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WHO FOOD ADDITIVES SERIES 46:Furfuryl Alcohol and Related Substances

First draft prepared by
Dr P.J. Abbott
Australia–New Zealand Food Authority, Canberra, Australia

Evaluation

Introduction

Estimated daily intake

Metabolic considerations

Application of the Procedure for the Safety Evaluation of Flavouring Agents

Consideration of combined intakes

Conclusions

Relevant background information

Explanation

Additional considerations on intake

Biological data

Absorption and transformation

Metabolism

Toxicological studies

Acute toxicity

Short-term studies of toxicity and long-term studies of toxicity and carcinogenicity

Genotoxicity

References

1. EVALUATION

1.1 Introduction

The Committee evaluated a group of 15 furfuryl derivatives (Table 1) by the Procedure for the Safety Evaluation of Flavouring agents. The group comprises the parent furfuryl alcohol, the corresponding aldehyde, furfural, five esters formed from furfuryl alcohol and simple aliphatic carboxylic acids, five esters formed from simple aliphatic alcohols and furoic acid, and three structurally related furfuryl derivatives (5-methylfurfural, 2-benzofurancarboxaldehyde, and 2-phenyl-3-carbethoxyfuran). These flavouring agents were grouped on the basis of the criterion that all are hydrolysed and/or metabolized to furoic acid or a substituted furoic acid.

Table 1. Summary of the results of the safety evaluation of furfuryl alcohol and 14 related flavouring agentsa

Flavouring agent

No.

CAS No. and structure

Step B3b
Does intake exceed the threshold for human intake?

Step B4
Adequate NOEL for substance or structurally related substance?

Conclusion based on current intake

Structural class II

Furfuryl alcoholc

451

98-00-0

chemical structure

No
Europe: 210
USA: 24

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 10 000 times the estimated daily intake of furfuryl alcohol when used as a flavouring agent.

No safety concern

Furfuryl acetatec

739

623-17-6

chemical structure

No
Europe: 18
USA: 21

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 100 000 times the estimated daily intake of furfuryl acetate when used as a flavouring agent.

No safety concern

Furfuryl propionatec

740

623-19-8

chemical structure

No
Europe: 2
USA: 5

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 100 000 times the estimated daily intake of furfuryl propionate when used as a flavouring agent.

No safety concern

Furfuryl pentanoatec

741

36701-01-6

chemical structure

No
Europe: 0.3
USA: 14

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 100 000 times the estimated daily intake of furfuryl pentanoate when used as a flavouring agent.

No safety concern

Furfuryl 3-methyl- butanoatec

743

13678-60-9

chemical structure

No
Europe: 0.03
USA: 1

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), the related substance, furfural (Jonker, 2000), furfuryl 3-methylbutanoate when used as a flavouring agent.

No safety concern

Furfuralc

450

98-01-1

chemical structure

No
Europe: 520
USA: 460

Yes. The NOEL of 53 mg/kg bw per day (Jonker, 2000) is > 1000 times the estimated daily intake of furfural when used as a flavouring agent.

No safety concern

5-Methylfurfural

745

620-02-0

chemical structure

No
Europe: 160
USA: 25

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 10 000 times the estimated daily intake of 5-methylfurfural when used as a flavouring agent.

No safety concern

Methyl-2-furoatec

746

611-13-2

chemical structure

No
Europe: 35
USA: 37

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 10 000 times the estimated daily intake of methyl 2-furoate when used as a flavouring agent.

No safety concern

Propyl 2-furoatec

747

615-10-1

chemical structure

No
Europe: N/D
USA: 0.1

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 10 million times the estimated daily intake of propyl 2-furoate when used as a flavouring agent.

No safety concern

Structural class III

Furfuryl octanoatec

742

39252-03-4

chemical structure

No
Europe: 0.01
USA: 6

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 1 000 000 times the estimated daily intake of furfuryl octanoate when used as a flavouring agent.

No safety concern

Amyl 2-furoatec

748

1334-82-3

chemical structure

No
Europe: N/D
USA: 0.1

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 10 million times the estimated daily intake of amyl 2-furoate when used as a flavouring agent.

No safety concern

Hexyl 2-furoatec

749

39251-86-0

chemical structure

No
Europe: N/D
USA: 0.1

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 10 million times the estimated daily intake of hexyl 2-furoate when used as a flavouring agent.

No safety concern

Octyl 2-furoatec

750

39251-88-2

chemical structure

No
Europe: 3
USA: 0.1

Yes. The NOEL of 53 mg/kg bw per day for the related substance, furfural (Jonker, 2000), is > 1 000 000 times the estimated daily intake of octyl 2-furoate when used as a flavouring agent.

No safety concern

2-Benzofurancarbox-aldehyde

751

4265-16-1

chemical structure

No
Europe: N/D
USA: 0.01

Yes. The NOEL of 25 mg/kg bw per day (Posternak et al., 1969) is > 100 million times the estimated daily intake of 2-benzofuran- carboxaldehyde when used as a flavouring agent.

No safety concern

2-Phenyl-3-carbeth- oxyfuran

752

50626-02-3

chemical structure

No
Europe: 0.01
USA: 2

Yes. The NOEL of 13 mg/kg bw per day (Posternak et al., 1969) is > 400 times the estimated daily intake of 2-phenyl-3-carbeth- oxyfuran when used as a flavouring substance.

No safety concern

CAS: Chemical Abstracts Service; N/D: no intake data reported

a Step 2: None of the substances in this group is expected to be metabolized to innocuous products.

b The thresholds for human intake for classes II and III are 540 µg/day and 90 µg/day, respectively. All intake values are expressed in µg/day.

c A group ADI of 0–0.5 mg/kg bw was established by the Committee at its present meeting for furfural, furfuryl alcohol, furfuryl acetate, furfuryl propionate, furfuryl pentanoate, furfuryl octanoate, furfuryl 3-methylbutanoate, methyl 2-furoate, propyl 2-furoate, amyl 2-furoate, hexyl 2-furoate, and octyl 2-furoate (see monograph addendum on furfural, p. 1).

The Committee has evaluated only one member of this group previously, namely furfural (No. 450). Furfural was considered by the Committee at its thirty-ninth and fifty-first meetings (Annex 1, references 101 and 137), but no ADI was established. At its present meeting, the Committee established a group ADI of 0–0.5 mg/kg bw for furfural, furfuryl alcohol, and a number of derivatives of furfuryl alcohol and furoic acid on the basis of a NOEL of 53 mg/kg bw per day in a 13-week study in rats given furfural, with a safety factor of 100 (see monograph addendum on furfural, p. 3).

Seven of the 15 substances have been detected as natural components of foods (Maarse et al., 1994, 1996) including roasted coffee, beer, milk, roasted almonds, white bread, and whisky.

1.2 Estimated daily intake

The total annual volume of production of the 15 substances in this group was reported to be 6600 kg in Europe (International Organization of the Flavor Industry, 1995) and 4500 kg in the USA National Academy of Science, 1989; (Lucas et al., 1999). These values are equivalent to total daily per capita intakes of 940 µg in Europe and 590 µg in the USA. Furfural accounted for approximately 55% of the total per capita intake in Europe (520 µg/day) and 77% of that in the USA (460 µg/day). The annual volumes of use and estimated per capita intake of furfuryl alcohol and 14 related substances are shown in Table 2.

Table 2. Annual volume and estimated per capita intake of furfuryl alcohol and related substances in Europe and the United Statesa

Substance (No.)

Most recent annual volume (kg)a

Intakeb

Consumption ratioc

µg/day

µg/kg bw per day

Furfuryl alcohol (451)

 

 

3800

 

Europe

1438

210

3

 

USA

186

24

0.4

 

Furfuryl acetate (739)

 

 

85

 

Europe

129

18

0.3

 

USA

159

21

0.3

 

Furfuryl propionate (740)

 

 

 

Europe

14

2

0.03

 

USA

37

5

0.1

 

Furfuryl pentanoate (741)

 

 

 

Europe

2

0.3

0.005

 

USA

104

14

0.2

 

Furfuryl octanoate (742)

 

 

 

Europe

0.1

0.01

0.0002

 

USA

45

6

0.1

 

Furfuryl 3-methylbutanoate (743)

 

 

 

Europe

0.2

0.03

0.0005

 

USA

10

1

0.02

 

Furfural (450)

 

 

 

66

Europe

3613

520

9

 

USA

3470

460

8

 

5-Methylfurfural (745)

 

 

750

 

Europe

1120

160

3

 

USA

191

25

0.4

 

Methyl-2-furoate (746)

 

 

3

 

Europe

243

35

0.6

 

USA

279

37

0.6

 

Propyl 2-furoate (747)

 

 

 

Europe

N/D

N/D

N/D

 

USA

0.5

0.1

0.001

 

Amyl 2-furoate (748)

 

 

 

Europe

N/D

N/D

N/D

 

USA

0.5

0.1

0.001

 

Hexyl 2-furoate (749)

 

 

 

Europe

N/D

N/D

N/D

 

USA

0.5

0.1

0.001

 

Octyl 2-furoate (750)

 

 

 

Europe

18

3

0.04

 

USA

0.5

0.1

0.001

 

2-Benzofurancarboxaldehyde (751)

 

 

 

Europe

N/D

N/D

N/D

 

USA

0.1

0.01

0.0002

 

2-Phenyl-3-carbethoxy furan (752)

 

 

 

Europe

0.1

0.01

0.0002

 

USA

13

2

0.03

 

N/D, no intake data reported; –, no quantitative information available on natural occurrence in foods

a From International Organization of the Flavour Industry (1995) and Lucas et al. (1999)

b Intake (µg/person per day) calculated as follows: [(annual volume, kg) ´ (1 ´ 109 µg/kg) / (population ´ survey correction factor ´ 365 days)], where population (10%, ‘eaters only’) = 32 ´ 106 for Europe and 26 ´ 106 for the USA. The correction factor = 0.6 for Europe and 0.8 for the USA, representing the assumption that only 60% and 80% of the annual volume of the flavour, respectively, was reported in the poundage surveys (International Organization of the Flavor Industry, 1995; Lucas et al., 1999). Intake (µg/kg bw per day) calculated as follows: [(µg/person per day)/body weight], where body weight = 60 kg. Slight variations may occur from rounding.

c Calculated as follows: (annual consumption in food, kg)/(most recent reported volume as a flavouring agent, kg)

1.3 Metabolic considerations

Furfuryl esters are hydrolysed to furfuryl alcohol and the corresponding carboxylic acid. Furfuryl alcohol (No. 451) is subsequently oxidized to furfural (No. 450), which is then oxidized to 2-furoic acid. Furoate esters (Nos 746–750) are or are predicted to be hydrolysed directly to 2-furoic acid and the corresponding alcohol. Furoic acid forms a coenzyme A (CoA) thioester, which may be either metabolized to a glycine conjugate that is excreted in urine or condensed with acetyl CoA to form 2-furanacryloyl CoA, which is converted to a glycine conjugate and excreted in urine. The three remaining furfuryl derivatives (Nos 745, 751, and 752) are expected to follow similar metabolic pathways, i.e. ester hydrolysis, oxidation, and glycine conjugation, with side-chain oxidation (No. 745) or aromatic oxidation (Nos 751 and 752). In rodents, a minor pathway has been identified which involves furan ring oxidation to produce carbon dioxide and as yet unidentified metabolites.

1.4 Application of the Procedure for the Safety Evaluation of Flavouring Agents

Step 1.

In applying the Procedure for the Safety Evaluation of Flavouring Agents to the above-mentioned substances, the Committee assigned nine of the 15 substances (Nos 450, 451, 739–741, 743, and 745–747) to structural class II (Cramer et al., 1978). Furfuryl propionate (No. 740) was assigned to this class because it is structurally closely related to furfuryl acetate (No. 739) and furfuryl pentanoate (No. 741). The remaining six substances (Nos 742 and 748–752) were assigned to structural class III.

Step 2.

The data on the metabolism of individual members of the group were sufficient to draw conclusions about their probable metabolic fate. Most (Nos 450, 451, 739–743, and 746–750) are predicted to be metabolized to 2-furoic acid or a 2-furoic acid derivative, which is either conjugated with glycine and excreted in the urine or condensed with acetyl CoA and conjugated with glycine before excretion in the urine. Because of concern about the results of the toxicological studies on furfural in rodents, these substances cannot be predicted to be metabolized to innocuous products. The evaluation of all substances in this group therefore proceeded via the right-hand side of the scheme.

Step B3.

The estimated daily per capita intakes of all 15 substances in this group are below the threshold of concern for the respective structural classes (i.e. 540 µg/day for structural class II and 90 µg/day for structural class III). Accordingly, the evaluation of all 15 substances in the group proceeded to step B4.

Step B4.

For furfural, the NOEL of 53 mg/kg bw per day in a 13-week feeding study in rats (Jonker, 2000) provides an adequate margin of safety (> 1000 times) in relation to the known levels of intake of this substance. This NOEL is also appropriate for furfuryl alcohol (No. 451) and the structurally related substances furfuryl acetate (No. 739), furfuryl propionate (No. 740), furfuryl pentanoate (No. 741), furfuryl octanoate (No. 742), and furfuryl 3-methylbutanoate (No. 743), because all of these esters would be hydrolysed to furfuryl alcohol (No. 451) and then oxidized to furfural (No. 450). The NOEL for furfural is also appropriate for the esters of furoic acid, methyl 2-furoate (No. 746), propyl 2-furoate (No. 747), amyl 2-furoate (No. 748), hexyl 2-furoate (No. 749), and octyl 2-furoate (No. 750), which would be hydrolysed to furoic acid, the major metabolite of furfural. The NOEL for furfural is also appropriate for 5-methylfurfural (No. 745), which would participate in the same metabolic pathways and also undergoes alkyl oxidation. For 2-benzofurancarboxal-dehyde (No. 751), the NOEL of 25 mg/kg bw per day in a 90-day feeding study in rats (Posternak et al., 1969) provides an adequate margin of safety (> 1 000 000 times) in relation to the known levels of intake of this substance. For 2-phenyl-3-carbethoxyfuran (No. 752), the NOEL of 13 mg/kg bw per day in a 90-day feeding study in rats (Posternak et al., 1969) provides an adequate margin of safety (> 1000 times) in relation to the known levels of intake of this substance.

Table 1 summarizes the evaluation of furfuryl alcohol and 14 related substances used as flavouring agents.

1.5 Consideration of combined intakes

In the unlikely event that all foods containing the nine substances in structural class II (together with allyl 2-furoate evaluated previously by the Committee) were consumed concurrently on a daily basis, the estimated combined intake would exceed the threshold for human intake for class II. In the unlikely event that all foods containing the six substances in structural class III were consumed concurrently on a daily basis, the estimated combined intake would exceed the threshold for human intake for class III. Given the wide margin of safety between the level of intake and the NOEL for furfural and the fact that the available detoxication pathways (glycine conjugation or condensation followed by glycine conjugation) would not be saturated at the current levels of intake, the Committee concluded that the combined intake would not raise concern about safety.

1.6 Conclusions

On the basis of the predicted metabolism of these substances and data on their toxicity, the Committee concluded that consumption of furfuryl alcohol and the 14 related substances in this group at the current levels of intake would not raise concern for safety. In applying the Procedure, the Committee noted that all of the available data on toxicity are consistent with the results of the safety evaluation.

2. RELEVANT BACKGROUND INFORMATION

2.1 Explanation

This monograph summaries key data relevant to the evaluation of the 15 flavouring substances in this group, which includes the parent alcohol, furfuryl alcohol, the corresponding aldehyde furfural, five esters formed from furfuryl alcohol and simple aliphatic carboxylic acids, five esters formed from simple aliphatic alcohols and furoic acid, and three structurally related furfuryl derivatives (5-methylfurfural, 2-benzofurancarboxyaldehyde, and 2-phenyl-3-carbethoxyfuran).

2.2 Additional considerations on intake

Seven of the 15 substances have been detected as natural components of foods (Maarse et al., 1994, 1996). Quantitative data on natural occurrence and consumption ratios have been reported for five substances in the group, and these indicate that they are consumed predominantly from traditional foods (i.e. consumption ratio >1) (Stofberg & Kirschman, 1985; Stofberg & Grundschober, 1987; see Table 2).

The daily per capita intake of this group of flavouring agents is 940 µg/day in Europe (16 µg/kg bw per day) and 600 µg/day in the USA (10 µg/kg bw per day). Furfural accounted for approximately 55% of the total per capita intake in Europe (520 µg/day) and 77% in the USA (460 µg/day).

A recent study showed that furfural is formed in vivo during oxidative damage to DNA by hydroxylation of the C5’ repair of deoxyribose (Dix et al., 1996). The oxidized deoxyribose fragment forms furfural, which may react subsequently with adenine bases to produce kinetin (N6-furfuryladenine), which has been found in human DNA (Barciszewski et al., 1996, 1997a,b). The amount of furfural formed by this mechanism would be expected to be extremely small and the substance would be short-lived.

2.3 Biological data

Substances were considered to be members of this group on the basis that all furfuryl alcohol derivatives are hydrolysed and/or metabolized to furoic acid or a substituted furoic acid.

2.3.1 Absorption and transformation

Furfural is converted to furfuryl alcohol by enteric bacteria under both aerobic and anaerobic conditions (Boopathy et al., 1993). Both substances are therefore anticipated to be present in the gastrointestinal tract of animals given furfural. Furfuryl alcohol and furfural are rapidly absorbed in the gastrointestinal tract of rodents (Nomeir et al., 1992). At doses of 0.1–200 mg/kg bw, both are absorbed, metabolized, and excreted, primarily in the urine (Rice, 1972; Nomeir et al., 1992; Parkash & Caldwell, 1994). The results of the studies described below support this conclusion.

When [14C]furfuryl alcohol at doses up to 27.5 mg/kg bw or [14C]furfural at doses up to 12.5 mg/kg bw were administered to rats by gavage in corn oil, 83–89% of the radiolabel was excreted in the urine and 2–4% in the faeces, and 7% was exhaled as 14C-carbon dioxide within 24 h. Residual radiolabel was distributed primarily to the liver and kidneys, the amount generally being proportional to the dose (Nomeir et al., 1992). Similar results were obtained by Parkash & Caldwell (1994) after oral administration of [14C]furfural at doses up to 60 mg/kg bw in rats and up to 200 mg/kg bw in mice.

A similar pattern of absorption, distribution, and excretion was reported for alkyl-substituted furfural derivatives. In rats given [14C]5-methylfurfural at doses up to 500 mg/kg bw by gavage, 70–82% of the administered dose was excreted in urine and 8–13% in faeces within 48 h. In mice given the same dose, a similar pattern of excretion were observed (Godfrey et al., 1999).

2.3.2 Metabolism

In general, furfuryl esters (furfuryl acetate, furfuryl propionate, furfuryl pentanoate, furfuryl octanoate, and furfuryl 3-methylbutanoate) are expected to be hydrolysed to furfuryl alcohol and the corresponding saturated aliphatic carboxylic acid, while furoate esters (methyl 2-furoate, propyl 2-furoate, amyl 2-furoate, hexyl 2-furoate, and octyl 2-furoate) are expected to be hydrolysed to 2-furoic acid and the corresponding saturated aliphatic alcohol. Hydrolysis is catalysed by classes of enzymes recognized as carboxylesterases or esterases (Heymann, 1980), the most important of which are the A-esterases. In mammals, A-esterases occur in most tissues of the body (Heymann, 1980; Anders, 1989), but they predominate in the hepatocytes (Heymann, 1980).

Evidence that hydrolysis may occur in the gastrointestinal tract comes from experiments by Grundschober (1977), who demonstrated that the structurally related substances isoamyl furylpropionate and ethyl furylpropionate were completely hydrolysed within 2 h by pancreatin. Similarly, Paul et al. (1948) showed that the glycine conjugate of furoic acid is the major metabolite in the urine of rats given furfuryl diacetate, furfuryl propionate, or methyl furylacrylate orally. This experiment demonstrates that these esters are hydrolysed in vivo to furfuryl alcohol, the metabolic precursor of furoic acid. The esters of furfuryl and furoate can be predicted to be hydrolysed to the parent alcohol and acid, respectively. Buck (2000) demonstrated rapid hydrolysis of furfuryl alcohol esters by preparations of rat liver, rat intestinal mucosa, and rat blood. While the rate of hydrolysis of these esters was slower in a human blood preparation, it was faster than those for other compounds with sterically hindered ester bonds, such as cinnamyl and linalyl esters.

After hydrolysis of the furfuryl esters, furfuryl alcohol is oxidized to furfural, which is subsequently oxidized to 2-furoic acid (Paul et al., 1948; ; Rice, 1972; Nomeir et al., 1992; Parkash & Caldwell, 1994). The major metabolic detoxication pathway for furoic acid involves formation of a CoA thioester, which is then either conjugated with glycine and excreted in the urine or condensed with acetyl CoA to form the CoA thioester of 2-furanacrylic acid. 2-Furanacryloyl CoA is also conjugated with glycine and excreted primarily in the urine (see Figure 1). A minor metabolic pathway has been reported in rodents whereby carbon dioxide is produced, presumably by furan-ring oxidation (Nomeir et al., 1992; Parkash & Caldwell, 1994).

Figure 1

A number of experiments provide evidence that these pathways exist. In rats, the glycine conjugate of furoic acid was detected in urine collected for 6 h after a single oral dose of 20 mg of furfuryl alcohol, furfural, furoic acid, furfuryl diacetate, furfuryl propionate, furanacylic acid, or methyl furanacrylate (Paul et al., 1948).

Furfuryl alcohol and furfural have been shown to participate in common pathways of detoxication in rodents. In groups of four male Fischer 344 rats, [14C]furfuryl alcohol at oral doses up to 27.5 mg/kg bw or [14C]furfural at 12.5 mg/kg bw were oxidized to furoic acid, which was excreted mainly in the urine, either as the glycine conjugate (73–80%) or free (1–6%). Furoic acid was also condensed with acetyl CoA and excreted in the urine as the glycine conjugate of furanacrylic acid (3–8%). In rats given furfural at 12.5 mg/kg bw, 7% was exhaled as carbon dioxide. Over the dose ranges studied, the extent of metabolism, the relative amounts of metabolites, and the rates of excretion were linear (Nomeir et al., 1992).

Single oral doses of [14C]furfural (0.1, 10, or 60 mg/kg bw) given to male and female Fischer 344 rats or [14C]furfural (1, 20, or 200 mg /kg bw) given to male and female CD-1 mice were metabolized to the glycine conjugates of furoic acid (76–84% in rats and 65–89% in mice) and furanacrylic acid (16–24% in rats and 10–17% in mice) within 24 h. Male mice at the high dose expired < 5% of the radiolabel as [14C]carbon dioxide, but expired radiolabel was not measured in mice at other doses. The absorption, tissue distribution, extent of metabolism, relative amounts of metabolites, including carbon dioxide, and the rates of excretion in rodents were linear over the range of doses investigated (0.1–200 mg/kg bw) (Parkash & Caldwell, 1994).

The condensation of furoic acid with acetyl CoA to yield furanacrylic acid appears to be a dynamic equilibrium favouring the CoA thioester of furoic acid (Parkash & Caldwell, 1994), as suggested by the observation that furoic acid was excreted in the urine of dogs given furanacrylic acid (Friedmann, 1911). An analogous equilibrium was established between other aromatic carboxylic acids (e.g. benzoic acid and cinnamic acid) (Nutley et al., 1994). Excretion of free furoic acid and furanacrylic acid in animals given higher doses suggests that the capacity for glycine conjugation may be limited, probably by the supply of endogenous glycine (Gregus et al., 1993).

In rats, the metabolic fate of 5-methylfurfural is similar to that of furfural. Two urinary metabolites were identified when rats were given an oral dose of an aqueous solution containing 5-methylfurfural at 80, 120, or 160 mg/kg bw. The principal metabolite was the glycine conjugate of 5-methylfuroic acid (> 40%); 5-methylfuryl methyl ketone was a minor metabolite (6.6–7.8%). 5-Methylfuryl methyl ketone was also a urinary metabolite of 5-methylfuroic acid, suggesting that the ketone is formed directly from the acid (Liebert, 1988). In a manner similar to the formation of furan-acrylic acid from furfural, the CoA thioester of 5-methylfuroic acid condenses with acetyl CoA to form an alpha-ketoester which sequentially undergoes hydrolysis and decarboxylation to form 5-methylfuryl methyl ketone. 5-Methylfuryl methyl ketone may be excreted in the urine or reduced to the corresponding alcohol before excretion, in a manner similar to that of structurally related furyl ketones (Boyd et al., 1975).

Groups of male Fischer 344 rats and male B6C3F1 mice were given [14C]-5-methylfurfural at a dose of 5, 10, 100, or 500 mg/kg bw by oral gavage. 5-Hydroxymethyl-2-furoic acid was the major urinary metabolite in both species and accounted for 77–90% of the recovered radiolabel at each dose. The quantity of the glycine conjugate N-(5-hydroxymethyl-2-furoyl)-glycine excreted by rats was inversely proportional to the dose, possibly due to glycine depletion at higher doses. 2,5-Furandicarboxylic acid accounted for only 2–4% of the recovered radiolabel in rats and 4–6% in mice (Godfrey et al., 1999). Similarly, 5-hydroxymethylfurfural administered to rats as single oral doses of 0.08–330 mg/kg bw was excreted mainly as 5-hydroxymethyl-2-furoic acid and to a lesser extent as N-(5-hydroxymethyl-2-furoyl)glycine (Germond et al., 1987).

The formation of labelled carbon dioxide in rats and mice presumably occurs via decarboxylation of furoic acid. No evidence of decarboxylation has been observed in humans (Flek & Sedivec, 1978). Since heteroaromatic and aromatic carboxylic acids do not normally decarboxylate in vivo (Caldwell, 1982), it can be assumed that oxidation of furoic acid in rodents precedes the loss of carbon dioxide. Epoxidation (Ramsdell & Eaton, 1990) or hydroxylation (Ravindranath & Boyd, 1985; Koenig & Andreesen, 1990) of the furan ring may yield reactive intermediates such as furfural-2,3-epoxide, acetylacrolein or alpha-ketoglutaric acid, which are readily decarboxylated. Biochemical changes in the lungs and livers of animals exposed to furfural indicate that ring oxidation may be catalysed by a cytochrome P450b isoenzyme to yield a reactive intermediate such as an epoxide or acylacrolein, which is subsequently conjugated with glutathione (Gupta et al., 1991; Mishra et al., 1991). There is no evidence of ring oxidation in humans at low levels of exposure. Essentially all the furfural absorbed (2 mg/kg bw) by inhalation in a study in humans was excreted in the urine as furoylglycine and furanacrylic acid, and no free furoic acid was found (Flek & Sedivec, 1978).

In summary, the component linear saturated alcohols and carboxylic acids (C1–C8) formed by ester hydrolysis of furfuryl esters and furoic acid esters participate in fatty acid beta-oxidation and the citric acid cycle or in the C1 tetrahydrofolate pathway, eventually to yield carbon dioxide and water (Voet & Voet, 1990). The available data indicate that most of the 15 furfuryl derivatives would be hydrolysed and/or oxidized to yield furoic acid. In humans, furoic acid would be efficiently excreted as either 2-furoylglycine or 2-furanacryloylglycine (2-furanacryluric acid).

2.3.2 Toxicological studies

2.3.2.1 Acute toxicity

LD50 values after oral administration are available for four of the 15 furfuryl derivatives. The values reported in rodents range from 50 mg/kg bw for furfural (Fassett, 1963) to 2200 mg/kg bw for 5-methylfurfural (Moreno, 1978). Most of the values fall between 100 and 250 mg/kg bw (Boyland, 1940; Gajewski & Alsdorf, 1949; Haag et al., 1959; Jenner et al., 1964). In rodents, signs of acute toxicity are seen mainly in the liver, and high doses are associated with hepatic cirrhosis accompanied by sporadic eosinophilic degeneration of hepatic cells. Nuclear pyknosis, eosinophilic necrosis, and increased hepatocyte mitosis have also been reported (Shimizu & Kanisawa, 1986). The changes observed in cytosolic and mitochondrial enzyme activities are indicative of increased hepatocellular catabolism (Jonek et al., 1975; Kaminska, 1977).

2.3.2.2 Short-term and long-term studies of toxicity and carcinogenicity

The results of short-term and long-term studies of the toxicity of the substances in this group are shown in Table 3. Details of the studies that were critical to evaluating the safety of furfuryl alcohol, furfural, 2-benzofurancarboxaldehyde, and 2-phenyl-3-carbethoxy furan are given below.

Table 3. Results of short-term studies of toxicity and long-term studies of toxicity and carcinogenicityon furfuryl alcohol and related substances

No.

Substance

Species, sex

No. test groupsa/ no. per groupb

Route

Duration

NOEL (mg/kg bw per day)

Reference

738

Furfuryl alcohol

Mice; M, F

5/5

Inhalation

16 days

Not identified

National Toxicology Program (1999)

738

Furfuryl alcohol

Mice; M, F

6/10

Inhalation

14 weeks

Not identified

National Toxicology Program (1999)

738

Furfuryl alcohol

Mice; M, F

4/50

Inhalation

105 weeks

Not identified

National Toxicology Program (1999)

738

Furfuryl alcohol

Rats; M, F

5/5

Inhalation

16 days

Not identified

National Toxicology Program (1999)

738

Furfuryl alcohol

Rats; M, F

6/10

Inhalation

14 weeks

Not identified

National Toxicology Program (1999)

738

Furfuryl alcohol

Rats; M, F

4/50

Inhalation

105 weeks

Not identified

National Toxicology Program (1999)

744

Furfural

Mice; M, F

5/10

Gavage

16 days

Not identified

National Toxicology Program (1990)

744

Furfural

Mice; M, F

5/20

Gavage

13 weeks

Not identified

National Toxicology Program (1990)

744

Furfural

Mice; M, F

3/100

Gavage

2 years

Not identified

National Toxicology Program (1990)

744

Furfural

Rats; M, F

5/10

Gavage

16 days

Not identified

National Toxicology Program (1990)

744

Furfural

Rats; ,M, F

5/20

Gavage

13 weeks

Not identified

National Toxicology Program (1990)

744

Furfural

Rats; M, F

2/100

Gavage

2 years

Not identified

National Toxicology Program (1990)

744

Furfural

Rats; M, F

5/5

Diet

14 days

120

Jonker (1998)

744

Furfural

Rats; M, F

4/20

Dietc

13 weeks

60

Jonker (2000)

744

Furfural

Hamsters; M, F

1/70

Intratracheal

36 weeks

Not identified

Feron (1972)

751

2-Benzofuran carboxaldehyde

Rats; M, F

1/32

Diet

90

25 (M)d
27 (F)d

Posternak et al. (1969)

752

2-Phenyl-3-carbethoxy furan

Rats; M, F

1/30

Diet

90

13

Posternak et al. (1969)

M, male; F, female

a Total number of test groups does not include control animals.

b Total number per test group includes both male and female animals.

c Furfural was administered in the food in microencapsulated form.

d Single dose

The component aliphatic acyclic alcohols and carboxylic acids formed by hydrolysis of the furfuryl and furoic acid esters are acetic acid, propionic acid, valeric acid, octanoic acid, methanol, propanol, pentyl alcohol, hexyl alcohol, and octyl alcohol. The alcohols are readily oxidized to the corresponding acids, which are endogenous to humans. The results of short-term and long-term studies of oral administration of seven of these simple aliphatic acids indicate no evidence of toxicity at an intake of 400 mg/kg bw per day or more (Butterworth et al., 1978; Bueld & Netter, 1993).

Furfuryl alcohol (No. 738)

No short- or long-term studies on the toxicity of furfuryl alcohol administered orally were available, but the substance has been administered by inhalation to both mice and rats. Since furfuryl derivatives are expected to be absorbed rapidly (Flek & Sedevic, 1978), regardless of the route of administration, these studies are described here; however, the NOELs reported by the authors of these studies are not relevant to ingestion of furfural alcohol in the diet, since the toxic effects observed were confined mainly to the olfactory system and respiratory tract (Feron & Kruysse, 1978; Mellick et al., 1991; National Toxicology Program, 1999). While these studies are of limited value for assessing the potential toxicity of oral exposure to furfuryl alcohol, the findings may provide some indication of potential long-term toxicity.

Groups of 10 B6C3F1 mice of each sex were exposed to furfuryl alcohol by inhalation at a concentration of 0, 2, 4, 6, 8, 16, or 32 ppm for 6 h/day, 5 days/week, for 14 weeks. No deaths were reported. The hearts of males exposed to 32 ppm weighed significantly less than those of controls. Dose-dependent increases in the incidences of non-neoplastic lesions of the respiratory, olfactory, and transitional epithelium were observed in all treated groups (National Toxicology Program, 1999).

Groups of 50 B6C3F1 mice of each sex were exposed to furfuryl alcohol by inhalation at a concentration of 0, 2, 4, 8, or 32 ppm for 6 h/day, 5 days/week, for 105 weeks. The body weights were measured weekly for the first 12 weeks, monthly until week 91, and every 2 weeks thereafter. Clinical signs of toxicity were recorded monthly for the first 91 weeks and every 2 weeks thereafter. Complete necropsies and microscopic examinations were performed on all test and control animals. The survival rates for all treated groups were comparable to those of chamber controls. The mean body weights of exposed females were significantly reduced during the second year of exposure, but the body weights of males were similar to those of controls throughout the study. Male mice exposed to 32 ppm had a significantly increased incidence of renal tubular degeneration (control, 0/50; 32 ppm, 48/50) and a significantly increased combined incidence of renal tubular adenomas and carcinomas (control, 0/50; 32 ppm, 5/50). The incidences of a variety of non-neoplastic lesions of the nose were significantly increased in all treated groups with respect to controls. Corneal degeneration was significantly more frequent in females exposed to 32 ppm furfuryl alcohol than in control mice (control, 3/49; 32 ppm, 26/50) (National Toxicology Program, 1999).

Groups of 10 Fischer 344/N rats of each sex were exposed to furfuryl alcohol by inhalation at a concentration of 0, 2, 4, 6, 8, 16, or 32 ppm for 6 h/day, 5 days/week, for 14 weeks. No deaths were reported. The body weights of females exposed to 32 ppm of furfuryl alcohol were significantly reduced at the end of the study when compared with chamber controls. Dose-dependent increases in the incidences of non-neoplastic lesions of the respiratory, olfactory, and transitional epithelium were observed in all treated groups (National Toxicology Program, 1999).

Groups of 50 Fischer 344/N rats of each sex were exposed to furfuryl alcohol by inhalation at a concentration of 0, 2, 4, 8, or 32 ppm for 6 h/day, 5 days/week, for 105 weeks. The observations and examinations followed the same protocol used in the corresponding study in mice, described above. All males exposed to 32 ppm had died by week 99, but the percentage survival of the other groups was comparable to that of the chamber control group. The terminal body weights of males exposed to 32 ppm were significantly lower than those of controls. No treatment-related clinical effects were observed. Males at the highest dose had significantly increased incidences of mineralization and renal tubular hyperplasia, as revealed in step-section analysis of kidney tissues. A dose-related increase in the severity of renal nephropathy was reported in exposed males and females. Significantly increased incidences of parathyroid gland hyperplasia (control, 10/50; 32 ppm, 25/50) and fibrous osteodys-trophy in the bones (control, 2/50; 32 ppm, 34/50) were reported in males at the highest dose (National Toxicology Program, 1999).

In a 13-week study, groups of 10 Fischer 344 rats of each sex were exposed by inhalation to atmospheres containing furfuryl alcohol at a concentration of 0, 2, 4, 8, 16, or 32 ppm. No treatment-related effects were observed on survival or organ weights. The final body weights of animals of each sex at 32 ppm were slightly reduced. Sperm morphology and vaginal cytology in animals at 0, 2, 8, and 32 ppm did not reflect significant reproductive toxicity, except for a slight increase in the number of spermatid heads in males at 8 and 32 ppm. Histological evaluation revealed lesions typical of chronic irritation of the nasal cavity and respiratory epithelia. These changes were minimal in animals at 2 and 4 ppm. No hepatic effects were reported (Mellick et al., 1991).

Furfural (No. 744)

A 16-day study in B6C3F1 mice given furfural at a dose of 0, 25, 50, 100, 200, or 400 mg/kg bw per day, a 13-week study in B6C3F1 mice at doses of 0, 75, 150, 300, 600, or 1200 mg/kg bw per day, and a 2-year study in B6C3F1 mice at doses of 0, 50, 100, or 175 mg /kg bw per day, all by gavage in corn oil (National Toxicology Program, 1990) were evaluated by the Committee at its fifty-first meeting (Annex 1, reference 137).

Two sets of studies of orally administered furfural have been conducted in Fischer 344N rats: one by the National Toxicology Program (1990) in which furfural was administered by gavage in corn oil, and one conducted by Jonker (1998, 2000) with microencapsulated furfural in the diet. A 16-day study in rats given furfural at a dose of 0, 15, 30, 60, 120, or 240 mg/kg bw per day, a 13-week study in rats at a dose of 0, 11, 22, 45, 90, or 180 mg/kg bw per day, and a 2-year study in rats at a dose of 0, 30, or 60 mg/kg bw per day, all by gavage in corn oil (National Toxicology Program, 1990) were evaluated by the Committee at its fifty-first meeting (Annex 1, reference 137). A 14-day study in rats at doses of 0, 30, 60, 90, 120, or 180 mg/kg bw per day and a 13-week study in rats at doses of 0, 30, 60, 90, or 180 mg/kg bw per day, both with microencapsulated furfural, were evaluated by the Committee at the present meeting and are summarized in the monograph addendum on furfural.

Syrian golden hamsters were given 0.2 ml of 1.5% furfural in physiological saline (about 25 mg/kg bw), 0.5% benzo[a]pyrene (8.3 mg/kg bw), or 1.5% furfural plus 0.5% benzo[a]pyrene intratracheally once per week for 36 weeks. No respiratory tract or peritracheal tumours were found. No tumorigenic effects were observed after the administration of furfural alone (Feron, 1972).

The effect of furfural on the carcinogenic potential of benzo[a]pyrene and N-nitrosodiethylamine was evaluated in male and female hamsters exposed to atmospheres containing 400 ppm (1550 mg/m3) of furfural for 7 h/day, 5 days/week, for 9 weeks, 330 ppm (1280 mg/m3) for the next 11 weeks, and 250 ppm (970 mg/m3) for an additional 32 weeks. The respiratory effects included atrophy and downward growth of the olfactory epithelium, degenerative changes in Bowman’s glands, and the appearance of cyst-like structures in the lamina propria beneath the olfactory epithelium. Although exposure to furfural was irritating to the olfactory epithelium, the treatment was not toxic to the liver (Feron & Kruysse, 1978).

2-Benzofurancarboxaldehyde (No. 751)

Groups of 16 Charles River rats of each sex were maintained on basal diets or diets containing 2-benzofurancarboxaldehyde at a concentration calculated to result in an average daily intake of 25 mg/kg bw for males and 27 mg/kg bw for females, for 90 days. Weekly measurements of body weight and food intake showed no significant differences between treated and control animals. Clinical chemistry, haematology, and urine analyses conducted during weeks 7 and 13 revealed normal values. The organ weights at necropsy, gross examination, and histology showed no treatment-related effects. The NOEL was 25 mg/kg bw per day (Posternak et al., 1969).

2-Phenyl-3-carbethoxy furan (No. 752)

Groups of 15 Wistar rats of each sex were maintained on basal diets containing 2-phenyl-3-carbethoxy furan at a concentration calculated to result in an average daily intake of 13 mg/kg bw, for 90 days. Weekly measurements of body weight and food intake showed no significant differences between treated and control animals. Clinical chemistry, haematology, and urine analyses conducted during weeks 7 and 13 revealed normal values. The organ weights at necropsy, gross examination, and histology showed no treatment-related effects. The NOEL was 13 mg/kg bw per day (Posternak et al., 1969).

2.3.2.3 Genotoxicity

The results of studies of the genotoxicity of furfurylalcohol and related substances are shown in Table 4.

Table 4. Studies of the genotoxicity of furfuryl alcohols and related substances

No.

Substance

End-point

Test object

Concentration

Resulta

Reference

738

Furfuryl alcohol

Reverse mutation

S. typhimurium TA98, TA100, TA1535, TA1537

294 µg/plate

Negativea,b

Florin et al. (1980)

738

Furfuryl alcohol

Reverse mutation

S. typhimurium TA98, TA100, TA1535

Ł 10 000 µg/plate

Negativea,b

Mortelmans et al. (1986)

738

Furfuryl alcohol

Reverse mutation

S. typhimurium TA100

2500–12 500µg/ml

Negativea,b

Stich et al. (1981a)

738

Furfuryl alcohol

Reverse mutation

S. typhimurium TA98, TA100, TA102

Ł 198 000 µg/plate

Negativea,b

Aeschbacher et al. (1989)

738

Furfuryl alcohol

Reverse mutation

S. typhimurium TA98, TA100

81–323 µg/plate

Negativea,b

Shinohara et al. (1986)

738

Furfuryl alcohol

Reverse mutation

S. typhimurium TA1535, TA100, TA1537 (modified assay)

200 000 µg/ml

Positivea,b

McGregor et al. (1981)

738

Furfuryl alcohol

DNA repair and H17 (rec+)

B. subtilis M45 (rec–) µg/disc

2000–20 000

Positivea,b

Shinohara et al. (1986)

738

Furfuryl alcohol

Sister chromatid exchange

Chinese hamster ovary cells

245 µg/ml

Positivea,b

Stich et al. (1981b)

738

Furfuryl alcohol

Sister chomatid exchange

Human lymphocytes

Ł 196 µg/ml

Negative

Jansson et al. (1986)

738

Furfuryl alcohol

Siser chromatid exchange

Human lymphocytes

Ł 970 µg/ml

Negative

Gomez-Arroyo & Souza (1985)

738

Furfuryl alcohol

Chromosomal aberration

Chinese hamster ovary cells

2000 µg/ml

Positive

Stich et al. (1981b)

738

Furfuryl alcohol

Gene conversion

S. cerevisiae strain D7

13 500–16 000 µg/ml

Positivea

Stich et al. (1981a)

738

Furfuryl alcohol

Sex-linked recessive l lethal mutation

D. melanogaster

Ł 6500 ppm by injection

Negative

Rodriguez-Arnaiz et al. (1989)

738

Furfuryl alcohol

Sister chromatid exchange

Adult human lymphocytes

32 300 mg/m3 in occupational atmosphere

Negative

Gomez-Arroyo & Souza (1985)

738

Furfuryl alcohol

Sister chomatid exchange

Adult human lymphocytes

32 300 mg/m3 in occupational atmosphere

Negative

Gomez-Arroyo & Souza (1985)

738

Furfuryl alcohol

Chromosomal aberration

Mouse bone-marrow cells drinking-water

0.5 mg/kg bw in

Negative

Sujatha & Subramanyam (1994)

 

 

 

 

1–2 mg/kg bw in drinking-water

Positive

 

738

Furfuryl acetate

Reverse mutation

S. typhimurium TA1535, TA98, TA100

33–666 µg/plate

Positivea,b

Mortelmans et al. (1986)

744

Furfural

Reverse mutation

S. typhimurium TA 1535, TA100, TA1537, TA1538, TA98

0.1–1000 µg/ml

Negativea,b

McMahon et al. (1979)

744

Furfural

Reverse mutation

S. typhimurium TA100, TA98, TA1535

Ł 3460 µg/plate

Negativea,b

Loquet et al. (1981)

 

 

 

 

5766 µg/plate

Positivea (weakly)

 

744

Furfural

Reverse mutation

S. typhimurium TA100, TA98, TA102

Ł 115 320 µg/plate

Negativea,b

Aeschbacher et al. (1989)

744

Furfural

Reverse mutation

S. typhimurium TA100, TA98

15–63 µg/plate

Negativea,b

Shinohara et al. (1986)

744

Furfural

Reverse mutation

S. typhimurium TA104

5–500 µg/plate

Positiveb

Shane et al. (1988)

744

Furfural

Reverse mutation

S. typhimurium TA100, TA102

5–500 µg/plate

Negativeb

Shane et al. (1988)

744

Furfural

Reverse mutation

S. typhimurium TA104, TA102

96 µg/plate

Negative

Marnett et al. (1985)

744

Furfural

Reverse mutation

S. typhimurium TA98, TA100, TA1535

Ł 6667 µg/plate

Negativea,b

Mortelmans et al. (1986)

744

Furfural

Reverse mutation

S. typhimurium TA98, TA100

Ł 1000 µg

Negativea

Osawa & Namiki (1982)

744

Furfural

Reverse mutation

S. typhimurium TA98, TA100, TA1535, TA1537

33– 6666 µg/plate

Negativea,b
Equivocal in TA100a

National Toxicology Program (1990 )

744

Furfural

Reverse mutation

S. typhimurium TA100

8000 µg/plate

Positivea,b

Zdzienicka et al. (1978)

744

Furfural

Reverse mutation

S. typhimurium TA98

8000 µg/plate

Negativea,b

Zdzienicka et al. (1978)

744

Furfural

Reverse mutation

S. typhimurium TA100, TA102

100–10 000 µg/plate

Negativea

Dillon et al. (1998)

744

Furfural

Reverse mutation

S. typhimurium TA104

100–10 000 µg/plate

Equivocala

Dillon et al. (1998)

744

Furfural

Reverse mutation

S. typhimurium TA102, TA104

100–10 000 µg/plate

Negativeb

Dillon et al. (1998)

744

Furfural

Reverse mutation

S. typhimurium TA100

100–10 000 µg/plate

Equivocalb

Dillon et al. (1998)

744

Furfural

Reverse mutation

S. typhimurium TA100 (modified assay)

426 µg/plate

Negativea,b

Kim et al. (1987)

744

Furfural

Reverse mutation

S. typhimurium TA100, TA1535, TA1537 (modified assay)

200 000 µg/ml

Negative

McGregor et al. (1981)

744

Furfural

Reverse mutation

E. coli WP2, WP2 uvrA (modified assay)

0.1–1000 µg/ml

Negativea,b

McMahon et al. (1979)

744

Furfural

SOS induction

S. typhimurium TA1535/ pSK1002

1932 µg/ml

Negativea,b

Nakamura et al. (1987)

744

Furfural

DNA repair

B. subtilis H17 (rec+) and M45 (rec)

Ł 1000 µg

Negativea

Osawa & Namiki (1982)

744

Furfural

DNA repair

B. subtilis H17 (rec+) and M45 (rec)

0.6 ml

Negativea,b

Matsui et al. (1989)

744

Furfural

DNA repair

B. subtilis H17 (rec+) and M45 (rec)

1700–17 000 µg/disc

Positivea,b

Shinohara et al. (1986)

744

Furfural

Forward mutation

L5178Y mouse lymphoma cells, Tk+/– locus

25–100 µg/ml
200 µg/ml

Negativea
Positivea

McGregor et al. (1988)

744

Furfural

Sister chromatid exchange

Chinese hamster ovary cells

2500–4000 µg/ml

Positivea,b

Stich et al. (1981b)

744

Furfural

Sister chromatid exchange

Chinese hamster ovary cells

Ł 1170 µg/ml

Positivea,b

National Toxicology Program (1990)

744

Furfural

Sister chromatid exchange

Human lymphocytes

Ł 0.035 mmol/La
0.07– 0.14 mmol/Lc

Negativea,b
Positivea,b

Gomez-Arroyo & Souza (1985)

744

Furfural

Chromosomal aberration

Chinese hamster ovary cells

500 µg/ml
1000–2000 µg/ml

Negative
Positive

Nishi et al. (1989)

744

Furfural

Chromosomal aberration

Chinese hamster ovary cells

Ł 40 mmol/L
(3840 mg)

Positivea,b

Stich et al. (1981b)

744

Furfural

Chromosomal aberration

Chinese hamster ovary cells

3000 µg/ml

Positive

Stich et al. (1981a)

744

Furfural

Chromosomal aberration

Chinese hamster ovary cells

Ł 1230 µg/ml

Positivea,b

National Toxicology Program (1990)

744

Furfural

Unscheduled DNA synthesis

Human liver slices

0.005–10 mmol/L

Negative

Adams et al. (1998)

744

Furfural

Sex-linked recessive lethal mutation

D. melanogaster

1000 mg/kg of diet

Negative

Woodruff et al. (1985)

744

Furfural

Sex-linked recessive lethal mutation

D. melanogaster

100 mg/kg by injection

Positive

Woodruff et al. (1985)

744

Furfural

Sex-linked recessive lethal mutation

D. melanogaster

Ł 6500 mg/kg by injection

Negative

Rodriguez-Arnaiz et al. (1989)

744

Furfural

Chromosomal loss

D. melanogaster

Oral or injected dose of 3750–5000 mg/kg of diet. Mated with repair-proficient females

Negative

Rodriguez-Arnaiz et al. (1992)

744

Furfural

Chromosomal loss

D. melanogaster

Oral or injected dose of 3750–5000 mg/kg of diet. Mated with repair-deficient females

Positive

Rodriguez-Arnaiz et al. (1992)

744

Furfural

Reciprocal trans- location

D. melanogaster

100 mg/kg by injection

Negative

Woodruff et al. (1985)

744

Furfural

Sister chromatid exchange

Mouse bone-marrow cells

50–200 mg/kg bw by injection

Negative

National Toxicology Program (1990)

744

Furfural

Spermhead abnormalities

Mice

4000 mg/kg of diet daily for 5 weeks

Negative

Subramanyam et al. (1989)

744

Furfural

Somatic chromo-somal mutation

Swiss albino mouse bone- marrow cells

1000–2000 mg/kg of diet

Negative

Subramanyam et al. (1989)

 

 

 

 

4000 mg/kg bw for 5 days

Positive

 

744

Furfural

Sister chromatid exchange

Adult human lymphocytes

9454 mg/m3 in occupational atmosphere

Negative

Gomez-Arroyo & Souza (1985)

744

Furfural

Chromosomal aberration

Adult human lymphocytes

9454 mg/m3in occupational atmosphere

Negative

Gomez-Arroyo & Souza (1985)

744

Furfural

Unscheduled DNA synthesis

B6C3F1 mice

50–320 mg/kg bw orally

Negative

Edwards (1999)

744

Furfural

Unscheduled DNA synthesis

Fischer 344 rats

5–50 mg/kg bw orally

Negative

Phillips et al. (1997)

745

5-Methylfurfural

Reverse mutation

S. typhimurium TA1537, TA100, TA1535

288 µg/plate

Negativea,b

Florin et al. (1980)

745

5-Methylfurfural

Reverse mutation

S. typhimurium TA98, TA100, TA102

96,100 µg/plate

Negativea,b

Aeschbacher et al. (1989)

745

5-Methylfurfural

Reverse mutation

S. typhimurium TA98, TA100

79–316 µg/plate

Negativea,b

Shinohara et al. (1986)

745

5-Methylfurfural

DNA repair

B. subtilis H17 (rec+) and M45 (rec)

0.55–5500 µg/disk

Positivea,b

Shinohara et al. (1986)

745

5-Methylfurfural

Sister chromatid exchange

Chinese hamster ovary cells

2200–4070 µg/ml

Positivea,b

Stich et al. (1981b)

a Without metabolic activation from a 9000 ´ g supernatant of rat liver

b With metabolic activation

c Concentration added to culture

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    See Also:
       Toxicological Abbreviations
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