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Concise International Chemical Assessment Document 71

First draft prepared by Drs S. Hahn, J. Kielhorn, J. Koppenhöfer, A. Wibbertmann, and I. Mangelsdorf, Fraunhofer Institute of Toxicology and Experimental Medicine, Hanover, Germany

Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals.

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WHO Library Cataloguing-in-Publication Data

Resorcinol.

(Concise international chemical assessment document ; 71)

First draft prepared by S. Hahn, J. Koppenhöfer, A. Wibbertmann, and I. Mangelsdorf.

1. Resorcinols - adverse effects. 2. Resorcinols - toxicity. 3. Environmental exposure.
4. Risk assessment. I. Hahn, S.K. II. World Health Organization. III. International
Programme on Chemical Safety, IV. Series.

ISBN 92 4 153071 5          (NLM Classification: QV 223)
ISBN 978 92 4 153071 2

©World Health Organization 2006

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FOREWORD

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International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the CICAD, to provide the reader with concise information on the protection of human health and on emergency action. They are produced in a separate peer-reviewed procedure at IPCS. They may be complemented by information from IPCS Poison Information Monographs (PIM), similarly produced separately from the CICAD process.

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Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever possible. These examples cannot be considered as representing all possible exposure situations, but are provided as guidance only. The reader is referred to EHC 170.¹

While every effort is made to ensure that CICADs represent the current status of knowledge, new information is being developed constantly. Unless otherwise stated, CICADs are based on a search of the scientific literature to the date shown in the executive summary. In the event that a reader becomes aware of new information that would change the conclusions drawn in a CICAD, the reader is requested to contact IPCS to inform it of the new information.

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• there is the probability of exposure; and/or

• there is significant toxicity/ecotoxicity.

Thus, it is typical of a priority chemical that:

• it is of transboundary concern;

• it is of concern to a range of countries (developed, developing, and those with economies in transition) for possible risk management;

• there is significant international trade;

• it has high production volume;

• it has dispersive use.

Advice from Risk Assessment Steering Group Criteria of priority: there is the probability of exposure; and/or there is significant toxicity/ ecotoxicity. Thus, it is typical of a priority chemical that it is of transboundary concern; it is of concern to a range of countries (developed, developing, and those with economies in transition) for possible risk management; there is significant international trade; the production volume is high; the use is dispersive. Special emphasis is placed on avoiding duplication of effort by WHO and other international organizations. A prerequisite of the production of a CICAD is the availability of a recent high-quality national/regional risk assessment document = source document. The source document and the CICAD may be produced in parallel. If the source document does not contain an environmental section, this may be produced de novo, provided it is not controversial. If no source document is available, IPCS may produce a de novo risk assessment document if the cost is justified. Depending on the complexity and extent of controversy of the issues involved, the steering group may advise on different levels of peer review: standard IPCS Contact Points above + specialized experts above + consultative group

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The CICAD Final Review Board has several important functions:

• to ensure that each CICAD has been subjected to an appropriate and thorough peer review;
• to verify that the peer reviewers’ comments have been addressed appropriately;
• to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and
• to approve CICADs as international assessments.

Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.

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This CICAD² on resorcinol was prepared by the Fraunhofer Institute of Toxicology and Experimental Medicine, Hanover, Germany. It is based on the BUA (1993) report, the German MAK Commission report (MAK, 2003), the Health Council of the Netherlands (2004) report, and a preliminary IUCLID for the USEPA HPV Challenge Program (INDSPEC, 2004). Information on the source documents and their peer review is presented in Appendix 2. A comprehensive literature search of relevant databases was conducted up to February 2005 to identify any relevant references published subsequent to those incorporated in these reports. Information on the peer review of this CICAD is presented in Appendix 3. This CICAD was considered and approved as an international assessment at a meeting of the 13th Final Review Board, held in Nagpur, India, on 31 October – 3 November 2005. Participants at the Final Review Board meeting are presented in Appendix 4. The International Chemical Safety Card for resorcinol (ICSC 1033), produced by IPCS (2003), has also been reproduced in this document. At the time of approval of the CICAD on resorcinol, an assessment of the chemical was also being undertaken as part of the HPV Chemicals Programme of the OECD. Peer review of this CICAD was extended to OECD Member countries during August and September 2005. As part of ongoing cooperation, any new information provided in the course of the OECD assessment will be provided by the OECD to IPCS.

Resorcinol (CAS No. 108-46-3) is a white crystalline compound. The chemical is soluble in water and has a low vapour pressure and .-octanol/water partition coefficient.

The resorcinol moiety has been found in a wide variety of natural products, and resorcinol is a monomeric by-product of the reduction, oxidation, and microbial degradation of humic substances.

The largest user of resorcinol is the rubber industry (about 50%). Resorcinol is also used for high-quality wood bonding applications (about 25%) and is an important chemical intermediate in the manufacture of speciality chemicals. Other uses include the manufacture of dyestuffs, pharmaceuticals, flame retardants, agricultural chemicals, fungicidal creams and lotions, and hair dye formulations.

Resorcinol is released into the environment from a number of anthropogenic sources, including production, processing, and consumer uses, especially from hair dyes and pharmaceuticals. In addition, localized high concentrations can appear in coal conversion wastewater or wastewater in regions with oil shale mining.

Calculations predict the hydrosphere to be the main target compartment of resorcinol. Data indicate that resorcinol is essentially non-volatile from aqueous solution.

In the hydrosphere, hydrolysis is not expected to occur. However, in aqueous solution, autoxidation of resorcinol takes place, and it can be assumed that resorcinol reacts in water bodies with hydroxyl and peroxyl radicals. Resorcinol is readily biodegradable under aerobic conditions and is likely to be biodegraded under anaerobic conditions.

In the upper atmosphere, resorcinol is rapidly degraded (half-life about 2 h) by reaction with photochemically produced hydroxyl radicals.

Experimental data using silty loam indicate a very low soil sorption of resorcinol, leading to a high potential for mobility. Bioaccumulation is not to be expected, based on the calculated BCF.

Localized concentrations are available only for coal conversion wastewater or wastewater in oil shale regions. These values are unsuitable for a risk assessment of the emissions from anthropogenic sources, because they are not representative of the background or local concentrations. Therefore, estimates of environmental concentrations were made for Europe using the software EUSES 2.0.3.

The results of the calculations show that the highest concentrations are expected at local point sources, such as at sites where hair dyes are formulated or rubber products are manufactured. These estimated concentrations in water are 1 order of magnitude higher than the local concentrations resulting from emissions from the use of consumer products containing resorcinol, which are released on a continental scale.

The results of pharmacokinetic studies in rats, rabbits, and humans suggest that resorcinol is absorbed by the oral, dermal, and subcutaneous routes, rapidly metabolized, and excreted principally as glucuronide conjugates in the urine. The available studies give no indication of bioaccumulation. There is a limited potential for absorption of resorcinol through intact skin using a hydroalcoholic vehicle.

In animal studies, the toxicological effects reported to be caused by administration of resorcinol include thyroid dysfunction, skin irritation, CNS effects, and altered relative adrenal gland weights. In some studies, decreases in body weight gain and decreased survival were noted.

Acute lethal toxicity data in experimental animals showed resorcinol to be of low toxicity following inhalation and dermal exposure but of higher toxicity after oral, intraperitoneal, or subcutaneous administration. Resorcinol is irritating to eyes and skin and may cause sensitization by skin contact.

Short-term (17 days) oral exposure studies via gavage in F344 rats and B6C3F1 mice dosed 5 days/ week resulted in NOAELs of 27.5 mg/kg body weight and 75 mg/kg body weight, respectively, for clinical signs such as hyperexcitability, tachypnoea, and tremors, which were most probably caused by an acute effect of resorcinol on the CNS. No gross or microscopic lesions were seen.

In a 13-week study in F344 rats and B6C3F1 mice, LOAELs for adrenal gland weight were in the range of 28–32 mg/kg body weight and the NOAEL for liver weight was 32 mg/kg body weight (dosing 5 days/week), without a clear dose–response. The highest dose levels (420–520 mg/kg body weight) caused tremors and increased mortality. No differences were seen in haematology or clinical chemistry, and no gross or microscopic lesions in dosed animals were found.

No signs of carcinogenicity were seen in male F344 rats and B6C3F1 mice of both sexes dosed with 0–225 mg/kg body weight and female rats exposed to 0–150 mg/kg body weight for 5 days/week for 104 weeks (NTP, 1992). Clinical signs of ataxia and tremors were noted at about 100 mg/kg body weight, but no differences in haematology, clinical chemistry, or other clinical pathology parameters were seen. There was a NOAEL of 50 mg/kg body weight for acute clinical signs indicative of effects on the CNS. A study with transgenic CB6F1-Tg rasH2 mice gavaged with 0 or 225 mg/kg body weight 5 days/week for 24–26 weeks showed only a slight, non-significant increased incidence of adenomas in the lungs. Negative results were mostly reported in the initiation–promotion studies performed using several species. However, three studies using nitrosamines as the initiator showed increased tumour incidences.

In bacterial mutagenicity assays, resorcinol showed mostly negative results. However, it induced mutations in the TK locus in mouse lymphoma cells. Resorcinol did not induce unscheduled DNA synthesis in hepatic cells or single-strand DNA breaks in mammalian cells in vitro. Studies for SCE and chromosomal aberrations in vitro in isolated cells and cell lines gave both negative and positive results. Cytogenetic studies in vivo (micronuclei in bone marrow in rats and two strains of mice; SCE in male and female rats) gave consistently negative results.

In a dose range-finding drinking-water study in male and female rats dosed continuously with resorcinol up to 360 mg/l for a minimum of 28 consecutive days prior to mating, no adverse effects concerning reproductive performance, mortality, and body or organ weights were observed (RTF, 2003). In the following two-generation drinking-water study, doses of 0, 120, 360, 1000, or 3000 mg/l were administered. A NOEL of 1000 mg/l and a NOAEL of 3000 mg/l for parental systemic and reproductive toxicity as well as neonatal toxicity were derived. When expressed on a body weight basis (average of F₀ and F₁ animals), the NOAEL corresponded to approximately 233 mg/kg body weight per day for males over the entire generation, 304 mg/kg body weight per day for females during premating and gestation, and 660 mg/kg body weight per day for females during lactation (RTF, 2005). A battery of neurotoxicological tests was included in the reproductive dose range-finding study, but no effects in tests other than the locomotor activity test in male offspring were observed.

Earlier studies with pregnant rats and rabbits had also shown no effects on developmental toxicity. Dosing of rats via gavage at up to 500 mg/kg body weight on gestation days 6–15 caused no embryotoxicity and no adverse effects on mean numbers of corpora lutea, total implantations, viable fetuses, or mean fetal body weights. There was also no increase in fetal anomalies or malformations. Slight maternal toxicity (weight loss at 24 h with decrease in maternal weight gain at 72 h) was seen in rats in a further study at doses of >667 mg/kg body weight.

Effects on the thyroid gland have been described in 30-day and 12-week drinking-water studies in rats at a dose of 5 mg/kg body weight per day. No histopathological changes in the thyroid were found in subacute, subchronic, or chronic studies performed via gavage in rats or mice; however, T₃/T₄ levels were not determined, with the exception of the 0 and 130 mg/kg body weight dose groups in the 13-week rat study. In the long-term study (104 weeks), NOAELs for thyroid effects were 150–520 mg/kg body weight per day (5 days/week); however, these studies were not designed to investigate this end-point. In a one-generation dose range-finding drinking-water study, male and female rats were dosed continuously with resorcinol at up to 360 mg/l (males: 1, 4, 13, or 37 mg/kg body weight per day; females: 1, 5, 16, or 47 mg/kg body weight per day). Some effects on the thyroid gland were reported, but they were inconsistent, not statistically significant, and not dose related (RTF, 2003). In the two-generation drinking-water study (RTF, 2005), no statistically significant resorcinol-related changes in the mean concentrations of T₃, T₄, or TSH were observed in the F₀ and F₁ parental animals or in the F₁ and F₂ pups selected for analysis (PND 4 or PND 21). Higher TSH values were noted in the F₀ males at scheduled necropsy, but these were not considered as resorcinol-related effects in the absence of effects on T₃ or T₄, organ weights, or adverse macroscopic or microscopic findings. Test article-related decreased colloid within the thyroid glands of the 3000 mg/l F₀ males was not considered to be adverse due to a lack of associated functional effects.

Resorcinol administered at high doses to rodents can disrupt thyroid synthesis and produce goitrogenic effects. There are species-specific differences in synthesis, binding, and transport of thyroid hormones that complicate interpretation of goitrogenesis.

In vitro studies indicate that the anti-thyroidal activity observed following resorcinol exposure is due to the inhibition of thyroid peroxidase enzymes, as evidenced by disruption of thyroid hormone synthesis and changes in the thyroid gland consistent with goitrogenesis.

In humans, exposure to resorcinol has been associated with thyroid effects, CNS disturbances, and red blood cell changes. Dermal sensitization to resorcinol has been well documented, but in practice it is rare; the available data do not allow assessment of the sensitization potency.

There are two toxicological effects that could be used for deriving a tolerable intake: thyroidal and neurological effects. Both these effects have been reported in human case-reports from dermal application of high concentrations (up to 50%) of resorcinol in ointments for ulcers and in peelings, as well as in rodent studies at high concentrations. There is no rodent study covering both end-points adequately.

The human data describing thyroidal and neurological effects were case-reports giving only estimates of exposure and are therefore inadequate to provide a tolerable intake.

For this reason, the study chosen to derive a tolerable intake was the long-term NTP (1992) study in which a NOAEL of 50 mg/kg body weight per day (about 36 mg/kg body weight per day after correcting for 5 days/week dosing) for neurological effects (acute clinical signs) was derived. No histopathological changes were seen in the thyroid. There was no measurement of T₃/T₄ ratio. Application of uncertainty factors for interspecies (10) and intraspecies (10) differences results in a tolerable intake of 0.4 mg/kg body weight per day.

In a worst-case exposure study in human volunteers using 2% anti-acne cream, no thyroidal effects (i.e. no alterations in T₃/T₄/T₇/TSH levels) were seen at a dermal dose of 12 mg/kg body weight per day (estimated systemic dose levels of 0.4 mg/kg body weight per day).

Therefore, the tolerable intake of 0.4 mg/kg body weight per day derived from the NTP (1992) study would be protective for both neurological and thyroidal effects.

From valid test results available on the toxicity of resorcinol to various aquatic organisms, resorcinol can be classified as being of low to high toxicity in the aquatic compartment. The lowest NOEC was determined for Daphnia magna in a full life cycle toxicity test based on measured concentrations (21-day NOEC = 172 µg/l). However, higher concentrations were not tested, so the actual NOEC is likely to be higher. Nethertheless, a PNEC_aqua of 3.4 µg/l can be derived using an assessment factor of 50 according to the EU Technical Guidance Document (EC, 2003a), as results from chronic studies from two trophic levels (fish and daphnia) are available.

Using this PNEC value and PEC values for surface water, the risk (PEC/PNEC) from resorcinol for the aquatic environment (surface water) was estimated.

For regional surface waters, calculations showed a low risk. The rubber industry is the largest consumer of resorcinol. The PEC/PNEC value indicates a risk for surface waters, assuming that the wastewater of the rubber production sites is connected to a wastewater treatment plant. If this is not the case, the calculated risk from rubber industry effluent would be increased.

Applications as hair dyes and pharmaceuticals result in a low probability for negative effects on the surface water ecosystem. In contrast, at local point sources, such as at sites where hair dyes are formulated, a risk cannot be excluded using the conservative approach. However, in sewage treatment plants, as indicated by a simulation test, there is a higher removal of resorcinol, which would result in a reduced calculated risk.

In conclusion, there may be a risk from resorcinol in the aquatic environment from sites where hair dyes are formulated and from rubber production plants.

The data availability for toxicity to terrestrial organisms is not sufficient for a quantitative risk assessment. However, an estimation of risk using the equilibrium partitioning method can be made. Using this method, a low risk was found for the regional soil compartment, but a risk at local point sources cannot be excluded.

Resorcinol (CAS No. 108-46-3) is a white crystalline compound with a weak odour and a bittersweet taste (Schmiedel & Decker, 2000). It has the chemical formula C₆H₆O₂, and its relative molecular mass is 110.11. The IUPAC name is 1,3-dihydroxybenzene; other names are 1,3-benzenediol, .-benzenediol, .-dihydroxybenzene, .-hydroquinone, 3-hydroxyphenol, and resorcin. Resorcinol can be regarded as a phenol derivative in which a hydrogen atom is substituted by a hydroxyl group in the meta.position to the OH. Its chemical structure is shown in Figure 1.

Resorcinol exists in at least two crystalline modifications (phases) (Kofler, 1943). At normal pressure, the alpha-phase is stable below about 71 °C, whereas the beta-phase is stable above that temperature up to the melting point (Schmiedel & Decker, 2000). Crystalline resorcinol turns pale red in the presence of air and light (Kirk-Othmer, 1981; O’Neil, 2001) and is hygroscopic (Health Council of the Netherlands, 2004). The water solubility data indicate that resorcinol is almost completely miscible in water. The pKa values of 9.32 and 9.81 (at 25 °C) indicate that resorcinol is present almost entirely in the protonated form under environmental conditions (pH 5–8). At pH 8, less than 2% of resorcinol is ionized; at pH 5, less than 0.1% is ionized.

Technical-grade resorcinol is available with a purity of a minimum of 99.5% and contains phenol, catechol, .-cresol, .-/.-cresol, and 3-mercaptophenol (maximum 0.1% each) as impurities (Schmiedel & Decker, 2000). In older studies, two commercial products were mentioned: flaked and industrial. This distinction is no longer made.

The physicochemical properties of resorcinol are summarized in Table 1. Additional physicochemical properties for resorcinol are presented in the International Chemical Safety Card (ICSC 1033) reproduced in this document. Conversion factors³ at 101.3 kPa and 20 °C are as follows: 1 ppm = 4.57 mg/m³; 1 mg/m³ = 0.219 ppm.

Table 1: Physical and chemical properties of resorcinol.

In general, dihydroxybenzenes can be determined by gas chromatography using a capillary column and by liquid chromatography. Semiquantitative determination of dihydroxybenzenes by thin-layer chromatography gives detection limits of 0.008–4 µg, depending on which reagent spray is used (Kirk-Othmer, 1981). For quantitative analysis of resorcinol, high-performance liquid chromatography and gas chromatography are suitable (Dressler, 1994). Curtis & Ward (1981) used the direct photometric method for phenol described in APHA et al. (1976) for measuring the concentration in aquatic toxicity tests.

Table 2 summarizes the most commonly used methods to quantify resorcinol in environmental and biological samples.

Table 2: Determination of resorcinol in environmental and biological samples.

ECD, electron capture detection; FID, flame ionization detection; GC, gas chromatography; HPLC, high-performance liquid chromatography; MS, mass spectrometry; TLC, thin-layer chromatography; UV, ultraviolet; UV-VIS, ultraviolet-visible spectrum detection

The resorcinol moiety has been found in a wide variety of natural products. In particular, the plant phenolics, of which resorcinol ring-containing constituents are a part, are ubiquitous in nature and are well documented. Resorcinol itself has been found in the broad bean (Vicia faba), detected as a flavour-forming compound in the honey mushroom (Armillaria mellea) (Dressler, 1994), and found in exudates of seedlings of the yellow pond lily (Nuphar lutea) (Sütfeld et al., 1996). Resorcinol has also been found in extracts of tobacco leaves (Dressler, 1994) and is a component of tobacco smoke (see section 6). In terms of resorcinol derivatives, resorcinol ethers are components of fragrance agents, and there is considerable literature on long-chain alk(en)yl resorcinols in plants and bacteria (Dressler, 1994).

Resorcinol is a monomeric by-product of the reduction, oxidation, and microbial degradation of humic substances. Humic substances are also present in coals, shales, and possibly other carbonaceous sedimentary rocks. This occurrence may explain the detection of resorcinol in wastewater effluents of coal conversion processes due to thermal breakdown (Cooksey et al., 1985). Chou & Patrick (1976) found resorcinol in some samples as a decomposition product of corn residues in soil.

Resorcinol is produced commercially worldwide in only a few specialized plants. All of these plants use benzene as the main feedstock, and only two production routes are used commercially on a large scale. Resorcinol is produced either via sulfonation of benzene under conditions promoting disubstitution in the meta position followed by fusion with anhydrous caustic ("classical" route via 1,3-benzenedisulfonic acid) or via hydroperoxidation of 1,3-diisopropylbenzene (Dressler, 1994; Schmiedel & Decker, 2000; CEH, 2001). Resorcinol is also a by-product of meta-amino phenol manufacture, as produced from metanilic acid fused with sodium hydroxide (T. Chakrabati, personal communication).

In Japan, resorcinol is produced in two plants (Sumitomo Chemical and Mitsui Petrochemical) via 1,3-diisopropylbenzene. The United States produces it in one plant (INDSPEC Chemical Corporation), using the "classical" route via 1,3-benzenedisulfonic acid (Dressler, 1994; Schmiedel & Decker, 2000; CEH, 2001). The same route was used by Hoechst AG (Germany), although production ceased in 1991 (Hoechst AG, 1992; CEH, 2001). According to CEH (2001), there are also three small-capacity plants located in China and four in India.

The total worldwide consumption of resorcinol was given as about 40 000 tonnes in 1990 (Schmiedel & Decker, 2000) and 44 800 tonnes in 2000 (see Table 3; CEH, 2001; EC, 2002), suggesting a slight increase over the decade. The total imports into Western Europe for 2000 are estimated to be 14 800 tonnes, with 1100 tonnes being re-exported, and the consumption was given as 13 500 tonnes. The projection for consumption in 2005 for Western Europe was approximately 12 700 tonnes (CEH, 2001; EC, 2002).

Table 3: Annual consumption of resorcinol by application and region in 2000.^a

A detailed description of the uses of resorcinol is given in Dressler (1994). The largest user of resorcinol is the rubber industry (about 50%). Resorcinol is the essential component of an adhesive system, together with formaldehyde and synthetic rubber latex, used in the manufacture of tyres for passenger cars, trucks, off-road equipment, and other fibre-reinforced rubber mechanical goods, such as conveyor and driving belts. Resorcinol is also used for high-quality wood bonding applications (about 25%) in adhesives formulated from resorcinol–formaldehyde resins or phenol-modified resorcinol–formaldehyde resins for use, for example, under conditions of extreme heat or moisture. Resorcinol is an important chemical intermediate in the manufacture of speciality chemicals, such as hexylresorcinol, .-aminosalicylic acid, and light screening agents for the protection of plastics from exposure to UV light. Other uses include the manufacture of dyestuffs, pharmaceuticals, flame retardants, agricultural chemicals, fungicidal creams and lotions, explosive primers, antioxidants, a chain extender for urethane elastomers, and a treatment to improve the mechanical and chemical resistance of paper machine fabrics (Schmiedel & Decker, 2000; CEH, 2001).

Although of comparatively low tonnage, the use of resorcinol in oxidative hair dyes and anti-acne creams and peeling agents is relevant for consumer exposure. A total of 150 tonnes of resorcinol was used in oxidative hair dyes by the cosmetics industry in the year 2000 (COLIPA survey, cited in HCTS, 2002). In oxidative hair dyes, resorcinol is regulated to 5% or below (EC, 2003b); in practice, however, many manufacturers limit the level of free resorcinol in oxidative hair dyes to 1.25% (EC, 2002). Resorcinol is limited to 0.5% in shampoos and hair lotions (EC, 2003b). Resorcinol is used in pharmaceutical preparations for the topical treatment of skin conditions such as acne, seborrhoeic dermatitis, eczema, psoriasis, corns, and warts. Resorcinol is usually present in anti-acne preparations at a maximum concentration of 2%. The concentration of resorcinol can be much higher in peels, in some cases around 50% (Karam, 1993; Hernández-Pérez & Carpio, 1995; Hernández-Pérez, 1997, 2002; Hernández-Pérez & Jáurez-Arce, 2000; see also sections 6 and 9). Jessner’s solution (resorcinol in ethyl alcohol, 14% w/v; lactic acid, 14%; and salicylic acid, 14%) is commonly used in chemical peeling.⁴ A specialized medical use of resorcinol is in biological glues (gelatin–resorcinol–formaldehyde glue) for cardiovascular surgery, in particular aortic operations (Bachet & Guilmet, 1999; Kazui et al., 2001; von Oppell et al., 2002).

Resorcinol is released into the environment during production and processing. It will also be released directly during uses and disposal of resorcinol-containing consumer and professional products. Furthermore, resorcinol can appear as a degradation intermediate of other anthropogenic environmental contaminants, especially resorcinol derivatives. For example, resorcinol was detected as an intermediate in the anaerobic degradation of .-methoxyphenol (Boyd et al., 1983) and as an irradiation product of 3-chlorophenol in aqueous solution (Boule et al., 1982).

Owing to the low vapour pressure and high water solubility of resorcinol, the releases during production, formulation, and use of resorcinol are mainly via the hydrosphere (see section 5). Release into air via dust can occur during the life cycle steps of production or industrial use (e.g. as an intermediate) and is relevant only for occupational exposure, owing to resorcinol’s short half-life in air (indirect photochemical degradation).

No measurements of resorcinol releases during production, use, and disposal or recent resorcinol concentrations in the effluent of wastewater treatment plants are available. Thus, the emissions of resorcinol primarily into the hydrosphere and atmosphere during the life cycle steps of production or industrial use have to be estimated.

Production plants are point sources for releases of resorcinol, which is produced in only a few specialized plants. Although no quantifications exist, releases from production processes of less than 0.05% would be expected (RTF, 2002). Using this estimate of 0.05% and annual consumption of 44 800 tonnes, the global releases would be 22.4 tonnes per year, with a European contribution of 6.75 tonnes per year. At least some manufacturers operate a "no release" policy for aqueous waste streams. According to the generic tables of the EU Technical Guidance Document (EC, 2003a), for chemicals with a production volume of >1000 tonnes per year, the fraction of the wastewater released during production is estimated at 0.3%. The release of resorcinol into air is 0% and into soil 0.01%. For Germany, estimated releases into wastewater during production were 33 tonnes in 1991 (Hoechst AG, 1992; BUA, 1993).

The Resorcinol Task Force estimated the releases of resorcinol during its life cycle steps, and the results were published in EC (2002). The figures, which illustrate the releases per use pattern and compartment, are reproduced as Figures 2 and 3. As a result of this estimation, the uses in the rubber industry and as a wood adhesive are the most relevant for air releases. For the water compartment, releases from the use of resorcinol in hair dyes and pharmaceuticals are the most important.

Fig. 2: Resorcinol losses to air for Western Europe (total 2.8 tonnes per year, 0.02% of the total yearly consumption)
(EC, 2002).

Fig. 3: Resorcinol losses to water for Western Europe (total 168.7 tonnes per year, 1.25% of the total yearly consumption)
(EC, 2002).

In the rubber industry, which consumes the highest tonnage of resorcinol, the percentage loss of resorcinol during production of tyres is around 0.1%. Most of the resorcinol lost in the processing of tyres is removed from the extraction air by water-based scrubbers (resorcinol is highly soluble) and then treated off site at wastewater treatment plants. Assuming that the scrubbers are at least 80% effective, the total amount of resorcinol reaching European wastewater plants from this source would be around 5 tonnes annually, with a further 1.5 tonnes possibly reaching the atmosphere (EC, 2002). According to the OECD emission scenario document on additives in the rubber industry (OECD, 2004), the percentage of processing aids (bonding agents) remaining in the rubber product is 99.9%. Thus, the release into wastewater can be estimated to be 0.1% (equal to 6.48 tonnes per year). However, for the releases into air and soil, the A-Tables of the EU Technical Guidance Document (EC, 2003a) can be consulted (IC11 "Polymer industry") according to OECD (2004), resulting in releases into air of 0.1% (equal to 6.48 tonnes per year) and into soil of 0.05% (equal to 3.24 tonnes per year). Further releases are the result of tyre abrasion and emissions from leachates of landfills. No resorcinol has been detected in leachates of cured rubber and at further extraction works. Although work continues on this issue, it is impossible to identify any meaningful mechanism for the release of resorcinol from cured rubber. Accordingly, no emissions can currently be ascribed to in-use or end-of-life phases of resorcinol in rubber tyres (EC, 2002).

Although the percentage use as hair dyes and pharmaceuticals from the total tonnage is only 1% and 0.5%, respectively (see Table 3), these releases seem to be the most relevant. Since hair dyes are manufactured in a closed process under vacuum, there are no losses to the atmosphere. However, losses in aqueous wastewater resulting from batch processing can amount to 1% because of the relatively small batch sizes used (EC, 2002). This represents 1.5 tonnes of the 150 tonnes used by the industry annually in Western Europe.

Concerning consumer usage of hair dyes, approximately all non-reacted resorcinol is rinsed off to the wastewater after the 30-min period of typical use as hair dyes. Estimates of non-reacted resorcinol range from 52% to 72% (Tsomi & Kalopissis, 1982; EC, 2002; HCTS, 2002). In addition, the amount of residual in the packages, which is disposed of with waste or wastewater, has to be considered. According to the cosmetics industry, the amount that may enter the wastewater can be estimated to be approximately 70–80 tonnes per year for Western Europe (EC, 2002; HCTS, 2002).

For pharmaceutical applications such as topical ointments, it is assumed, as a worst case, that 100% of the resorcinol (75 tonnes for Western Europe) reaches the wastewater stream, either directly or from the output of domestic landfills (EC, 2002).

Disposal methods include complete incineration, land (soil) farming, and decomposition in activated sludge-type wastewater treatment plants. All disposal practices should be carefully evaluated for compliance with applicable local, state, and federal regulations (Dressler, 1994). Specific waste data for production in Germany or use as intermediates are available in BUA (1993).

Using the model calculation Mackay Level I (distribution of a substance in a unit world under steady-state conditions), the following distribution of resorcinol in different environmental compartments was predicted: air, <0.01%; water, 99.9%; sediment, 0.05%; soil, 0.05%; biota, <0.01% (Fh-ITEM, 2005a).⁵ According to the calculation, the hydrosphere is predicted to be the main target compartment.

Based on the calculated dimensionless Henry’s law constant of 4.21 × 10⁻⁹ (Fh-ITEM, 2005b), resorcinol can be classified as essentially non-volatile from aqueous solution, according to the scheme of Thomas (1990).

Soil sorption studies on resorcinol (5–50 mg/l) using silty loam (organic matter 5.1%; pH 5.7; temperature 20 °C) revealed a measured organic carbon-normalized partition coefficient (._oc) of 10.36 (Boyd, 1982). According to Litz (1990), a very low soil sorption is to be expected.

Experimental data on the phototransformation of resorcinol in air are not available. However, crystalline resorcinol turns pale red in the presence of air and light (O’Neil, 2001). A direct photodegradation of resorcinol is not to be expected, as the substance does not absorb sunlight at wavelengths above 295 nm to a significant extent (lambda_max = 274 nm; epsilon_max = 2000 l/mol·cm³; Perbet et al., 1979). The indirect photochemical degradation in air by hydroxyl radicals was calculated via AOPWIN v.1.91 to have a half-life of about 2 h using 500 000 hydroxyl radicals/cm³ as a 24-h average (Fh-ITEM, 2004).

Owing to the type of chemical structure of resorcinol, it is not possible to calculate the hydrolysis rate constant via HYDROWIN v.1.67 (Fh-ITEM, 2004). However, resorcinol possesses no functional groups susceptible to hydrolysis under environmentally relevant conditions, so hydrolysis is not expected to occur (Harris, 1990).

Photolysis and photo-oxidation of resorcinol take place in dilute aqueous solution by reaction with oxygen (Perbet et al., 1979). Trihydroxybenzene and hydroxybenzoquinone were identified as reaction products. In the presence of ozone, resorcinol can be degraded in aqueous solution via pyrogallol (1,2,3-trihydroxybenzene) and 3-hydroxybenzoquinone to glyoxalic acid, glyoxal, oxalic acid, carbon dioxide, and water (Leszczynska & Kowoal, 1980). Moussavi (1979) determined a half-life of 1612 h (= 67 days) for the autoxidation of resorcinol in aqueous solution at 25 °C and pH 9. By analogy with other phenolic compounds (resorcinol can be regarded as a derivative of phenol; see section 2), resorcinol should react in water bodies with hydroxyl and peroxyl radicals. For phenol and hydroquinone, half-lives of 100 and 20 h, respectively, with hydroxyl radicals as sensitizer and half-lives of 19 and 0.2 h, respectively, with peroxyl radicals were determined (Mill & Mabey, 1985). Shen & Lin (2003) studied the decomposition of resorcinol by 254-nm UV direct photolysis and by the UV–hydrogen peroxide process in aqueous solution. The light absorbance and photolytic properties were highly dependent on solution pH. In acidic and neutral solution (pH 3–7), resorcinol was predominantly decomposed by reaction with hydroxyl radicals; the contribution of this degradation path was about 99% of the total decomposition. Direct photolysis was relevant only at pH values >9. Based on the experimentally determined rate constant (k_OH = 1.4862/min at 25 °C and pH 7), a half-life of 0.5 min can be calculated.

The relevant studies for the assessment of the biodegradation are summarized in Table 4. Resorcinol proved to be biodegradable under aerobic and anaerobic conditions.

Table 4: Aerobic and anaerobic biodegradation of resorcinol.

Based on the results obtained in an aerobic biodegradation test conducted according to OECD TG 301C, resorcinol can be classified as readily biodegradable. After 14 days, a mineralization of 66.7% was measured (MITI, 1992). Furthermore, several studies on inherent biodegradability are available. Elimination rates of >90% were observed after 4–15 days in guideline studies (OECD TG 302B) and modifications thereof (Pitter, 1976; Wellens, 1990; Hoechst AG, 1992). In a wastewater treatment plant simulation test (modified German detergents test), degradation rates of 95–100% were observed based on DOC measurements at an initial resorcinol concentration of 138 mg/l and a hydraulic retention time of 3 h. For an initial concentration of 500 mg/l, the time for adaptation increases; afterwards, the decomposition is >60% (Gubser, 1969).

Resorcinol is likely to be biodegraded under anaerobic conditions. However, the results of the studies are not consistent. Using adapted anaerobic sludge and initial resorcinol concentrations of up to 500 mg/l, degradation rates of 36%, 83%, and 95% were determined, whereas no degradation was observed at concentrations of >1000 mg/l. Degradation with sludge from municipal wastewater treatment plants was 98% or 0% in the same test system, obviously depending on the origin of the used inoculum (Chou et al., 1979; Horowitz et al., 1982; Blum et al., 1986). The potential biodegradability of resorcinol under anaerobic conditions has been confirmed by studies using fixed film–fixed bed reactors or by fermentation (Tschech & Schink, 1985; Latkar & Chakrabarti, 1994).

Resorcinol in aqueous medium can be metabolized by bacteria and fungi via hydroxyhydroquinone (1,2,4-trihydroxybenzene) and maleyl acetate to beta-ketoadipate and via hydroxyhydroquinone and acetyl pyruvate to formic, acetic, and pyruvic acids (Chapman & Ribbons, 1976; Gaal & Neujahr, 1979; Ingle et al., 1985). Another potential pathway is via pyrogallol (Groseclose & Ribbons, 1981). Anaerobic degradation of resorcinol is catalysed by resorcinol reductase and hydratase. The products are 1,3-dioxocyclohexane, which is immediately hydrolysed to 5-oxohexanoate, and 5-oxohex-2-enecarboxylate, respectively. Further degradation probably proceeds via beta-oxidation (Heider & Fuchs, 1997).

The distribution in a sewage treatment plant can be calculated using the model "SimpleTreat", implemented in EUSES 2.0.3 (RIVM, 1996; EC, 2004). The model provides information on how much resorcinol that enters the sewage treatment plant goes to air, surface water, and sewage sludge and how much is degraded. Hence, the log octanol/water partition coefficient and the Henry’s law constant are needed, as well as the rate constant for degradation. The results are presented in Table 5.

Table 5: Distribution of resorcinol in sewage treatment plants (results from "SimpleTreat").^a

The percentage of biodegradation in a sewage treatment plant resulting from "SimpleTreat" is a conservative worst-case value. In reality, the fraction of degradation will be significantly higher, indicated by the result from the wastewater treatment plant simulation test (95–100% for a relatively high concentration of 138 mg/l; Gubser, 1969) listed in Table 4.

Experimental test results on bioaccumulation are not available. Based on a log octanol/water partition coefficient of <1 and an estimated BCF of 3.2 (log BCF = 0.5; BCFWIN v.2.15; Fh-ITEM, 2004), a low bioaccumulation is to be expected.

Resorcinol is a monomeric by-product of the reduction, oxidation, and microbial degradation of humic substances (Cooksey et al., 1985). Chou & Patrick (1976) examined the decomposition products of corn and rye residues in soil (incubation at 22–23 °C for 30 days). The soil was sampled in the fall at the Horticulture Experiment Station, Vineland Station, Ontario, Canada. The authors identified, among others, resorcinol at a concentration of <5 µg/g soil via paper chromatography, TLC, and GC/FID at an initial ratio of 400 g soil to 400 g chopped corn. At other ratios of soil to corn and in the decomposition study with rye, no resorcinol was found.

Resorcinol is one of the important pollutants in the effluent waters of chemical, fertilizer, and dye industries (Ingle et al., 1985) and is a typical constituent of coal conversion wastewater. It was identified at the milligram per litre level in the wastewater from a coal liquefaction plant in the United States by UV analysis (Jolley et al., 1975). It was quantified in the range of 176–272 mg/l at the Lurgi gasification facility in Westfield, Scotland, and at levels of 2000 mg/l in an aqueous process stream from the product scrubber of a bench-scale hydrocarbonization coal liquefaction operation (USEPA, 1978a). The typical concentration of resorcinol in coal conversion wastewater is given as 1000 mg/l (USEPA, 1978a; Blum et al., 1986). Resorcinol was detected at concentrations of 7–22 mg/l in the ammoniacal liquid of two typical coking ovens; a resorcinol concentration of 150 mg/l was found in a low-temperature carbonization ammoniacal liquor. However, no resorcinol was detected in the condensate of one oven’s waste gas or the drainage water (Cooper & Wheatstone, 1973).

Phenolic compounds like resorcinol, phenol, cresol, and dimethylphenols have been considered as major pollutants in the oil shale semi-coke dump leachates that contaminate the surrounding soils (Sooba et al., 1997; Kahru et al., 1998, 1999). Resorcinol has been determined in leachate samples associated with the oil shale industry from the north-east of Estonia at concentrations up to 8.7 mg/l (Sooba et al., 1997; Kahru et al., 1998). In wastewater samples from the same region, resorcinol concentrations up to 4.1 mg/l (total phenols 0.7–195 mg/l) have been found (Kahru et al., 1999). However, the amount of water-extractable phenols in the surrounding soils was very low (up to 0.7 mg/kg; Põllumaa et al., 2001). In a selected soil sample (polluted by leachates) with a relatively high concentration of steam-distillable phenols (43 mg/kg), the amount of resorcinol was quantified as <0.04 mg/kg and thus could be considered negligible (Kahru et al., 2002).

There are only a few recently measured concentrations of resorcinol in air, water, sediment, and soil, and concentrations in drinking-water or food are not available. However, the concentrations can be estimated using the emission values given in section 4 and a Mackay Level III fugacity model. In the following, the results of such a calculation are presented using EUSES 2.0.3 containing "SimpleTreat" and "SimpleBox" (http://ecb.jrc.it/existing-chemicals/); for further details (e.g. input parameters), see Appendix 5.

For calculating the regional and continental PECs, the model "SimpleBox" (EC, 2004; RIVM, 2004) is used. On the basis of the estimated emissions during the manufacture of rubber products, during the formulation and use of hair dyes, as well as during the use of pharmaceuticals (see Appendix 5), the regional PECs are:

Resorcinol is used in the production of rubber products as a bonding agent. Using the specific emission scenario document composed by OECD (2004), releases of 1.1 kg/day to both wastewater and air at the production site can be estimated (see Appendix 5). Considering the connection to a sewage treatment plant, the PECs for air and water are:

During the formulation of hair dyes, releases of resorcinol to wastewater up to 3.5 kg/day can occur (see Appendix 5), resulting in the following PEC for surface water:

Taking into account a higher removal during sewage treatment (95%), indicated by a simulation test, in the calculation of Clocal_water, the local PEC for surface water is:

Hair dyes and pharmaceuticals are used by professional and private consumers. The worst-case releases are 0.0814 kg/day for hair dyes and 0.0411 kg/day for pharmaceuticals, which are disposed of to the same municipal sewage treatment plant. Hence, the local concentrations are summed, and a combined PEC for surface water is calculated:

The results of the calculations show that the highest concentrations are expected to be at local point sources such as at sites where hair dyes are formulated or rubber products are manufactured. These estimated concentrations in water are 1 order of magnitude higher than the local concentrations resulting from emissions from the use of consumer products containing resorcinol, which are released on a continental scale.

6.2.1 Occupational exposure

There are very few data on occupational exposure.

Concentrations up to 45 mg/m³ (the occupational TWA limit in many countries) were reported in a production plant in the United States from sampling records ranging from 3.5 to 30 min (Flickinger, 1976). From a plant producing resorcinol by sulfonation of benzene — and also producing beta-resorcylic acid, resorcinol–formaldehyde resins, sulfites, and sulfates — 8-h TWA values are available from personal and area measurements for grinders, flaker operators, and operators making pharmaceutical-grade resorcinol. Workers in these groups were exposed primarily to resorcinol, but the exposure to other agents was not measured, and there were also no measurements of resorcinol in other areas of the plant. For 20 samples, the resorcinol concentrations were in a range of 0.6–66 mg/m³, and the distribution of exposure concentrations was given as follows: grinders 2–45 mg/m³ (four personal samples) and 2–66 mg/m³ (four area samples); flaker operators 0.6–2 mg/m³ (four personal samples) and 1–53 mg/m³ (four area samples); operators making pharmaceutical-grade resorcinol 0.7–2 mg/m³ (four personal samples) (Flickinger, 1978).

In a study on rubber workers, exposure to resorcinol was less than 0.3 mg/m³ (Gamble et al., 1976). In the tyre industry, occupational exposure to resorcinol occurs in the weighing, mixing, and preparation areas. Here, typical airborne concentrations are less than 0.1 mg/m³ and remain below 5 mg/m³ (8-h TWA) (EC, 2002).

Hairdressers using oxidative hair dyes are exposed to resorcinol. In a study of skin exposure to resorcinol, it was found that hairdressers do not always use gloves for hair dying, especially when only strands of hair are being dyed. Hair that had been rinsed after dyeing still contained traces of resorcinol, and the hairdressers had hand contact with the hair during cutting and styling of the hair. Resorcinol was found in hand rinse samples (22–738 nmol per hand) in 20 out of 29 hairdressers after cutting newly dyed hair (Lind et al., 2005).

6.2.2 Consumer exposure

There is a lack of quantitative data on the concentrations of resorcinol in food and drinking-water. Resorcinol and its derivatives are to be found in trace amounts in many natural products and foods to which the consumer is exposed. For example, Japanese mugi-cha tea is made by roasting of barley seeds. Resorcinol has been detected in roast barley (Shimizu et al., 1970), in cane molasses (Hashizume et al., 1967), and as a coffee flavouring compound (Walter & Weidemann, 1968).

Resorcinol has been detected in the mainstream of cigarette smoke at levels ranging from 0.8 to 8 µg per cigarette (Commins & Lindsey, 1956; Rustemeier et al., 2002).

Resorcinol is used in oxidative hair dyestuffs, anti-acne creams, and peels, and these seem to be the most relevant sources of consumer exposure to the compound (see also section 4).

6.2.2.1 Human exposure scenarios

1) Exposure estimate for resorcinol in hair dyes

Oxidation dyes are used in hair dyeing preparations composed of .- or .-phenylenediamines or aminophenols as the precursor (developer) and a dihydroxybenzene such as resorcinol as the coupler. On addition of the oxidant, usually hydrogen peroxide solutions, azine- and oxazine-type dyes are formed (Dressler, 1994, 1999). A resorcinol concentration of 5% is permitted in oxidative hair dyes (Cosmetic Ingredient Review, 2004); in practice, however, many manufacturers limit the level of free resorcinol in oxidative hair dyes to 1.25% (RTF, 2002). In vivo and in vitro studies suggest that only a small amount of resorcinol penetrates the skin during the actual process of hair colouring, but that some of the free compound is retained in the stratum corneum and is made slowly available to the systemic circulation, the time required for 50% excretion of the total excreted dose being 31 h in a human volunteer study (Wolfram & Maibach, 1985) (see section 7). The percentage of total dose excreted over 4 days was 0.076%. Exposure to resorcinol through hair dyeing would be about 30 min every 4 weeks.

Based on a usage volume of 100 ml (50 ml hair dye cream with 5% resorcinol and 50 ml developer), the exposure estimate for resorcinol in hair dyes can be calculated as follows:

2) Exposure estimate for resorcinol in anti-acne cream

Resorcinol in anti-acne preparations is usually 2%. Anti-acne creams are likely to be used twice a day for an unlimited period, and the preparation remains on the skin and is not washed off, as in the case of hair dyes.

In a human volunteer study to measure absorption and metabolic disposition, 2% resorcinol (800 mg resorcinol per day, a maximal exaggerated-use level) was applied topically in a hydroalcoholic vehicle over an application area of 2600 cm² twice a day, 6 days a week, for 4 weeks to three male volunteers with one control volunteer (Yeung et al., 1983). Determination of resorcinol conjugates in the 24-h urine samples after 14 days of continuous product treatment showed that a maximal 23 mg (2.87%) of the daily dose was excreted. Assuming a body weight of 64 kg (IPCS, 1994) gives an exposure estimate of 0.4 mg/kg body weight.

In a report based on consumer research data (Gans, 1980), under reasonable maximum-use conditions (i.e. less than 1% of users), topical applications of resorcinol-containing ointments to treat acne would result in exposures of up to 1.2 mg/kg body weight per day (i.e. 77 mg resorcinol per day, assuming a body weight of 64 kg). More usual-use conditions would result in exposures of about 0.2 mg/kg body weight per day. Further details were not given. These figures agree well with the above exposure estimate based on the Yeung et al. (1983) study.

However, it should be considered that acned skin may be damaged due either to scratching or to the blemishes themselves. Therefore, the uptake may be higher than this, with up to 100% absorption in limited small areas, which would increase the daily systemic exposure.

As is well known in dermal absorption studies, the nature of the vehicle has a great influence on the absorption of a compound. Resorcinol seems to be absorbed much better from anti-acne preparations than from the hair dye preparations under normal usage conditions.

3) Exposure estimate for resorcinol in peels

The situation is even more critical in the case of resorcinol used in peels. Although resorcinol is not used or permitted in cosmetic surgery in many countries, it is still used in others, as can be seen from recent publications (Karam, 1993; Hernández-Pérez, 2002). In peeling, the compound, in concentrations up to about 50% alone or in combination with other agents, is purposely used to wound and disrupt the epidermis (Coleman, 2001). Although the application time is short (30 s to 10 min) and the "peel" is removed immediately, resorcinol could be 100% absorbed in this time. In some procedures, a series of 6–10 sessions 1 or 2 weeks apart are performed (Hernández-Pérez, 2002).

Assuming that 1000 mg is applied (SCCNFP, 2003), the exposure estimate for resorcinol with peeling can be calculated as follows:

A summary of these exposure scenarios is given in Table 6.

Table 6. Summary of estimated human exposure to resorcinol from cosmetic and hair dye products.

In three rabbits dosed orally with resorcinol at 100 mg/kg body weight, 13.5% of the applied dose was excreted as monosulfate, 52% as monoglucuronide, and 11.4% as free resorcinol via urine within 24 h. Trihydroxybenzenes were not detected (Garton & Williams, 1949).

In F344 rats (. = 3 per sex), resorcinol with a purity of 97% was readily absorbed, rapidly metabolized, and excreted after single oral dosing with [¹⁴C]resorcinol at 112 mg/kg body weight. Within 24 h, most of the applied dose was excreted via urine (90.8–92.8%) and faeces (1.5–2.1%). The remaining ¹⁴C activity in blood and main tissues such as liver, skin, fat, muscle, large intestine content and also thyroid gland gave no indication of bioaccumulation. There were no significant sex differences. At least 50% of the excreted dose undergoes enterohepatic circulation, to be eventually excreted via urine. The major metabolite (about 65%) was a glucuronide conjugate, and minor metabolites included a monosulfate conjugate, a mixed sulfate–glucuronide conjugate, and a diglucuronide conjugate. In females, a greater proportion was excreted as sulfate conjugate, whereas males excreted a higher proportion of a diconjugate (both sulfate and glucuronide groups). From these data, the authors concluded that male rats have a higher capacity for glucuronidation than females. After dosing with 225 mg/kg body weight or daily doses of 225 mg/kg body weight for 5 consecutive days, comparable results were obtained (Kim & Matthews, 1987).

After single subcutaneous dosing of male Sprague-Dawley rats with [¹⁴C]resorcinol at 10, 50, or 100 mg/kg body weight, the ¹⁴C activity in plasma decreased rapidly (approximately 90% clearance within the first 2 h post-administration). The elimination was biphasic, with half-lives of 18–21 min and 8.6–10.5 h. Within 24 h after dosing with 10 mg/kg body weight, 98% of the applied dose was excreted via urine and 1% via faeces, mainly as glucuronide conjugate (84%). The ¹⁴C activity was rapidly distributed in major tissues such as muscles, kidneys, and liver, without indication of bioaccumulation (Merker et al., 1982).

In one female patient with leg ulcers treated dermally for 13 years with large amounts (~500 g/week) of an ointment containing 12.5% resorcinol, 2.1% of the applied dose was found in urine as glucuronide and monosulfate metabolites (Thomas & Gisburn, 1961).

Yeung et al. (1983) studied the absorption and metabolism of resorcinol in three male human volunteers after topical application. Twenty millilitres of 2% resorcinol in a hydroalcoholic vehicle were applied twice daily to face, shoulders, upper chest, and upper back areas on 6 days/week over 4 weeks (150 µg/cm² per application to 2600 cm² of body surface; daily dose: 12 mg/kg body weight). In 24-h urine, about 0.5–2.9% of the applied dose was detected as glucuronide or sulfate conjugates, and flux was calculated as 0.37 µg/cm² per hour. In plasma, levels of free resorcinol or its conjugates were below the detection limit of 0.1 µg/ml. There was no information given on the remaining part of the dose. Measured thyroid functions (T₃/T₄/T₇/TSH) gave no significant changes. In an in vitro.test with excised full-thickness human skin (application of 390 µg/cm²), the flux was 0.86 µg/cm² per hour.

In an investigation in three human volunteers using conditions similar to those used in hair dyeing, ¹⁴C-ring-labelled 1.2% resorcinol was mixed with 6% hydrogen peroxide, and the mixture (approximately 100 g) was worked into dry hair for 5–8 min and left on the hair for a further 20 min followed by rinsing. Only 0.076% of the total dose was excreted. The urinary excretion was found to follow first-order kinetics, and the time required for 50% excretion was 31 h. This suggests that only a small amount of resorcinol penetrates the skin during the actual process of hair colouring. The bulk of the urine-recovered dye must have been taken up into the horny layer of the skin and then slowly released into the circulation. A cumulative 4-day absorption (assuming 700 cm² of scalp) was given as 0.46 µg/cm² (Wolfram & Maibach, 1985).

In in vitro human skin studies, resorcinol was evaluated from a representative hair dye formulation that contained 0.61% resorcinol (total dyes 2.7%) after dilution with developer. Mean data for 3 donors and 16 replicates indicate a plateau in receptor fluid concentration between 24 and 48 h, as reflected by cumulative absorption values of 1.17 and 1.30 µg/cm² (average 1.23 µg/cm²) (Dressler, 1999).

In in vitro permeability studies using human skin testing 10% w/v resorcinol, resorcinol showed a long lag time (80 min). A steady-state permeability coefficient (._p) of 0.000 24 cm/h was calculated (Roberts et al., 1977).

8.1.1 Oral studies

For male albino rats (strain not given; . = 5 per group) dosed with resorcinol (flake grade) by gavage, an LD₅₀ of 980 mg/kg body weight was reported. Animals that died showed hyperaemia and distension of stomach and intestine, while there were no gross lesions at necropsy in survivors (Flickinger, 1976).

In another study with CFY rats (. = 5 per sex and group), an LD₅₀ of 370 mg/kg body weight was obtained. Dosed animals showed lethargy and piloerection, whereas no adverse findings were reported at sacrifice (14 days) (Lloyd et al., 1977).

For rats (sex and strain not given), an LD₅₀ value of 301 mg/kg body weight was reported by Koppers Company (1970). Signs of intoxication included fibrillation, tremors, convulsions, salivation, dyspnoea, sedation, and emaciation. Gross autopsy of survivors gave no adverse effects, whereas haemorrhages of the lungs, inflammation of the gastrointestinal tract, and hyperaemia in livers were noted in animals that died.

For female Wistar rats, an LD₅₀ of 202 mg/kg body weight was reported by Hoechst AG (1979). Signs of intoxication included motor difficulties, decubitus position, passivity, shivering, twitching, tonic–clonic seizures, cyanosis, and breathing difficulties. Sacrificed animals showed brown-dyed stomach walls and filling of stomach and small intestine with a dark-brown to orange substance. These findings were not noted in survivors.

In rabbits (giant chinchilla), doses of <500 mg/kg body weight caused no apparent toxic effects, whereas after dosing with 600 mg/kg body weight, temporary muscular twitching and increased respiration rate were noted (Garton & Williams, 1949).

8.1.2 Dermal studies

The acute dermal toxicity of resorcinol was studied in male albino rabbits (Koppers Company, 1962). For flaked resorcinol, the LD₅₀ was given as 3360 mg/kg body weight. Dosing with 1000 mg/kg body weight caused slight hyperkeratosis and moderate to severe irritation after 24 h, body weight loss, but no gross lesions. At >2000 mg/kg body weight, skin necrosis was seen. For industrial resorcinol, the LD₅₀ was 2830 mg/kg body weight. Dosing with 1000 mg/kg body weight caused no irritation, body weight loss, but no gross lesions. In both studies, the treatment with >2000 mg/kg body weight caused skin necrosis.

In another study with rabbits (sex and strain not given), an LD₅₀ of 3830 mg/kg body weight was obtained by Koppers Company (1970). Signs of intoxication included salivation, tremors, and convulsions, and treated skin areas showed slight erythema and extreme dryness. The gross autopsy of survivors gave no significant findings, whereas haemorrhages of the gastrointestinal tract were noted in the dead animals.

8.1.3 Inhalation studies

In Harlan-Wistar rats (. = 6 females per group) exposed to resorcinol–water solutions (approximately >1 µm size), no deaths were seen at concentrations up to 7800 mg/m³ (1 h) or up to 2800 mg/m³ (8 h). Survivors showed no exposure-related lesions at necropsy after 14 days (Flickinger, 1976).

For male rats (strain not given), a 1-h LC₅₀ of >160 mg/m³ was reported by Koppers Company (1970). There were no signs of intoxication, and gross autopsy showed haemorrhages of the lungs.

8.1.4 Other routes

In mice (. = 6 per group), the LD₅₀ after subcutaneous injection was given as 213 mg/kg body weight. Immediately after dosing, the animals showed tremor, asphyxia, and cramps (Marquardt et al., 1947).

Angel & Rogers (1972) gave the dose applied intraperitoneally causing myoclonic convulsions in 50% of urethane-anaesthetized male albino mice (Sheffield strain) as 0.92 mmol (101 mg/kg body weight).

After subcutaneous daily administration of resorcinol at 2 × 50 mg/kg body weight given 6 h apart to male Sprague-Dawley rats over 14 and 30 days, no adverse effects concerning body or organ weights (liver, kidneys, brain, spleen, and testes), haematological parameters, serum T₃/T₄ levels, or microscopic appearance of the thyroid gland, spinal cord, or brain were reported. After subcutaneous injection of 55, 88, 140, 220, or 350 mg/kg body weight in male CD(SD) rats (n = 5 per group), slight tremors progressing from moderate to marked tonic–clonic convulsions were seen within 10 min at >140 mg/kg body weight. Complete recovery in all animals occurred within 1–1.5 h after dosing (Merker et al., 1982). A NOAEL of 100 mg/kg body weight was chosen..

After subcutaneous injection of 70–180 mg/kg body weight as aqueous solution to groups of four rats each, the ¹³¹I uptake by the thyroid gland 2 h after dosing was about 14–24% when compared with controls (Arnott & Doniach, 1952).

Doniach & Fraser (1950) dosed single female Lister rats subcutaneously with >5 mg/kg body weight and noted a decreased uptake of iodine by the thyroid gland of 11–20% of normal values measured 2 h post-dosing. This effect could not be increased with higher dosing (up to 300 mg/kg body weight). Dosing with >50 mg/kg body weight caused severe tremors for the first half-hour post-application.

Of the following studies, the repeated-dose toxicity studies that were deemed to be most relevant to the risk assessment are summarized in Appendix 6.

8.2.1 Oral studies

In a study performed by NTP (1992), five male and female F344 rats were dosed with resorcinol in deionized water via gavage at 0, 27.5, 55, 110, 225, or 450 mg/kg body weight once daily on 5 days/week over 17 days (12 doses total). Hyperexcitability and tachypnoea were observed in males receiving 225 and 450 mg/kg body weight. Females receiving doses of 55 mg/kg body weight and greater showed hyperexcitability, and those receiving 110 and 450 mg/kg body weight showed tachypnoea. High-dose females had significantly decreased absolute and relative thymus weights. No other biologically significant differences in organ weights were observed. There were no gross or microscopic lesions attributable to resorcinol administration. The NOAEL was 27.5 mg/kg body weight (NTP, 1992).

In a parallel study, five male and female B6C3F1 mice were dosed with resorcinol in deionized water via gavage at 0, 37.5, 75, 150, 300, or 600 mg/kg body weight once daily on 5 days/week over 17 days (12 doses total). At 600 mg/kg body weight, 5/5 females and 4/5 males died on the first day, whereas 1/5 males dosed with 300 mg/kg body weight died before study termination. Clinical findings, including prostration and tremors, were recorded among males receiving >150 mg/kg body weight and among females receiving >300 mg/kg body weight. In both sexes, no gross or microscopic lesions were noted. The NOAEL was 75 mg/kg body weight (NTP, 1992).

The exposure of female Wistar Crl:(WI) BR rats fed on a low-iodine, low-protein diet to 0 or 9 µmol resorcinol per day via drinking-water (about 5–10 mg/kg body weight) over 30 days caused an enlargement of the thyroid gland and decreased ability of their thyroids to incorporate ¹²⁵I into the active thyroid hormones T₃ and T₄ (see also section 8.8; Cooksey et al., 1985).

The oral dosing of male F344 rats with 0.8% resorcinol via diet (approximately 480 mg/kg body weight per day) over 8 weeks caused no adverse effects concerning mortality, body weight gain, or food and water consumption, and the examination of the forestomach/glandular stomach gave no increased incidence of hyperplasia or labelling indices (Shibata et al., 1990).

8.2.2 Dermal studies

To investigate the effect of resorcinol as a peeling agent, 1% or 3% resorcinol in vaselinum flavum or Unguentum Cordes was applied onto the ears or shaven flanks of male guinea-pigs, once per day over 14 days. Resorcinol showed a concentration-dependent increase in labelling index ([³H]thymidine), acanthosis, and papillomatosis. The mode of peeling is therefore via proliferation hyperkeratosis (Windhager & Plewig, 1977).

After application of an ointment containing 12.5% resorcinol onto the shaved bellies of six albino rats of both sexes (and six controls) for 0.25 h twice daily over 3 weeks (about 300 mg/kg body weight per day), no significant changes in thyroid gland weights were found (see also section 8.8; Doniach & Logothetopoulos, 1953).

To study the goitrogenic activity of resorcinol, female Wistar rats were treated twice daily for 28 days by rubbing 6 g of an ointment containing 12.5% resorcinol (about 750 mg/kg body weight per day) onto shaved (. = 6) or shaved and scarified skin (. = 4 with and without resorcinol). Increased thyroid gland weights (2.5–4 times) and histological alterations were seen, indicating a goitrogenic effect (see also section 8.8; Samuel, 1955).

8.2.3 Inhalation studies

The exposure of rats, rabbits, and guinea-pigs to resorcinol at a concentration of 34 mg/m³ for 6 h/day over 2 weeks gave no evidence for toxic effects (lung or trachea damage, allergic reaction in the respiratory tract). Animals were maintained for several months with periodic sacrifices (Flickinger, 1976).

In a throat spray test, groups of guinea-pigs and rats (sex and strain not given) received three daily throat sprayings with 1% resorcinol in water over 2 weeks. The animals were then examined weekly for 10 additional weeks. During application, the throats of the animals showed signs of irritation, which was reversible after termination of the exposure. There was no gross evidence for respiratory damage, and the histopathological examination of the lungs revealed no adverse effects when compared with controls (water spray) (Flickinger, 1976).

Of the following studies, the repeated-dose toxicity studies that were deemed to be most relevant to the risk assessment are summarized in Appendix 6.

8.3.1 Oral studies

In a study performed by NTP (1992), 10 F344 rats and 10 B6C3F1 mice of both sexes were dosed with resorcinol by gavage in deionized water (rats: 0, 32, 65, 130, 260, or 520 mg/kg body weight; mice: 0, 28, 56, 112, 225, or 420 mg/kg body weight) on 5 days/week over 13 weeks. In high-dosed groups, 10/10 female rats and 8/10 male rats as well as 8/10 mice of both sexes died. In male rats dosed with 130–260 mg/kg body weight and in female rats dosed with 65–260 mg/kg body weight, significantly increased absolute and relative liver weights were found. Absolute/relative adrenal gland weights were significantly increased in all surviving males without clear dose–response. In high-dosed male mice, final mean body weights were significantly less than controls, while final mean body weights and changes in mean body weights of all other mice were comparable with controls. In high-dosed mice, clinical signs of intoxication included dyspnoea, prostration, and tremors, which generally appeared within 30 min after dosing. In male mice dosed with 28–225 mg/kg body weight, significantly decreased absolute/relative adrenal gland weights were seen. In both species, there were no adverse effects on final mean body weights, haematology, or clinical chemistry parameters, and no chemical-related gross or microscopic lesions were observed.

In another study, rats were exposed to 0 or 0.004% resorcinol via drinking-water (about 5 mg/kg body weight) over 12 weeks, and effects on the thyroid gland (increased mean follicular epithelial cell height, decreased mean follicle diameters, and decreased follicle epithelium indices) were observed (see also section 8.8; Seffner et al., 1995). No thyroid hormone measurements were performed.

8.3.2 Inhalation studies

Groups of 25 male and 25 female HLA-SD rats were exposed to resorcinol at about 1000 mg/m³ as atomized mist on 8 h/day on 60 days (over more than 4 months) or 90 days (over more than 5.75 months) (Koppers Company, 1977). Two groups of 5 males and 5 females (pair fed and normal controls) were used as controls. Because of high mortality (20% in males; 28% in females), the exposure was temporarily terminated after 64 weeks. Fifty per cent of survivors were sacrificed 1 week later, and blood and urine samples were taken. After a 2-week pasture period, the remaining animals were further exposed (total of 90 exposures). Apart from effects such as altered relative organ weights (liver, kidneys, spleen, adrenals) or changes in haematological parameters, the most important changes were seen in the thyroid gland: 39% (15/38 animals) showed a hyperplasia, which was not seen in controls. Although the data are limited due to interruption of the exposure, this study gives an indication of systemic effects after uptake via inhalation.

Of the following studies, the repeated-dose toxicity studies that were deemed to be most relevant to the risk assessment are summarized in Appendix 6.

8.4.1 Oral studies

In one study performed with male Syrian golden hamsters, which focused only on effects on the forestomach, pyloric region, and urinary bladder, the animals were dosed with 0 or 0.25% resorcinol via the diet (about 375 mg/kg body weight) over 20 weeks (Hirose et al., 1986). A mild hyperplasia of the forestomach was noted, but this was not statistically different from the controls. No other adverse effects were described.

Eastin et al. (1998) dosed heterozygote p53^def (C57BL/6) mice with 0 or 225 mg/kg body weight via gavage, 5 times per week over 24 weeks, and found no increased incidence of neoplastic or non-neoplastic lesions (no further information available). The p53^def (p53^+/−) mouse model is heterozygous for the wild-type tumour suppressor gene Trp53, and the loss of p53 tumour suppressor function is associated with progression of tumours to malignancy.

In an interlaboratory study (two laboratories), transgenic CB6F1-Tg rasH2 mice or non-transgenic littermates were dosed with resorcinol in deionized water via gavage at 0 or 225 mg/kg body weight, 5 times per week, and sacrificed after 24–26 weeks. The histopathological examination of the lungs and spleen gave a slightly (non-significant) increased incidence of adenomas in the lung and no increase in haemangiosarcomas in the spleen (Maronpot et al., 2000). Lung tumours and splenic tumours are typically seen tumours in this transgenic mice strain, and therefore the study focused mainly on these tumour types (tumours in other organs were not investigated).

In a study performed by NTP (1992), F344 rats and B6C3F1 mice of both sexes were dosed with 0, 112, and 225 mg/kg body weight (male rats, male and female mice) or with 0, 50, 100, and 150 mg/kg body weight (female rats) on 5 days/week over 104 weeks. In both species, clinical signs such as ataxia and tremors were noted at about 100 mg/kg body weight. An interim sacrifice at 15 months gave no difference in haematology, clinical chemistry, or other clinical pathology parameters and no increased incidence of neoplasms or non-neoplastic lesions. Also, at final sacrifice, there was no evidence of carcinogenic activity in males or females of both species. The NOAEL was 50 mg/kg body weight (adjusted to 36 mg/kg body weight per day for 5 days/ week dosing).

8.4.2 Dermal studies

Two long-term studies with Swiss mice or NZW rabbits, where the animals were treated with 0.02 ml of 5, 25, or 50% resorcinol dissolved in