resorcinol; 1,3-benzenediol

Endpoint summary

Description of key information

Following OECD TG 401, the acute oral LD50 of resorcinol in rats is 510 mg/kg bw. Clinical signs of toxicity included ptosis, respiratory effects, lethargy, abnormal gait, tremors, convulsions and salivation.  An additional acute oral toxicity study in rats resulted in an LD50 of 980 mg/kg bw. Hyperemia and distention of stomach and intestines were observed in the animals that died during the observation period. Using the fixed dose procedure, another study determined the maximum non-lethal dose of resorcinol to be 200 mg/kg in rats. At this dose, CNS effects were observed on day 1 following treatment, with complete recovery by day 2. In rats exposed by inhalation to an aerosol of resorcinol, the 1 hr and 8 hr LC0 values were >= 7800 mg/m3 and  2800 mg/m3, respectively.  No lesions attributable to inhalation of the aerosol were seen at gross necropsy. The rabbit 24 hour dermal LD50 was 3360 and 2830 mg/kg bw for flaked and industrial grade resorcinol, respectively.  Both grades produced necrosis of the skin; reported clinical signs included salivation, tremors, and convulsions prior to death. The overt CNS effects were considered to be associated with bolus dosing.   

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Provides basic data. Article did not reveal if study was conducted under GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

not specified

Test type:

other:

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: A vehicle was used but the name of the vehicle was not identified.

Doses:

no data

No. of animals per sex per dose:

30

Details on study design:

LD50 tests were conducted  "blind" and in accordance with OECD TG 401, 1981 rather than the 1987 test guideline  in order that information on both sexes would be available for comparision with the fixed dose test results.  The only modification in the guideline study was that, where the limit dose studies were indicated, the maximum dose used would be 2000 mg/kg by weight rather than 5000 mg/kg dose prescribed in the 1981 OECD guideline study.   One laboratory conducted the classical LD50 test following the OECD guideline as indicated above, while the remaining 31 laboratories conducted the fixed-dose testing (for comparison purposes.)  Each substance was tested at least 26 times by different laboratories using identical procedures (not all 31 laboratories were used to test for resorcinol). In the fixed dose method one of the following preset doses is to be  selected 5, 50, or 500 with an additional dose of 2000 mg/kg bw.  These  doses were selected as at the time, they matched the EC classification  system and would thus allow for appropriate classification. 

The classic LD50 study was conducted using 30 Sprague Dawley rats while  the fixed dose testing used 370 rats (a variety of rats), as laboratories  were given the freedom to select the rat strain.  This concluded in 21  laboratories performing the study using Sprague Dawley rats, 9  laboratories using Wistar and one laboratory using the Fischer 344 rats.   A total of 26 fixed dose studies was conducted using 370 rats for an  average of 14.23 rats per study. Fixed dose method:  Resorcinol was administered orally by gavage.  At least 10 animals (5 female and male) are used for each dose level.  The dose level to be used by the laboratory should be one of the four levels associated with classification, 5, 50, 500 and 2000 mg/kg/bw.  A 14 day observation period.  Animals are observed for signs of toxicity including behavioural and clinical abnormalities, gross lesions, body-weight changes, and other toxic effects.  All animals are subject to gross necropsy.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

510 mg/kg bw

95% CL:

>= 439 - <= 642

Mortality:

In the classic LD50 study: In males (only)LD50 was determined to be 533 mg/kg bw with the 95% confidence limits being (425  - 725 mg/kg bw).  In females (only) the LD50 was determined to be 489 mg/kg/bw with the 95% confidence limits being (397 -650 mg/kg bw).  In the males and females the LD50 was determined to be 510 mg/kg bw with the 95% confidence limits being (439 - 642 mg/kg bw).  The slope was determined to be 8(s.e. 2.1).  In accordance with the EC criteria at the time, resorcinol was classified as harmful.   There were no necropsy findings in the classic LD50 study.  9 animals were found dead (dose level not indicated).
In the fixed dose studies:  A total of 146 animals were found dead (dosing not indicated) for an average of 5.62 per test.  These results are only stated in general terms and are not associated with any one given chemical that was tested.

Clinical signs:

other: In the classic LD50 study the following clinical signs were observed:  Ptosis, posture, respiratory effects, lethargy, abnormal gait, tremors, convulsions and salivation. In the fixed dose studies: In these studies, 26 laboratories responded in which the

Gross pathology:

In the fixed dose studies: Autoposy findings in the fixed-dose tests with resorcinol:  Liver, kidney, stomach and intestine discoloured.  Oedma of glandular gastric mucosa.  Rapid heart beat.

Fixed Dose studies:

Results of fixed dose testing indicated that in 25 fixed dose studies conducted in separate laboratories each one of them had consistent results that resulted in a classification as harmful, in accordance with the EC
criteria at the time.  In only 1 instance did the results indicate "Unclassified."  

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information In accordance with CLP Criteria used for interpretation of results: other:

Conclusions:

The author concluded a classification of harmful is assigned to test substances that have less than 100% survival at 2000 mg/kg bw. Following the current European Classification, Labeling and Packaging Regulation (EC 1272/2008); the substance would be considered a Category IV substance for acute oral toxicity.

Endpoint conclusion

Dose descriptor:

LD50

Value:

510 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Provides basic data

Guideline:

other:

Principles of method if other than guideline:

Method: other

GLP compliance:

not specified

Species:

rat

Strain:

other: Harlan Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

In groups of 6, rats, weighing between 87 and 126 g

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

other:

Details on inhalation exposure:

Samples were dissolved in distilled water and the resulting solutions were aerosolized using a D18 Dautrebande aerosol generator operated at 30 psi.  At this operating pressure, the D18 generator delivered droplets of 1µ or smaller.  The concentration of the sample solutions was adjusted so that the airbourne concentration approximated 2,000 mg/m3 (444 ppm) of the sample in air.  Airborne concentrations were determined by measurement of the volume loss of solution following aerosolization.  The weight of sample present in that volume was then calculated and related to the total volume of air in generating the aerosol to obtain chamber concentrations.

Duration of exposure:

8 h

Concentrations:

2000 mg/m3 (444 ppm) , ca. 2480 mg/m3 (551 ppm) and 2800 mg/m3 (622 ppm)

No. of animals per sex per dose:

Groups of 6 rats

Details on study design:

The acute toxic effects of catechol-, resorcinol- and phenol-water aerosols were investigated at comparable airborne concentrations.

In groups of 6, rats, weighing between 87 and 126 g, were subjected to a single 8 hour inhalation period of the aerosolized sample.  

At the 8 hour time interval, rats were exposed to concentrations of 2800 (27% weight/unit volume), 2480 (18.2% weight/unit volume) and 2000 mg/mg3 (18.2% weight/unit volume) (444, 551 and 622 ppm, respectively).  It should be noted that in the study conducted at a concentration of 2480 mg/m3, the solution turned milky. And some precipitate was noted.  It is likely that flow concentrations were less than the concentration indicated.

The animals were held for 14 days following exposure and were then weighed and sacfrificed for gross necropsy.

Key result

Sex:

female

Dose descriptor:

LC0

Effect level:

> 2 800 mg/m³ air

Exp. duration:

8 h

Mortality:

No deaths resulted when rats inhaled resorcinol-water aerosols for eight hour time periods at concentrations of 2,000, 2,480 ca mg/m3 and 2,800 mg/m3 (444, 551 and 622 ppm, respectively) for an 8 hour period.

Body weight:

All animals had normal 14-day weight gains.

Gross pathology:

No lesions attributable to inhalation of the aerosol were seen at gross necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

No toxic effects are anticipated from the acute exposures to resorcinol at aerosol concentrations approximating 2,800 mg/m3 (622 ppm) for 8 hours. Classification is limited to the highest concentration tested which results in a classification of Toxicity Category III.

Endpoint conclusion

Dose descriptor:

LC50

Value:

2 800 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline Study; Not GLP

Guideline:

other:

Principles of method if other than guideline:

Method: Federal Register of August 12 1961, pages 7333-7341.

The study was conducted in accordance with Federal Hazardous Substances Labeling Act (FHSLA), Federal Register Aug. 12, 1961, p 7333-7341, Part 191 "Hazardous Substances Definitions and Procedural and Interpretative Regulations, Final Order"

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Sex:

male

Vehicle:

physiological saline

Doses:

1000, 2000, 3980 and 7950 mg/kg

No. of animals per sex per dose:

4/dose group, males

Control animals:

not specified

Details on study design:

Four groups of male albino rabbits were used (4/dose group), weighing between 2.3-3.0 kg after undergoing a seven day laboratory observation and acclimatization period.

The rabbits were administered the following doses of industrial resorcinol: 1000, 2000, 3980 and 7950 mg/kg. Prior to exposure, the animals were prepared by clipping the skin of the trunk, approximately 10% of the body surface, free of hair. One-half of each group was further prepared by making epidermal abrasions every two or three centimeters longitudinally over the area of future exposure. The abrasions were sufficiently deep to penetrate the stratum corneum but not to disturb the derma and cause bleeding. The skin and the material, which was evenly distributed on cotton gauze in an amount calculated to yield the desired dosage level, were moistened with physiological saline. The gauze and material were applied to the skin of the rabbits and the entire trunk was wrapped in an impervious plastic film. The maximum justifiable dosage level for solids in this procedure is approximately 4. 0 gm. /kg. which is twice the upper limit for the "toxic substance" category as defined in the regulations pursuant to the FHSLA. Following dosing, the rabbits were immobilized in stocks for 24 hours after which the dam and any excess chemical were removed and the skin was examined for gross changes. Mortality due to the effect of the chemical was considered complete after 14 days. All fatalities were subjected to autopsies to exclude extraneous causes of death while some survivors were sacrificed and examined for the existence of gross lesions.

Statistics:

The skin penetration LD50, based upon mortality attributable to the material during the 14-day observation period, was estimated employing Thompson's method of moving averages using the tables of Weil.

Sex:

male

Dose descriptor:

LD50

Effect level:

2 830 mg/kg bw

Gross pathology:

No internal gross lesions were observed at necropsy.

Other findings:

The material produced necrosis of the skin in all the rabbits exposed to 3980 mg/kg and above for the Flaked Grade and to 2000 mg/kg and above for the Industrial Grade. The rabbits exposed to 1000 mg/kg Flaked Grade showed only slight hyperkeratosis following signs of moderate to severe irritation after 24 hours contact. However the same dose of the Industrial Grade showed no signs of irritation seven days following contact.

RS-Freetext:

Industrial Grade:
Dosage mg/kg                No. Died/No. Dosed        Days after dosing on which death occurred
1000                         0/4                        -
2000                         0/4                         -
3980                         4/4                         1 (4)
7950                         4/4                         1 (4)

95% confidence limits: cannot be calculated due to the all or none response.

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 is 2830 mg/kg bw . The results were evaluated in association with the EC 1272/2008 (CLP). The substance does not fall within any categories identified.

Endpoint conclusion

Dose descriptor:

LD50

Value:

2 830 mg/kg bw

Additional information

Oral:

In 1990 the OECD was evaluating fixed dose methods and as a result performed a blind comparison between oral toxicity studies following the OECD TG 401 and fixed dosing methods (Van De Heuvel et al., 1990).  One laboratory conducted the classic LD50 study following OECD TG 401 while in the case of resorcinol, 25 laboratories conducted fixed dose testing for comparison purposes. The classic LD50 study following OECD TG 401 study used 30 Sprague-Dawley rats while the fixed dose testing used a variety of 370 rats.  No specifics are given on the exact doses used in the classic LD50.  Each of the 25 laboratories testing resorcinol following the fixed dose method was to administer at least one of the following doses:   5, 50, 500 or 2000 mg/kg bw by oral bolus dosing (gavage). At least 5 males and 5 females were used for each dose level tested.  In the classic LD50 study the LD₅₀ in males was = 533 mg/kg bw, the LD50 in females was = 489 mg/kg bw; a combined LD₅₀(male/female) was = 510 mg/kg bw.  Using the fixed dose method, a definitive LD₅₀ was not determined for rats.  Autopsy findings in the fixed-dose tests showed the liver, kidney, stomach and intestine to be discolored, odema of the glandular gastric mucosa and rapid heartbeat. Common clinical signs included ptosis, respiratory effects, lethargy, abnormal gait, tremors, convulsions and salivation.  

In a study conducted in accordance with U.S. Federal Hazardous Substances Labeling Act (FHSLA) groups of 5 male albino rats (strain not specified) were administered 398, 795, 1580 or 3160 mg/kg bw of flaked or industrial grade resorcinol via oral bolus dosing (gavage) (Koppers Company, 1962; Flickinger, 1976; and NIOSH, 1992).  The LD₅₀ was = 980 mg/kg bw.   Hyperemia and distention of stomach and intestines were observed in the animals that died during the observation period.  There were no effects on body weight gain and no findings at necropsy in surviving animals. 

No overt effects were seen in female rats given 55 mg/kg bw resorcinol by gavage, but hyperexcitability and tachypnea were seen at 110 mg/kg bw. These doses were actually given daily for 17 days, but were considered to be acute effects associated with bolus dosing (NTP, 1992).

In a fixed dose study conducted according to GLP and OECD Guidelines (with minor deviations), rats were administered resorcinol via oral gavage at single doses of 200, 500 or 2000 in a preliminary test and a dose of 200 mg/kg in the main experiment. Hypoactivity or piloerection, dyspnoea and tremors were observed in all animals on day 1, with recovery complete on day 2. No mortality, treatment-related effects on bodyweight or gross abnormalities were observed. The dose of 200 mg/kg was identified as the maximum non-lethal dose of resorcinol under these experimental conditions (CIT, 2004).

Inhalation:

In an aerosol inhalation study, groups of 6 female Harlan-Wistar rats were exposed for one or eight hours to concentrations of 2130 and 7800 mg/m³ and 2000, 2480 and 2800 mg/m³, respectively (Flickinger, 1976 a and b).  Aerosols were generated after dissolving resorcinol in water.  Animals were sacrificed 14 days post-exposure.  It should be noted that in the study conducted at a concentration of 2480 and 7800 mg/m³, the solution turned milky and some precipitate was noted.  It is likely that flow concentrations were less than the concentration indicated.  All animals had normal weight gains and no lesions attributable to inhalation of the aerosol were seen at gross necropsy.  The one hour LC₀ was > 7800 mg/m³ (1732 ppm) and the eight hour LC₀ was > 2800 mg/m³ (>622 ppm) in rats.

Dermal:

In a study conducted in accordance with FHSLA, groups of 4 male albino rabbits (strain not specified) were administered 1000, 2000, 3980 and 7950 mg/kg bw of flaked and industrial grade resorcinol. The test substance was applied to abraded and intact trunk skin via gauze for 24 hours and covered with an impervious plastic film (Koppers Company, 1962 and Flickinger, 1976). In flaked grade resorcinol in rats administered 1000, 2000, 3980 and 7950 mg/kg bw the following number deaths were observed:  0, 1, 2 and 4, respectively.  In industrial grade resorcinol in rats administered 1000, 2000, 3980 and 7950 mg/kg bw the following number of deaths were observed:   0, 0, 4 and 4, respectively.  The LD₅₀ was determined to be 3360 and 2830 mg/kg bw for flaked and industrial grade resorcinol, respectively.  Flaked grade resorcinol produced necrosis of the skin in all rabbits exposed to 3980 mg/kg bw and above; industrial grade resorcinol produced necrosis in 3 of the rabbits exposed to 2000 mg/kg bw.  The rabbits exposed to 1000 mg/kg flaked grade resorcinol showed only slight hyperkeratosis following signs of moderate to severe irritation after 24 hours contact.  However, the same dose of industrial grade resorcinol showed no signs of irritation seven days following contact.  Body weight gains were reduced in surviving animals.  There were no findings at necropsy. 

Resorcinol was applied as a paste to the skin to groups of five albino rabbits (strain not specified) at 2150, 3160, 4640 and 6810 mg/kg bw.  The LD₅₀ was = 3830 mg/kg bw (exposure time not stated) (Koppers Company, 1970b).  Clinical signs occurred within 12 hours of administration and included salivation, tremors, and convulsions prior to death.  Time of recovery was dose dependent with no symptoms being present after 1 day at 2150 mg/kg bw, while 3160 and 4640 mg/kg bw group animals had recovery times of 3 and 4 days, respectively.  Very slight erythema and extreme dryness was noted.  Necropsy on the surviving animals showed no significant findings, while animals that died showed hemorrhage of the gastrointestinal tract.

Justification for classification or non-classification

Based on an acute oral LD50 of 510 mg/kg/day, resorcinol is classified as an Acute Category 4 based on EC 1272/2008, Classification, Labelling and Packaging (CLP). Based on available data, the substance is not classifiable for acute toxicity via the inhalation and dermal routes. The fixed dose study that identified a maximum non-lethal dose of 200 mg/kg was used for the self-classification of STOT SE CAT 1 for CNS and blood.