Furfuryl alcohol

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP status not reported but modified guideline study. Pre-publication for inclusion in peer reviewed literature. Fully adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Evaluation of furfuryl alcohol sensitisation potential following dermal and pulmonary exposure: Enhancement of airway responsiveness

Author:

Franko J et al

Year:

2012

Bibliographic source:

Toxicol. Sci. (2012) 125 (1): 105-115

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Deviations:

not specified

Remarks:

as per the method described in the ICCVAM Peer Review Panel report (NIEHS, 1999) with minor modifications.

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.2600 (Skin Sensitisation)

Deviations:

not specified

Test guideline 3

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)

Deviations:

not specified

Principles of method if other than guideline:

A combined irritancy local lymph node assay (LLNA).

GLP compliance:

not specified

Type of study:

mouse local lymph node assay (LLNA)

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
- Other: No further details reported

In vivo test system

Test animals

Species:

mouse

Strain:

Balb/c

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms (German, NY)
- Age: Purchased at 6-8 weeks
- Weight at study initiation:
- Housing: 5 per cage in ventilated plastic shoebox cages with hardwood chip bedding
- Diet (e.g. ad libitum): Ad libitum, NIH-31 modified 6% irradiated
rodent diet (Harlan Teklad)
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 5 days minimum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22.2°C (68 to 72° F)
- Humidity (%): 36 to 57%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hour cycle

IN-LIFE DATES: Not detailed

Study design: in vivo (LLNA)

Vehicle:

other: acetone

Concentration:

10-75%

No. of animals per dose:

5 per dose

Details on study design:

RANGE FINDING TESTS: Done to evaluate the toxicity of furfuryl alcohol following dermal exposure
- Compound solubility: 10-75% in acetone
- Systemic toxicity was evaluated by clinical observation (morbidity or extensive irritation) and changes in bodyweight from pre-exposure to the time of sacrifice. There was no overt dermal toxicity at exposure to 75% furfuryl alcohol; therefore the maximum concentration was used for the dermal studies.
MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: Combined irritancy local lymph node assay (LLNA). According to the method described in the ICCVAM Peer Review Panel report (NIEHS, 1999) with minor modifications.
- Criteria used to consider a positive response: Stimulation indices (SI) were calculated by dividing the mean disintegrations per minute (DPM) per test group by the mean DPM for the vehicle control group. EC3 values (concentration of chemical required to induce a 3-fold increase over the vehicle
control) were calculated based on the equation from Basketter et al. (Basketter et al., 1999).

TREATMENT PREPARATION AND ADMINISTRATION: Mice were exposed (by topical application of 25 μl to the dorsal surface of each ear) to acetone vehicle, increasing concentrations of furfuryl alcohol, or positive control for three consecutive days. On day 6, mice received iv injection via the lateral tail vein with 20 μCi 3H-thymidine (Dupont NEN; specific activity 2 Ci/mmol). Five hours after 3H-thymidine injection, animals were euthanized via CO2 inhalation, and the left and right cervical draining lymph nodes (DLNs) were excised and pooled for each animal. Single cell suspensions were made and incubated overnight in 5% trichloroacetic acid and samples were counted using a Packard Tri-Carb 2500TR liquid scintillation analyzer.

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Statistics:

Homogeneity was confirmed using the Barlett’s Chi Square test. If homogeneous, this was followed by a one way analysis of varience (ANOVA). Where ANOVA showed significance at p < 0.05 or less, the Dunnett’s Multiple Range t test was used to compare treatment groups with the control group. LLNA data were further evaluated by calculating the DPM values of the 3H incorporation from the DLNs of the animals from each group. The data were compared between groups by using SI values calculated from the DPM values of each group. Linear trend analysis was performed to determine if furfuryl alcohol had exposure concentration-related effects for specific endpoints. Differences were considered to be significant if p < 0.01 as compared to vehicle controls.

Results and discussion

Positive control results:

HCA (30%) positive control for the LLNA gave an average SI value of 7.2.

In vivo (LLNA)

Results

Results 1

Parameter:

SI

Remarks on result:

other: The SI values were 1.3; 2.9, 4.3 and 5.9 at 10%, 20%, 50% and 75%, respectively.

Results 2

Parameter:

other: disintegrations per minute (DPM)

Remarks on result:

other: Detail not reported

Any other information on results incl. tables

A significant increase (p < 0.05) in ear swelling (14%) was observed in mice following dermal exposure to 75% furfuryl alcohol, indicative of significant skin irritation. The positive control (2.5%TDI) resulted in a statistically significant increase (66%) in ear swelling 24 hours after final exposure.

The authers report exposure significantly increased the percentage of IgE+B220+ (24.2 ± 5.3 @ 75%) and B220+ cell populations (35.1 ± 1.9 @ 75%) in the DLN at all concentrations tested (25-75%).The absolute number of B220+ cells was significantly higher at all concentrations while the absolute number of IgE+B220+ cell was significantly higher at 75% furfuryl alcohol. Mice exposed to 75% also had a mild but statistically significant increase in serum IgE antibody production (493± 98 ng/ml; p < 0.05) compared to vehicle control (180 ± 65 ng/ml). No changes in organ or body weights were observed in these animals (data not reported). Positive IgE control TDI (2.5%) resulted in significant mean elevations of total IgE (1356 ± 37 ng/ml), IgE+B220+ (38.7 ± 4.6%), and B220+ (41.5 ± 4.5%).

Applicant's summary and conclusion

Interpretation of results:

other: the LLNA indicates weak skin sensitising properties for furfuryl alcohol. Evidence of skin irritation at 75%

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The LLNA indicates that furfuryl alcohol has the potential to induce skin sensitisation. An EC3 value of 25.6% was derived.

Executive summary:

Statistically significant increases in proliferative activity were recorded with 50% and 75% furfuryl alcohol, concentrations that provoked positive responses (SI values of 3 or greater). Only 75% furfuryl alcohol caused significant skin irritation, measured as a function of induced increases in ear thickness. Using the LLNA data the investigators derived an EC3 value of 25.6%, on which basis skin sensitising activity would be categorised as ‘weak’.