resorcinol; 1,3-benzenediol

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result:

Toxicokinetic studies in rats and rabbits suggest that orally-administered resorcinol is rapidly absorbed, metabolized and excreted in the urine primarily as monoglucuronide conjugate. Minor metabolites included a monosulphate conjugate, a mixed sulfate-glucuronide conjugate, and a diglucuronide conjugate. Rats given repeated oral doses appeared to increase the rate of metabolism.

Short description of key information on absorption rate:

When applied to intact skin dermal absorption is low in humans but utilises the same urinary excretion pathway and forms common metabolites as via the oral route. A 2% absorption rate was identified as being conservative absorption rate, while recent studies suggest the dermal absorption to be < 1%. (0.82%)

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

2

Additional information

Three rats/sex were exposed to 112 mg ¹⁴C resorcinol/kg bw; resorcinol was readily absorbed, rapidly metabolized and excreted after this single oral dosing (Kim and Matthews, 1987). Within 24 hrs most of the administered dose was excreted via urine (90.8 – 92.8%) with a minimal amount excreted via the faeces (1.5 – 2.1%). The remaining ¹⁴C activity was detected in blood and major tissues such as liver, skin, fat, muscle, large intestine content and thyroid gland, and gave no indication of bioaccumulation. At least 50% of the excreted dose undergoes enterohepatic circulation and is excreted via urine. The major metabolite (ca. 65%) was a monoglucuronide conjugate and minor metabolites included a monosulphate conjugate, a mixed sulfate-glucuronide conjugate, and a diglucuronide conjugate. In females a greater proportion was excreted as sulfate conjugate, while 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 of resorcinol than females. In the same study after dosing with 225 mg/kg bw or daily doses of 225 mg/kg bw for 5 consecutive days, comparable results were obtained; in rats, resorcinol was excreted primarily through the urine.

 

In an OECD TG 408 study, three groups of 10 Sprague-Dawley rats/sex received resorcinol, daily by gavage at 0, 40, 80 or 250 mg/kg bw/day for 13 weeks (CIT 2004a). At 0 and 250 mg/kg bw/day, 6 rats/sex were treated for 13 weeks and then kept for a 4-week recovery period.  Six rats/sex exposed to 40, 80 or 250 mg/kg bw/day were used for a toxicokinetic investigation; blood samples were taken at day 1 and week 13 at 0.5, 1, 2, 4, 8, and 24 hours post dosing. In general, plasma levels of resorcinol were quantifiable for at least for two animals at all time points when measured on day 1 for animals exposed to 40, 80 and 250 mg/kg bw/day.  In contrast, at week 13, plasma levels of the test item were quantifiable only at 0.5 to 2 hours for the 80 and 250 mg/kg bw/day groups.  Plasma levels generally increased rapidly at 0.5 hours on day 1 with a first maximum C_max at 0.5 – 2 hours. In some cases, a second C_max was seen at 8 and/or 24 hours. There was no clear increase in blood levels of resorcinol with increasing test item exposure on day 1.  The mean concentration of resorcinol remained stable over the 24 hour period at 40 and 80 mg/kg bw/day, which may suggest enterohepatic recycling.  At 250 mg/kg bw/day, the C_max was reached at 0.5 hours and plasma levels gradually decreased thereafter.  At week 13, the maximal blood concentration was reached at 0.5 hours.  No clear conclusions were drawn by the authors regarding the dose, sex and time related observations, however, the rapid peaking of blood levels demonstrated rapid absorption after an oral dose, and the differences in blood levels at day 1 and week 13 (see below) suggest that the rats had adapted the way in which they handled resorcinol. 

 

In an OECD TG 416 study, four groups of male/female Sprague Dawley rats (30/sex/group) were exposed to resorcinol via drinking water for at least 70 days prior to mating (WIL, 2005).  Exposure levels were 0, 120, 360, 1000 and 3000 mg/L for the F0 and F1 generations.  Blood samples for determination of plasma resorcinol concentration were collected from 15 randomly selected F1 parental animals/sex/group at scheduled necropsy (following weaning of the F2 pups) which is at the end of maximum course of treatment on consecutive exposure days (143 – 155).      Blood resorcinol levels were detected in some (3/20) animals in the 3000 mg/L group at 116 to 621 ng/mL. The remaining resorcinol concentrations were below the limit of detection or the lower limit of quantification for the assay (100 ng/mL).  In conjunction with other studies showing rapid absorption, the low plasma levels in this study were evidence of rapid elimination.

 

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

 

Chinchilla-rabbits were exposed to 0.2 g/kg resorcinol by oral bolus dosing (gavage) to determine glucuronic acid and ethereal-sulfate excretions in urine (Garton and Williams, 1949). Even though resorcinol is expected to be highly conjugated, appreciable amounts (11 -12% by isolation) of resorcinol were excreted in the free-state. In this study, resorcinol was shown to be monoconjugated.

 

Discussion on absorption rate:

 

In conclusion, [14C]-Resorcinol in oxidative and non-oxidative test preparations was applied topically to human skin in vitro (Inveresk, 2005). Under the present experimental conditions, for [14C]-Resorcinol in the oxidative test preparation, most of the applied dose was removed at 30 min post dose (96.98% of the applied dose). At 24 h post dose, a further 0.37% was removed; therefore, the dislodgeable dose was 97.35% of the applied dose. At 24 h post dose, the absorbed dose and dermal delivery were 0.32% (0.84 μg equiv/cm2) and 0.40% (1.04 μg equiv/cm2) of the applied dose, respectively. Under the present experimental conditions, for [14C]-Resorcinol in the non-oxidative test preparation, most of the applied dose was removed at 30 min post dose (94.05% of the applied dose). At 24 h post dose, a further 0.68% was removed; therefore, the dislodgeable dose was 94.73% of the applied dose. At 24 h post dose, the absorbed dose and dermal delivery were 0.82% (2.10 μg equiv/cm2) and 1.16% (2.95 μg equiv/cm2) of the applied dose, respectively. The dermal absorption figure to be taken into consideration for the calculation of the margin of safety is 1.04 μg equiv./cm2 for the oxidative test preparation and 2.95 μg equiv./cm2 for the non-oxidative test preparation.

 In a human volunteer study to measure absorption and metabolic disposition, 2% resorcinol (800 mg resorcinol/day, a maximal exaggerated use level) was applied topically in a hydro-alcoholic vehicle over an application area of 2600 cm²twice a day, six days a week for four weeks to three male volunteers with one control volunteer (Yeung et al. 1983).The test substance penetrated the skin at a rate of 0.37 µg/cm2/hour. After two weeks of application, an average of 1.64% of the dose was being excreted in 24-hr urine specimens as the glucuronide or as the sulfate conjugate. There was no resorcinol or its conjugates in blood drawn at week 1, 2, 3, and 4.

 

In Vitro Permeability Studies

In in vitro permeability studies using human skin treated with 10% w/v resorcinol, there was a long lag time (80 min) (Roberts et al., 1977). A steady state permeability coefficient (Kp) of 0.00024 cm/h was calculated.

 

A 2% absorption rate was identified as being conservative absorption rate, while recent studies suggest the dermal absorption to be < 1% (0.82%).

 

The following studies are have been discounted for permeability assessment of resorcinol.  Reasons are given in Table 5, but all relate to the methodological limitations rendering the studies unsuitable for assessment of the dermal penetration of resorcinol

 

Géniès et al. 2019; The study was a research study to understand if pig skin can be used as an alternative to human skin. To identify any species differences, the metabolism of 10 chemicals was investigated in a pig and human skin explant model. Both Phase I and phase II metabolic pathways in skin from both species were examined. The testing design was significantly different from those for permeability measurement but only for measuring metabolic behavior in the skin (as described in Table 5.1).

Géniès et al. 2020; The study is a research study investigating skin metabolism using the reconstructed epidermal skin model EpiSkin™. The testing design was significantly different from those for permeability measurement but only for measuring metabolic behavior in the skin (as described in Table 5.1).

 

Hewitt et al. 2020; although this study was conducted according to the OECD 428 for skin penetration measurement and high permeability of around 70% was suggested, the human skin employed were frozen ones and thus, inactivation of metabolic enzymes should have significantly contributed to this high permeability (as described in Table 5.1).