Hahn, S.S.HahnKielhorn, J.J.KielhornKoppenhöfer, J.J.KoppenhöferWibbertmann, A.A.WibbertmannMangelsdorf, I.I.Mangelsdorf2023-10-252023-10-252006https://publica.fraunhofer.de/handle/publica/293091This CICAD1 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 n-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 resorcinolrelated 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 g/l). However, higher concentrations were not tested, so the actual NOEC is likely to be higher. Nethertheless, a PNECaqua of 3.4 g/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.enresorcinols - toxicityresorcinols - adverse effectsrisk assessmentenvironmental exposureoccupational exposure615610620book