Memphis, TN)
- Impurities (identity and concentrations):Gas chromatography by two systems indicated one major peak and five impurities with areas greater than 0.1% relative to the major peak area; the combined impurity peak areas were 1.36% by one system and 1.17% by the second system
- Lot/batch No.: 7B19M-2
- Stability under test conditions: stable
- Storage condition of test material: under a nitrogen blanket at approx -20C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simenson Laboratories (Gilroy, CA)
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: group mean body weights: Male 98-102 g; female 91-96 g
- Fasting period before study: None
- Housing: Individually in stainless steel cages
- Diet: NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum except during exposure periods
- Water: tap water ad libitum
- Acclimation period: 12 to 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23.6-34.1C
- Humidity (%): Mean relative humidity: 55%-56%
- Air changes (per hr): 15/hr
- Photoperiod: 12hrs dark /12 hrs light

IN-LIFE DATES: From: 19 December 1988 To: 21 March 1989

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: not applicable

Details on inhalation exposure:

Furfuryl alcohol was pumped into the top of a glass evaporation column filled with glass beads. A heated nitrogen stream entered the column from below, vaporized the furfuryl alcohol, and carried it to a heated condenser column. The evaporation column was heated by wrapping with heat tape; additional heated nitrogen was added to the furfuryl alcohol vapor leaving the evaporation column to dilute the vapor.
No mixing chamber was used; the vapor was drawn through a heated line and then mixed with heated air at the entrance of a short vapor distribution manifold. An automatic controller maintained constant flow in the distribution manifold.

From the distribution manifold, individual temperature-exposure chamber. The study laboratory designed the inhalation exposure chamber so that uniform vapor concentrations could be maintained throughout the chamber with the catch pans in place. A small particle detector (Type CN, Gardner Associates, Schenectady, NY) was used with and without animals in the exposure controlled delivery lines carried the vapor to each chambers to ensure that furfuryl alcohol vapor, and not aerosol, was produced. The minimum resolvable level of the detector is approximately 200 particles per cubic centimeter. The chambers had concentrations below the limit of detection.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The chamber concentrations of furfuryl alcohol were monitored by a Hewlett-Packard Model 5890 on-line gas chromatograph. Samples were drawn through a 12-port stream select valve. The monitoring system was calibrated against a gravimetrically prepared standard of furfuryl alcohol in nitrogen. Additionally, the on-line monitor was calibrated by a comparison of chamber concentration data to grab samples analyzed by an off-line gas chromatograph. The operation of the chambermonitor was checked throughout the day against an on-line standard. The grab samples were collected in bubblers containing dimethylformamide and analyzed by an off-line gas chromatograph. The off-line gas chromatograph was calibrated with gravimetrically prepared furfuryl alcohol standards indimethylformamide. Chamber concentration uniformity was maintained throughout the studies.

The buildup of vapor concentration in the chamber to 90% of its final stable concentration (T90)at the beginning of exposure and the decay of concentration at the end of exposure to 10% were measured with and without animals in the chambers.

Duration of treatment / exposure:

14 weeks

Frequency of treatment:

6 hours per day, 5 days per week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 2, 4, 8, 16 or 32 ppm
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 8, 16, 32, 64 or 128 mg/m3
Basis:
nominal conc.

No. of animals per sex per dose:

20 per sex (10 for toxicity + 10 for special clinical pathology)

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked in table [No.1] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: prior to start and once weekly thereafter

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 3 and 23 (special clinical pathology animals), week 14 (toxicity animals)
- Anaesthetic used for blood collection: Yes 70% CO2/30% air
- Animals fasted: No data
- How many animals: 10/sex/group
- Parameters examined: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte and platelet count; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; total leukocyte count and differentials.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: days 3 and 23 (special clinical pathology animals), week 14 (toxicity animals)
- Anaesthetic used for blood collection: Yes 70% CO2/30% air
- Animals fasted: No data
- How many animals: 10/sex/group
- Parameters examined: urea nitrogen, creatinine, total protein, albumin, globulin, albumin/globulin ratio, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, total bile acid.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Sperm samples were collected from the 0, 2, 8, and 32 ppm groups at the end of the studies and evaluated for sperm count and motility. The left cauda epididymis, left epididymis, and left testis were weighed. Vaginal samples were collected for up to 12 consecutive days prior to the end of the studies and evaluated for the relative frequency of estrous stages and for estrous cycle length.

Sacrifice and pathology:

GROSS PATHOLOGY: No data

ORGAN WEIGHTS: heart, right kidney, liver, lung, right testis, and thymus.

HISTOPATHOLOGY: Yes.
At 0 and 32 ppm the following tissues were examined: gross lesions and tissue masses, adrenal gland, bone and marrow, brain, clitoral gland, esophagus, heart and aorta, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lung, lymph nodes (mandibular, mesenteric, bronchial, mediastinal), mammary gland, thigh muscle, nose, ovary, pancreas, parathyroid gland, pharynx, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis (with epididymis and seminal vesicle), thymus, thyroid gland, trachea, urinary bladder, uterus, and vagina.
In the 2, 4, 8, and 16 ppm groups the nose and gross lesions were examined.

Statistics:

Pairswise comparisons between exposed and control for organ and body weight data (Dunnett, Williams, or Shirly and Dunn multiple comparison).
Jonckheere's test for dose response trends.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

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:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality occured and there were no exposure related clinical findings.

BODY WEIGHT AND WEIGHT GAIN
At 32 ppm, a lower mean body weight gain in females was noted.

HAEMATOLOGY
On day 3, a minimal exposure-related erythrocytosis, evidenced by increases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, occurred in males and females exposed to 4 ppm or greater. The increased circulating red cell mass would be consistent with erythrocytosis of dehydration and would be related to hemoconcentration. The erythrocytosis was transient, and by day 23, hematocrit values, hemoglobin concentrations, and erythrocyte counts of exposed groups were similar to the chamber control values.

CLINICAL CHEMISTRY
On day 3, there was a minimal decrease in the serum alkaline phosphatase activity of 16 and 32 ppm males and females. Jenkins and Robinson (1975) reported that decreased feed consumption can result in decreased serum alkaline phosphatase activity.The clinical pathology data suggest that by day 3 of the study, exposed rats had decreased water and feed consumption, but that this effect was transient.

ORGAN WEIGHTS
Absolute lung and liver weights in females at 32 ppm were small and considered to be associated with the lower body weights.

HISTOPATHOLOGY: NON-NEOPLASTIC
Exposure-related increases in the incidences of squamous metaplasia of the respiratory and transitional epithelium, goblet cell hyperplasia of the respiratory epithelium, and hypertrophy of the respiratory epithelium lining the nasopharyngeal duct were observed in the nose of male and females. The incidences of degeneration, hyperplasia, metaplasia, and surface exudate of the olfactory epithelium generally increased with increasing exposure concentration in males and females. Squamous metaplasia transitional cuboidal epithelium was present at the lowest dose of 2 ppm and higher in males and females, increasing in severity with dose. This finding was present in 9/10 males and 9/10 females at 2 ppm, and in all animals at higher dose levels.

OTHER FINDINGS
Spermatid count and number of spermatid heads per testis were significantly increased in 16 and 32 ppm males. Toxicological relevance of this finding is doubtful. There were no significant differences in vaginal cytology parameters between exposed and chamber control females.

Effect levels

1

Dose descriptor:

NOAEC

Remarks:

systemic effects

Effect level:

16 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: lower body weight gain in females at 32 ppm (128 mg/m3)

2

Dose descriptor:

LOAEC

Remarks:

local effects

Effect level:

2 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: nasal lesions (inflammatory, degenerative and proliferative lesions of respiratory, transitional and olfactory epithelium) at lowest dose tested (2 ppm/ 8mg/m3)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Mean body weight change (g) of rats in the 14 week inhalation study with furfuryl alcohol 

Concentration (ppm)	males			females
	mean body weight (g)			mean body weight (g)
	initial	final	change	initial	final	change
0	102±3	316±7	213±6	96±2	195±4	99±3
2	98±3	315±7	218±6	96±2	194±2	98±2
4	98±2	325±5	227±5	92±2	194±4	101±3
8	99±3	316±5	217±4	93±3	186±4	93±4
16	98±3	302±6	203±5	91±2	187±2	96±2
32	100±2	304±6	204±5	92±2	176±3**	84±3**
** Significantly different (P≤0.01) from the chamber control group by Williams’ or Dunnett’s test Weights and weight changes are given as mean ± standard error.

 

 

Table 2: Incidence of non-neoplastic lesions of the nose in rats in the 14 week inhalation study with furfuryl alcohol 

Finding	concentration (ppm)
	males						females
	0	2	4	8	16	32	0	2	4	8	16	32
number examined	10	10	10	10	10	10	10	10	10	10	10	10
respiratory epithelium, squamous metaplasia	0	0	0	5*	10**	10**	0	0	0	6**	10**	10**
respiratory epithelium, Goblet cell hyperplasia	0	0	0	7**	6**	10**	0	0	0	2	8**	9**
transitional (cuboidal) epithelium, squamous metaplasia	0	9**	10**	10**	10**	10**	0	9**	10**	10**	10**	10**
nasopharyngeal duct, epithelium hypertrophy	0	0	0	2	6**	10**	0	0	0	0	3	9**
olfactory epithelium, degeneration	0	1	4*	9**	10**	10**	0	3	7**	10**	10**	10**
olfactory epithelium, hyperplasia	0	0	1	2	9**	9**	0	0	0	2	5*	10**
olfactory epithelium, metaplasia	0	0	0	0	0	2	0	0	0	0	1	5*
olfactory epithelium, surface exudate	0	0	0	0	6**	7**	0	0	0	2	6**	10**
lamina propia, mixed cell, cellular infiltrate	0	0	0	1	7**	10**	0	2	0	3	8**	6**
* Significantly different (P≤0.05) from the chamber control group by the Fisher exact test ** P≤0.01

 

Applicant's summary and conclusion

Conclusions:

In a 14 week inhalation study in rats the only evidence of systemic toxicity was lower body weight gain in females at 32 ppm (128mg/m3) but local changes were observed in the nasal passages of both sexes at all concentrations tested. The LOAEC for local effects was 2 ppm (equivalent to 8 mg/m3). The NOAEC for systemic effects was 16 ppm (equivalent to 64 mg/m3).

Executive summary:

Groups of 10 male and 10 female rats were exposed to 0, 2, 4, 8, 16 or 32 ppm furfuryl alcohol for 6 hr/day, 5 days per week for 14 weeks. Observations included clinical signs, body weight measurement, clinical pathology, organ weights and histopathology. Additional groups of 10 males and 10 females per group were exposed and used for clinical pathology measurements on days 3 and 23.

There were no mortalities and no adverse treatment related clinical findings. The final mean body weight and body weight gain of females at 32 ppm were lower than control. Transient changes in haematology and clinical chemistry were considered to be of no toxicological significance. Absolute liver and lung weights of 32 ppm females were lower than control reflecting the lower body weight. Histopathological findings were confined to the olfactory, respiratory and transitional epithelium. These changes were seen in males and females in all furfuryl alcohol exposed groups, increased in severity with increasing exposure concentration and are considered to reflect a local effect.

The LOAEC for local effects was 2 ppm (equivalent to 8 mg/m³). The NOAEC for systemic effects was 16 ppm (equivalent to 64 mg/m³), based on lower body weights in females at 32 ppm.