Hydroquinone

Endpoint summary

Description of key information

Skin irritation
Dermal toxicity studies with no indication of a skin irritating potential of hydroquinone (Sheppard, 2001; Topping et al., 2007; Julou et al., 1973).
Long-term eye injury
Observation of irreversible severe eye injury leading to visual loss after occupational exposure in early production of hydroquinone without preventive measures.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Observations on dermal irritation effects during an acute dermal toxicity study with occlusive application for 24 hrs at a test concentration similar to OECD Guideline 404; study acceptable to waive a skin irritation study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Dermal effects observed during acute dermal toxicity study

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Covance Reseaerch Products, Denver, PA, USA
- Age at study initiation: at least 3 mo
- Body weight at study initiation: males 2.329-2.492 kg, females 2.040-2.592 kg
- Fasting period before study: no
- Housing: single
- Diet: PMI #5325 ad libitum
- Water: ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.8-22.9
- Humidity (%): 47.8-70
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

other: moistened with water

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg

Duration of treatment / exposure:

24 h

Observation period:

14 d

Number of animals:

5 males and 5 females

Details on study design:

TEST SITE
- Area of exposure: dorsal skin
- % coverage: 10% of body surface
- Type of wrap if used: occlusive wrap (no further data)


REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24 h


SCORING SYSTEM: only qualitative visual inspection of effects

Irritation parameter:

erythema score

Remarks:

Qualitative assessment of skin irritation.

Basis:

mean

Remarks:

no individual data reported. Dermal application for 24 hours only

Time point:

24/48/72 h

Score:

ca. 0

Remarks on result:

other: Score of 0 assumed as default value for absence of adverse skin effects

Irritation parameter:

edema score

Remarks:

Qualitative assessment of skin irritation.

Basis:

mean

Remarks:

No individual data reported. Dermal application for 24 hours only

Time point:

24/48/72 h

Score:

ca. 0

Remarks on result:

other: Score of 0 assumed as default value for absence of adverse skin effects

Irritant / corrosive response data:

No adverse dermal effects reported

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the absence of any dermal effects at the application site, there was no indication of skin irritation in rabbits during a dermal toxicity study with test concentrations comparable to those used for skin irritation studies. A more severe test condition with a 24-hour occlusive application was applied than is usual for skin irritation studies according to OECD Guideline 404 .

Executive summary:

Groups of 5 male and 5 female rabbits were exposed to HQ moistened with water for 24 h under an occlusive dressing during a dermal toxicity study and skin findings were reported qualitatively (no skin scoring system applied to describe findings). These test conditions deviate from OECD Guideline 404 which requests a 4-h semi-occlusive exposure. However, as the test concentrations of 27-36 mg/cm², which were estimated based on the applied dose of 2000 mg/kg bw, are comparable to the 30 mg/cm² requested by OECD Guideline 404, this study can be used for the assessment of skin irritation. No adverse dermal effects were reported indicating the absence of an irritating potential of pure HQ (no vehicles used) under the conditions of this test.

Reference 2

Endpoint:

skin corrosion: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because an acute toxicity study by the dermal route does not indicate skin irritation up to the relevant limit dose level (2 000 mg/kg body weight)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

There is no skin irritation study available performed according to standard or guideline protocols.

Waiving is possible based on reported observations of dermal effects in acute dermal toxicity studies with rabbits (Sheppard, 2002; Topping et al., 2007) or rats (Julou et al., 1973). The available two studies are valid.

Groups of 5 male and 5 female rabbits were exposed to hydroquinone (HQ) moistened with water for 24 h under an occlusive dressing during an acute dermal toxicity study and skin findings were reported qualitatively (no skin scoring system applied to describe findings). These test conditions deviate from OECD Guideline 404 which requests a 4-h semi-occlusive exposure. However, as the test concentrations are in a range of 27-36 mg/cm²(estimation based on the applied dose of 2000 mg/kg bw) are comparable to the 30 mg/cm²requested by OECD Guideline 404, this study can be used for the assessment of skin irritation. No adverse dermal effects were reported indicating the absence of an irritating potential of pure HQ (no vehicles used) under the conditions of this test (Weight of evidence: Sheppard, 2002; Topping et al., 2007).

After a 24-hour open dermal application of 5 or 35% aqueous solutions of HQ to the shaved dorsal skin of rats, no local skin effects were reported during a 14-day post-observation period. No standard scoring system for dermal irritation was used (Weight of evidence: Julou et al., 1973). Although classification of skin irritation is not possible based on this study, it supports the absence of irritating effects.

Based on this two studies there are no indications to expect a skin irritating potential of HQ under guideline conditions, and HQ is classified as non-irritating to the skin.

 

Eye irritation in experimental animals

There is no eye irritation study in rabbits available performed according to standard or guideline protocols. No data are available to classify HQ for eye irritation based on test results from an animal assay

However, an eye irritation study in the rabbit is scientifically not justified and can be waived as HQ dust is known to produce severe irreversible eye injury in exposed workers (see below). Classification is possible based on these observations in humans.

 

Long-term eye injury in humans

Eye lesions other than the typical symptoms of acute eye irritation attracted attention during the early production of HQ. Long-term exposure conditions of the workmen included higher exposure levels of HQ dust (up to 25 -30 mg/m³) and benzoquinone (BQ) vapours before the installation of different protective measures (Key study: Anderson, 1947; Sterner et al., 1947; Oglesby et al., 1947; Grant and Schuman, 1993; endpoint study record presented in IUCLID Section 7.10.1). Health surveys of these workmen were supplemented by ophthalmoscopic examinations after a first case of characteristic eye injury had been recognized in 1946.

Exposure-related corneal injury was of two types: one a typical superficial greenish brown stain, and the other, greyish white opacities varying in size and involving all the layers of the cornea. In a few cases there had been a considerable loss of vision. The conjunctival and corneal stains were considered to represent end products of the oxidation and subsequent polymerisation of BQ or HQ. The corneal opacities were discussed to be due to the precipitation of corneal protein or a scar-forming effect.

The relative contribution of BQ vapour or HQ dust to the production of the eye lesions is difficult to assess. However, based on observations in workmen with predominant exposure to HQ, contact of the eyes with particles of HQ induces both conjunctival pigmentary changes and corneal opacity. Further, HQ is converted into the more volatile BQ in the presence of moisture. Eye injuries apparently developed gradually over a period of years with no serious cases in employees of less than five years plant experience. Removal from exposure resulted in considerable improvement in the staining but a questionable effect on corneal opacities. No values for individual exposure levels are available. A positive correlation was reported to exist to the length of exposure (Sterner et al., 1947). Based on measured air levels and observed eye effects, a maximum permissible workplace level to prevent eye injuries of 2-3 mg HQ/m³ (in the presence of 0.4 mg/m³= 0.1 ppm BQ) was suggested (Oglesby et al., 1947). After installation of measures to reduce exposure, concentrations of HQ dust in the packaging area, were exposure was almost exclusively to HQ, declined from up to 25-30 mg HQ/m³in 1944 to 1-4 mg HQ/m³in 1946 (Sterner et al., 1947).

Following the initial survey in 1946, workmen exposed to BQ vapours and HQ dust were followed by annual slit-lamp examination. Any worker who showed eye changes was transferred to another operative zone. A comprehensive screening in 1955 with 201 persons comprised almost all personnel who might have received significant exposure to HQ (including some executive and clerical personnel). In 1955/1956, the characteristic early changes (staining of conjunctiva and cornea, see above) were no longer encountered, and conjunctival lesions had in fact regressed or disappeared in those persons removed from exposure hazards.

However, for a number of men exposed prior to 1946, the corneas had undergone changes of a profound and irreversible nature, leading to alterations in the corneal curvature. The late eye effects, were characterized by Hudson-Staehli lines, striae and severe astigmatism, associated with visual loss, which had appeared although exposure had been discontinued. Presumably, these late changes are due to a minimal irritative insult that might result from prolonged exposure to HQ dust or BQ vapour but is known also to be induced from the irritative insult of other chemicals (Key study: Anderson and Oglesby, 1958; Grant and Schuman, 1993; endpoint study record presented in IUCLID Section 7.10.1).

Based on the health surveys in HQ-exposed workers, it is evident that HQ has the potential to induce severe irreversible eye damage.

Justification for selection of eye irritation endpoint:
No experimental data in animal studies, but irreversible adverse ocular effects were reported in the past in the workplace under what seemed to be conditions of high concentration of substance in the atmosphere. (description under "exposure related observations in humans")

Effects on eye irritation: highly irritating

Justification for classification or non-classification

Skin irritation

Based on a weight of evidence approach with data from acute dermal toxicity studies there are no indications to expect a skin irritating potential of hydroquinone under guideline conditions, and hydroquinone is not classified for skin irritation according to the criteria of EC directive 1272/2008 and GHS.

Eye irritation

According to the criteria of EC directive 1272/2008 and GHS, hydroquinone is classified to Eye Damage Category 1; H318: Causes serious eye damage, based on the observation of irreversible severe eye injury in workers after long-term exposure.