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Toxicological information

Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
other: reevaluation
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comprehensive collection of data in a non-peer reviewed critical review article, critical parameters were considered and confounders were adressed to make conclusions on the reliability of the primary data; review article acceptable as key study on the subject of HQ-induced ochronosis

Data source

Reference
Reference Type:
review article or handbook
Title:
The safety of hydroquinone: A dermatologist's response to the 2006 federal Register.
Author:
Levitt J
Year:
2007
Bibliographic source:
J Am Acad Dermatol 57, 854-872

Materials and methods

Type of study / information:
Compilation of data of clinical studies involving topical exposures to HQ, and of case reports of exogenous ochronosis
Endpoint addressed:
repeated dose toxicity: dermal
Principles of method if other than guideline:
Survey of world literature on the topic of human exposure to topical pharmaceutical hydroquinone preparations and exogenous ochronosis using the database PubMed (years 1966 - 2007) and cases cited in the Federal Register, inclusion of relevant references from these primary sources for identification of relevant article published before 1966

Test material

Reference
Name:
Unnamed
Type:
Constituent

Method

Ethical approval:
not applicable
Details on study design:
Evaluation of clinical studies:
The following data were compiled: Number of patients, duration of the study, concentration of HQ applied, frequency of application, diagnosed numbers of ochronosis. Evaluation was limited to studies with at least one month duration. Many studies had close physician follow-up.

Evaluation of case reports of ochronosis after use of skin bleaching creams: cases reported through December 2006
The following data were compiled: number of ochronosis cases reported in the publication, duration of application, concentration of HQ applied, information which agent was used leading to possible co-exposure with other substances that can also induce ochronosis, frequency of application, geography, information if diagnosis was proven by biopsy
Details on exposure:
TYPE OF EXPOSURE: topical

EXPOSURE LEVELS: clinical studies: 1 to up to 7.5% (extreme 30%); case reports: up to 16.7%, no information available for many cases

EXPOSURE PERIOD: clinical studies: 1 mo up to 12 mo (single study with duration up to several yrs), frequency once or twice daily; case reports: many yrs (up to 35 yrs), frequency up to many times a day

Results and discussion

Results:
Based on reliable data from clinical studies and cases reported in the United States of America, the appearance of exogenous ochronisis due to topical use of HQ-containing formuations for bleaching skin is a rare event, with one reported case per year and per 10 million tubes of skin bleaching products sold.
The more frequent reporting of cases of ochronosis in Africa after use of skin bleaching products is highly confounded by insufficient diagnosis, excessive, unsupervised use of high concentrations of HQ, and co-exposure to other agents known to induce ochronosis as phenol, resorcinol, and antimalarials.

Any other information on results incl. tables

Exogenous ochronosis is a skin condition in which foreign substances cause homogenistic acid to be deposited in the dermis, causing macular and papular hyperpigmentation.

In clinical studies there was no reported case of ochronosis. In total, 9,632 patients were included in the evaluation (a study with a questionable number of 10,000 patients was excluded), generally with exposures ranging from 1 to 12 months. 982 patients were exposed to 2% HQ. In the total group of 7,267 patients exposed to 3-5% HQ, 6,0615 were exposed to 4% HQ, and 65 to at least 5% HQ (total numbers including the questionable study).

Worldwide, 789 cases of ochronosis had been reported up to 2006. Only 22 were from the United States and 756 from Africa. Of the 756 African cases, 503 were biopsy proven, and 253 are based on clinical impression, which could be subject of overdiagnosis. Of the total 789 cases, 652 fail to specify the concentration of HQ used. In 116 cases, 1-2% HQ was used, in the remaining 22 cases, the HQ concentration was at least 3%. The duration of the vast majority of cases was on the order of years, if specified at all.

Especially in the African cases, information on the used HQ containing bleaching creams and on frequency and duration of application is not available. Presumably, there exists a practice of excessive, unsupervised and uncontrolled use of skin bleaching formulations with high concentrations of HQ in Africa. Additionally, skin bleaching formulations in Africa often contain skin penetration enhancing vehicles in combination with high concentrations of HQ and other ingredients, such as phenol and resorcinol, that are known to cause exogenous ochronosis. Additionally, diagnosis may be confounded by the relative high use of antimalarials which also induce ochronosis. Antimalarial use was not examined and documented in the African case reports as well as concomitant exposure to phenol or resorcinol.

In the United States, only 22 cases were reported during the period from 1983-2006, amounting to a single case per year. 21 cases were associated with the use of 1-2% HQ, a single case resulted from use of 4% HQ. The duration of use was typically on the order of years, with the exception of two cases with 3-month exposures to 2 and 4% HQ. It has been estimated that 10 million to 15 million tubes of skin lightening formulations containing HQ are sold annually in the U.S. resulting in a low incidence of one case per 10 million tubes sold.

Applicant's summary and conclusion

Conclusions:
Based on reliable data from clinical studies and cases reported in the United States of America, the appearance of exogenous ochronisis due to topical use of HQ-containing formuations for bleaching skin is a rare event, with one reported case per year and per 10 million tubes of skin bleaching products sold.
The more frequent reporting of cases of ochronosis in Africa after use of skin bleaching products is highly confounded by insufficient diagnosis, excessive, unsupervised use of high concentrations of HQ, and co-exposure to other agents known to induce ochronosis as phenol, resorcinol, and antimalarials.
Executive summary:

Exogenous ochronosis is a skin condition in which foreign substances cause homogenistic acid to be deposited in the dermis, causing macular and papular hyperpigmentation.

In clinical studies there was no reported case of ochronosis. In total, 9,632 patients were included in the evaluation (a study with a questionable number of 10,000 patients was excluded), generally with exposures ranging from 1 to 12 months. 982 patients were exposed to 2% HQ. In the total group of 7,267 patients exposed to 3-5% HQ, 6,0615 were exposed to 4% HQ, and 65 to at least 5% HQ (total numbers including the questionable study).

Worldwide, 789 cases of ochronosis had been reported up to 2006. Only 22 were from the United States and 756 from Africa. Of the 756 African cases, 503 were biopsy proven, and 253 are based on clinical impression, which could be subject of overdiagnosis. Of the total 789 cases, 652 fail to specify the concentration of HQ used. In 116 cases, 1-2% HQ was used, in the remaining 22 cases, the HQ concentration was at least 3%. The duration of the vast majority of cases was on the order of years, if specified at all.

Especially in the African cases, information on the used HQ containing bleaching creams and on frequency and duration of application is not available. Presumably, there exists a practice of excessive, unsupervised and uncontrolled use of skin bleaching formulations with high concentrations of HQ in Africa. Additionally, skin bleaching formulations in Africa often contain skin penetration enhancing vehicles in combination with high concentrations of HQ and other ingredients, such as phenol and resorcinol, that are known to cause exogenous ochronosis. Additionally, diagnosis may be confounded by the relative high use of antimalarials which also induce ochronosis. Antimalarial use was not examined and documented in the African case reports as well as concomitant exposure to phenol or resorcinol.

In the United States, only 22 cases were reported during the period from 1983-2006, amounting to a single case per year. 21 cases were associated with the use of 1-2% HQ, a single case resulted from use of 4% HQ. The duration of use was typically on the order of years, with the exception of two cases with 3-month exposures to 2 and 4% HQ. It has been estimated that 10 million to 15 million tubes of skin lightening formulations containing HQ are sold annually in the U.S. resulting in a low rate of one case per 10 million tubes sold.

Based on reliable data from clinical studies and cases reported in the United States of America, the appearance of exogenous ochronisis due to topical use of HQ-containing formuations for bleaching skin is a rare event, with one reported case per year and per 10 million tubes of skin bleaching products sold. The more frequent reporting of cases of ochronosis in Africa after use of skin bleaching products is highly confounded by insufficient diagnosis, excessive, unsupervised use of high concentrations of HQ, and co-exposure to other agents known to induce ochronosis as phenol, resorcinol, and antimalarials.