SCCS/1316/10
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`Scientific Committee on Consumer Safety
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`SCCS
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`OPINION ON
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`DIETHYLENE GLYCOL MONOETHYL ETHER
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`(DEGEE)
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`The SCCS adopted this opinion at its 8th plenary meeting
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`of 21 September 2010
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`Almirall EXHIBIT 2052
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`Amneal v. Almirall
`IPR2019-00207
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
`___________________________________________________________________________________________
`
`SCCS/1316/10
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`
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`About the Scientific Committees
`Three independent non-food Scientific Committees provide the Commission with the
`scientific advice it needs when preparing policy and proposals relating to consumer safety,
`public health and the environment. The Committees also draw the Commission's attention
`to the new or emerging problems which may pose an actual or potential threat.
`They are: the Scientific Committee on Consumer Safety (SCCS), the Scientific Committee
`on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and
`Newly Identified Health Risks (SCENIHR) and are made up of external experts.
`In addition, the Commission relies upon the work of the European Food Safety Authority
`(EFSA), the European Medicines Evaluation Agency (EMA), the European Centre for Disease
`prevention and Control (ECDC) and the European Chemicals Agency (ECHA).
`
`SCCS
`The Committee shall provide opinions on questions concerning all types of health and safety
`risks (notably chemical, biological, mechanical and other physical risks) of non-food
`consumer products (for example: cosmetic products and their ingredients, toys, textiles,
`clothing, personal care and household products such as detergents, etc.) and services (for
`example: tattooing, artificial sun tanning, etc.).
`
`
`Scientific Committee members
`Jürgen Angerer, Ulrike Bernauer, Claire Chambers, Qasim Chaudhry, Gisela Degen, Thomas
`Platzek, Suresh Chandra Rastogi, Vera Rogiers, Christophe Rousselle, Tore Sanner, Kai
`Savolainen, Jacqueline Van Engelen, Maria Pilar Vinardell, Rosemary Waring, Ian R. White
`
`
`Contact
`European Commission
`Health & Consumers
`Directorate C: Public Health and Risk Assessment
`Unit C7 - Risk Assessment
`Office: B232 B-1049 Brussels
`Sanco-Sc6-Secretariat@ec.europa.eu
`
`
` ©
`
` European Union, 2010
`ISSN 1831-4767
`doi:10.2772/26133
`
`The opinions of the Scientific Committees present the views of the independent scientists
`who are members of the committees. They do not necessarily reflect the views of the
`European Commission. The opinions are published by the European Commission in their
`original language only.
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`http://ec.europa.eu/health/scientific_committees/consumer_safety/index_en.htm
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`ISBN 978-92-79-12749-6
`ND-AQ-09-021-EN-N
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
`___________________________________________________________________________________________
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`SCCS/1316/10
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`
`
`
`(chairman, rapporteur)
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`ACKNOWLEDGMENTS
`
`
`Prof. J. Angerer
`Dr. U. Bernauer
`Dr. C. Chambers
`Prof. G. Degen
`
`Dr. S.C. Rastogi
`Prof. V. Rogiers
`Prof. T. Sanner
`Dr. J. van Engelen
`Prof. R. Waring
`Dr. I.R. White
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`
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`Keywords: SCCS, scientific opinion, diethylene glycol monoethyl ether, DEGEE, directive
`76/768/ECC, CAS 111-90-0, EC 203-919-7
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`
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`Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on
`diethylene glycol monoethyl ether, 21 September 2010
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
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`TABLE OF CONTENTS
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`
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`ACKNOWLEDGMENTS ........................................................................................... 3
`
`BACKGROUND ............................................................................................. 5
`
`TERMS OF REFERENCE.................................................................................. 6
`
`OPINION..................................................................................................... 7
`
`CONCLUSION ............................................................................................ 47
`
`MINORITY OPINION.................................................................................... 48
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`REFERENCES............................................................................................. 48
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`1.
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`2.
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`3.
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`4.
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`5.
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`6.
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
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`1. BACKGROUND
`
` A
`
` risk assessment on diethylene glycol monoethyl ether (DEGEE) with the chemical name 2-
`(2-ethoxyethoxy)ethanol and the INCI-name Ethoxydiglycol was done by a Member State
`(France). The risk assessment was based mainly upon data from the open scientific
`literature and on the skin absorption studies performed by industry. This risk assessment
`led the Member State to put certain restrictions on the use of this substance.
`
`According to the notification to the Commission, DEGEE is currently used in cosmetic
`products in shampoos (rinse-off) in a concentration up to 5% and in creams (leave-on) in a
`concentration up to 2%, excluding products intended to be used in the vicinity of the eyes.
`The notifying Member State concluded that the substance could be considered safe for the
`consumers, when used in a concentration up to 1.5% in cosmetics product except products
`for oral hygiene.
`
`As a consequence of the notification, the SCCP was asked to give its opinion on Diethylene
`glycol monoethyl ether (DEGEE). The first opinion was adopted on 19 December 2006 by
`the SCCP (SCCP/1044/06) with the following conclusion:
`
`"Based on the information provided, the SCCP is of the opinion that the use of diethylene
`glycol monoethyl ether (DEGEE) in all cosmetic products, except products for oral hygiene
`and eye products at a concentrations up to 1.5% does not pose a risk to the health of the
`consumer, provided that the level of ethylene glycol in DEGEE used is < 0.2%. The opinion
`relates to the dermal application. It does not include any other cosmetic exposure, such as
`exposure from possible aerosol/spray products."
`
`In December 2007 an updated risk assessment was submitted by COLIPA1. In addition to
`the overall use of DEGEE in a concentration up to 1.5%, the applicant applied for a specific
`use of DEGEE as a solvent in hair dyes formulations at a concentration up to 7.0% and to
`support this application, additional percutaneous absorption data was provided.
`
` A
`
` second opinion (SCCP/1200/08) on Diethylene glycol monoethyl ether (DEGEE) for its use
`as solvent in hair dye formulations was adopted on 16 December 2008 with the conclusion
`that:
`
`"The SCCP is of the opinion that the use of diethylene glycol monoethyl ether (DEGEE) as a
`solvent in an on-head concentration of up to 7.0% in oxidative hair dye formulations and in
`an on-head concentration of up to 5.0% in non-oxidative hair dye formulations in addition
`to the use of DEGEE at concentrations up to 1.5% in all cosmetic products except products
`for oral hygiene and eye products does not pose a risk to the health of the consumer,
`provided that the level of ethylene glycol in DEGEE used is < 0.2%.
`
`The opinion relates to the dermal application of cosmetic products only and does not include
`any other cosmetic exposure, such as exposure from possible aerosol/spray products.
`
`Aggregate exposure to diethylene glycol monoethyl ether (DEGEE) from non-cosmetic
`sources has not been considered".
`
`In January 2009 an additional submission was presented by EFfCI2, providing a subchronic
`3-month toxicity study in dogs. Based on this dossier, the applicant considers that DEGEE
`can be used safely in concentration up to 5.5% in leave-on products and up to 10.0% in
`rinse-off products.
`
`
`1 COLIPA – The European Cosmetic Association
`2 EFfCI The European Federation for Cosmetic Ingredients
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`2. TERMS OF REFERENCE
`
`1. Does the SCCS consider the use of DEGEE as a solvent in cosmetic products in a
`concentration up to 5.5% in leave-on products and/or in a concentration up to 10% in
`rinse-off products safe for the consumer, taken into account the provided scientific
`data?
`
`
`2. Does the SCCS consider that an additional use of the substance DEGEE as solvent in
`an on-head concentration up 7.0% in oxidative hair dye formulations and in an on-
`head concentration up 5.0% in non-oxidative hair dye formulations, is safe, taken into
`account the provided data?
`
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`3. Does the SCCS have any further scientific concerns with regard to the use of DEGEE?
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
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`SCCS/1316/10
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`Chemical identity
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`Primary name and/or INCI name
`
`2-(2-Ethoxyethoxy)ethanol
`Ethoxydiglycol
`
`Trade names and abbreviations
`
`3. OPINION
`The present Opinion contains the information provided for the previous Opinions on DEGEE
`adopted by SCCP on 19 December 2006 (SCCP/1044/06) and 16 December 2008
`(SCCP/1200/08) with additional data from a recent Submission. References from the new
`submission are referred to as N Ref.: xx, and are listed separately.
`
`3.1. Chemical and Physical Specifications
`
`3.1.1.
`
`3.1.1.1.
`
`IUPAC name:
`INCI name:
`
`3.1.1.2. Chemical names
`
`Diethylene glycol monoethyl ether, 3,6-Dioxa-1-octanol, Diethylene glycol ethyl ether,
`Diglycol monoethyl ether, Ethanol, 2,2'-oxybis-, monoethyl ether, Ethyl carbitol, Ethyl
`diethylene glycol, Ethyl digol,
`
`3.1.1.3.
`
`Carbitol, Carbitol solvent, Dioxitol, Dowanol 17, Dowanol DE, Ektasolve DE, Solvolsol,
`Transcutol CG, Transcutol P, Transcutol HP
`
`DEGEE
`
`3.1.1.4. CAS / EC number
`
`CAS:
`EC:
`
`3.1.1.5. Structural formula
`
`111-90-0
`203-919-7
`
`
`Empirical formula
`
`Physical form
`
`Molecular weight
`
`134.2
`
`3.1.1.6.
`
`Formula: C6H14O3
`
`3.1.2.
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`Liquid with a mild, pleasant odour; hydroscopic
`
`3.1.3.
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`Molecular weight :
`
`3.1.4.
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`The applicant states that from May 1998, the manufacturing process of DEGEE was
`improved in order to decrease the content in residual impurities.
`
`Purity, composition and substance codes
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
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`SCCS/1316/10
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`Impurities / accompanying contaminants
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`Solubility
`
`Partition coefficient (Log Pow)
`
`- 0.54 (exp)
`
`Transcutol CG: > 99.5% (cosmetics only)
`Transcutol P: > 99.7% (pharmaceutical, topical forms)
`Transcutol HP: > 99.9% (pharmaceutical, other administration routes)
`
`3.1.5.
`
`Impurities: Ethylene glycol. Commercial products may contain an appreciable amount of
`ethylene glycol (CAS No. 107-21-1).
`
`Transcutol CG contains < 0.062% (620 ppm) ethylene glycol.
`
`3.1.6.
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`In water: Miscible
`
`3.1.7.
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`Log Pow:
`
`3.1.8.
`
`Appearance:
`Melting point:
`Boiling point:
`Density:
`Rel. vapour density:
`Vapour Pressure:
`
`Conversion:
`1 ppm = 5.58 mg/m³
`1 mg/m3 = 0.179 ppm
`
`3.1.9.
`
`Shelf life: At least 3 years of storage under recommended conditions of original hermetically
`closed container (The product is packed under nitrogen and must be used shortly after
`opening).
`
`
`3.2. Function and uses
`
`DEGEE may be prepared from ethylene oxide and 2-ethoxyethanol in the presence of SO2.
`It is used in the chemical and paint industries as a solvent for nitro cellulose, resins, and
`dyes. DEGEE is not used in food or detergent products.
`
`Purified DEGEE (>99%) is used in cosmetics and dermatological preparations and as solvent
`in some medicine products. Its physical properties make DEGEE useful to solubilise lipophilic
`and hydrophilic compounds. Moreover DEGEE enhances the percutaneous absorption
`through the skin and mucosal barriers. It is used in some drugs to enhance absorption.
`
`In its previous opinions (SCCP/1044/06, SCCP/1200/08), the SCCP positively evaluated the
`use of DEGEE in cosmetic products up to 1.5% and in hair dyes up to 7.0% in oxidative and
`5% in non-oxidative formulations, based on the data available at the time. According to the
`recent application to the Commission, the applicant requested to increase the maximal
`concentration of DEGEE as a solvent in cosmetic products in a concentration up to 5.5% in
`leave-on products and up to 10% in rinse-off products, based on new studies provided.
`
`Additional physical and chemical specifications
`
`colourless liquid
`- 76 °C
`197 – 205 °C
`0.988
`/
`0.19 hPa
`
`Stability
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`Acute toxicity
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`3.3. Toxicological Evaluation
`
`3.3.1.
`
`3.3.1.1. Acute oral toxicity
`
`The acute toxicity after oral administration of DEGEE has been determined in several
`experiments. The results are summarized in Table 3.1.
`
`Table 3.1: Acute toxicity after oral administration of DEGEE
`
`
`Species
`
`Mouse
`Mouse
`Rat
`Rat
`Rat
`Rat
`Rat
`Rat
`Rat
`Guinea pig
`Rabbit
`
`LD50
`(mg/kg bw)
`7410
`6580
`7410
`5400-5500
`6000
`6310
`8690
`5540
`>5000
`3900
`3600
`
`Reference
`
`1
`2
`1
`3
`4
`5
`6
`2
`7
`1
`8
`
`
`
`Dogs
`
`Date of report:
`Guideline/method:
`Species/strain:
`Group size:
`Test substance:
`Batch:
`Dose levels:
`Dose volume:
`
`Vehicle:
`Route:
`Exposure period:
`
`June 2007
`/
`Dog/Beagle
`1 female
`Transcutol® HP (purity: >99.9%)
`450449013
`500, 1000, 1500, 2000 mg/kg bw
`5 ml/kg bw (500, 1000, 1500 mg/kg bw), 10 ml/kg bw (2000 mg/kg
`bw)
`Deionized water
`Oral (gavage)
`Single applications on days 0, 3, 6, 9 with increasing amounts of
`DEGEE
`Yes
`10.10.06 – 07.06.07
`
`GLP:
`Study period:
`
`Transcutol® HP was examined for its acute toxicity or tolerability in one female Beagle dog.
`The test substance was dissolved in deionized water and administered as a single dose
`orally by gavage on study days 0, 3, 6, and 9 followed by a 2-day non-dosing period before
`the next dose administration. Dose levels were 500, 1000, 1500 and 2000 mg/kg bw. The
`animal was observed twice daily for mortality and morbidity. Clinical examinations were
`performed daily. Detailed physical examinations were performed on the days of dosing and
`2 days following the final dose administration. Body weight was recorded on the days of
`dosing (prior to dose administration) and 2 days following the last dose. Food consumption
`was recorded daily, beginning at least 1 week prior to randomization. This animal was
`transferred to the stock colony at the end of the study.
`
`The authors reported that there were no test substance-related clinical findings or effects on
`body weight or food consumption during the escalating-dose phase of the study, where dose
`levels of 500, 1000, 1500 and 2000 mg/kg bw were administered. They concluded that the
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
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`SCCS/1316/10
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`oral (gavage) administration of Transcutol® HP to one female Beagle dog did not result in
`any test substance-related effects following single oral doses of 500, 1000, 1500 and 2000
`mg/kg bw.
`
`N Ref.: 35
`
`
`Comments
`It is noted that the study did only involve 1 dog. The experiment was terminated after 11
`days.
`
`
`Human
`In an isolated case report, an alcoholic male (aged 44) drank approximately 300 ml of a
`liquid containing 47% DEGEE (about 2000 mg/kg). Severe symptoms of central nervous
`and respiratory injury (dyspnoea) thirst and acidosis occurred. The urine contained albumin.
`The subject recovered following symptomatic treatment.
`
`
`3.3.1.2. Acute dermal toxicity
`
`The acute toxicity after dermal administration of DEGEE has been determined in several
`experiments. The results are summarized in Table 3.2.
`
`Table 3.2: Acute toxicity after dermal administration of DEGEE
`
`
`Ref.: 9
`
`Species
`
`Mouse
`Rat
`Rabbit
`Rabbit
`Guinea pig
`
`LD50
`(mg/kg bw)
`6000
`6000
`8300
`4200
`3200
`
`Reference
`
`10
`10
`10
`11
`11
`
`
`The Hazard Substances Data Bank (HSDB) cites:
`…..cosmetic preparations containing more than 5% Carbitol should not be used even for
`application to small areas of body …use … for this purpose may constitute an unexpected
`hazard, especially if applied to broken skin or in persons with renal disorders.
`
`Ref.: 9
`
`Ref.: 12
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`3.3.1.3. Acute inhalation toxicity
`
`LC50 rats = 5240 mg/m³
`
`Irritation and corrosivity
`
`
`General comment
`DEGEE has low acute toxicity by oral, dermal, and inhalation routes.
`
`3.3.2.
`
`3.3.2.1. Skin irritation
`
`Rabbit
`
`Guideline/method:
`
`Species/strain:
`Group size:
`Test substance:
`
`
`
`French authority method (Journal Officiel 21 April 1971) exceeding
`the requirement of the current OECD 404
`Rabbit/New Zealand White
`6 males
`50% aqueous diethylene glycol monoethyl ether (DEGEE)
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`Batch:
`Concentration:
`Route:
`Exposure:
`Observation period:
`GLP:
`Date:
`
`not stated
`50% 0.5 g of unchanged test substance
`intact and abraded skin
`24 h
`up to 72 h after patch removal
`No
`April 1974
`
` A
`
` 50% aqueous DEGEE solution was investigated for its acute dermal irritation potential in 6
`male New Zealand White rabbits on abraded and intact skin. The hair was clipped on the
`dorsal
`area of the trunk one day prior to application. Abraded skin areas were prepared by
`scarification with a 'vaccinostyle' (3 parallel incisions without damage to the dermis). An
`amount of 0.5 ml of the test substance was applied to the test site (0.25 ml/cm²) and held
`in place using a non-irritating tape covered by an occlusive dressing. The exposure lasted
`24 h. The animals were examined for erythema/eschar and oedema as well as for other
`local or systemic signs of toxicity for up to 72 h after patch removal.
`
`The authors reported that no signs of systemic toxicity, no mortality and no signs of
`irritation were noted during the whole observation period. The mean scores for
`erythema/eschar and oedema were 0.0 for each animal at each observation time point for
`the intact as well as for the abraded skin. They concluded that under the condition of this
`study, the 50% aqueous solution of DEGEE was shown to be non-irritating to the intact or
`abraded skin of New Zealand White rabbits.
`
`N Ref.: 10
`
`
`
`In addition to the study above, information exists on further skin irritation studies
`performed in rabbits and Guinea pigs. In these studies the tested substance revealed either
`a slight or no skin irritant effect in the experimental animals. However, it should be noted
`that only limited information on study methodology, substance characterization or details of
`results are available.
`
`N Ref.: 48, 51
`
`/
`Humans
`10 adult volunteers (females)
`Transcutol
`75412
`0.02 ml (undiluted), 50 mm²
`Skin (occlusive application)
`48 hours
`/
`In compliance
`January 1992
`
`
`Human
`
`Guideline:
`Species/strain:
`Group size:
`Test substance:
`Batch:
`Dose level:
`Route:
`Exposure period:
`Observation:
`GLP:
`Date:
`
`Transcutol was tested for potential irritation on human skin in a primary irritation single
`patch test as undiluted material. It was applied once at the dose level of about 0.02 ml per
`volunteer, on a surface of about 50 mm2 of skin on the back of 10 volunteers. Transcutol
`was kept in contact with the skin under an occlusive patch test for 48 hours. This
`application was performed in parallel and under same condition with patch test alone as
`“negative” control. Cutaneous macroscopic examinations were performed about 30 min
`after removal of the patches. Evaluation of the erythematous and oedematous reactions
`was made according to a given numerical scale. After the removal of the patches, only 1
`volunteer showed an erythema of grade 1 out of 4 grades
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`(i.e. very slight), while all other volunteers showed no erythema. It was concluded that the
`single epicutaneous application of Transcutol under the experimental conditions used was
`“well tolerated”.
`
`Ref.: 14
`
`
`3.3.2.2. Mucous membrane irritation
`
`Rabbit
`
`Comparable to OECD 405
`Guideline/method:
`Rabbit/New Zealand White
`Species/strain:
`3 males
`Group size:
`Transcutol
`Test substance:
`15809 (purity: 100%)
`Batch:
`0.1 ml of a 30% aqueous solution of Transcutol
`Concentration:
`Instillation in the conjunctival sac of the right eye
`Route:
`No
`Rinsing:
`Observation period: Up to 72 h after instillation
`GLP:
`Yes
`Date:
`June 1996
`
`The potential irritant effect of Transcutol® to the mucous membrane was investigated by
`instillation of 0.1 ml of a 30% aqueous solution of Transcutol® into the right conjunctival
`sac of each of three male animals. The left eyes remained untreated and served as controls.
`Both eyes of the animals were examined within 24 h before application and about 1, 24, 48,
`72 h after application. The evaluation and grading of the findings were performed according
`to the method of Draize (Federal Register 37, p. 8534, 1972).
`
`The treatment resulted in initial conjunctival chemosis of grade 1 in 1/3 rabbits and redness
`of grade 1 in 2/2 rabbits at the 1 hour reading. Thereafter on at 24, 48 or 72 hours readings
`no finding was observed in any of the 3 animals.
`
`The authors concluded that Transcutol tested as 30% aqueous solution was slightly and
`initially irritating to the eyes of 2 New Zealand White rabbits.
`
`N Ref.: 18
`
`
`
`OECD 405
`Guideline/method:
`Rabbit/New Zealand White
`Species/strain:
`3 males
`Group size:
`Transcutol
`Test substance:
`15809 (purity: 100%)
`Batch:
`0.1 ml of Transcutol (undiluted)
`Concentration:
`Instillation in the conjunctival sac of the right eye
`Route:
`No
`Rinsing:
`Observation period: Up to 72 h after instillation
`GLP:
`Yes
`Date:
`June 1996
`
`The potential irritant effect of Transcutol® to the mucous membrane was investigated by
`instillation of 0.1 ml of neat Transcutol® into the right conjunctival sac of each of three
`male animals. The left eyes remained untreated and served as controls. Both eyes of the
`animals were examined within 24 h before application and about 1, 24, 48, 72 h after
`application. The evaluation and grading of the findings were performed according to the
`method of Draize (Federal Register 37, p. 8534, 1972).
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`The treatment resulted in chemosis of grade 1 in 1/3, redness of grade 1 in 3/3 and
`congestion of grade 1 in 2/3 animals at the 24 hour reading (the period relevant for
`classification). At the 48 hour reading no chemosis or redness was observed anymore but
`grade 1 congestion was evident in 2/3 animals. At the 72 hour reading no finding was
`recorded anymore in any of the animals. Opacity was not recorded at any time in any
`animal.
`
`The authors concluded that Transcutol tested as neat substance was slightly and transiently
`irritating to the eyes of New Zealand White rabbits.
`
`N Ref.: 17
`
`
`Cat
`When DEGEE was applied to the eyes of cats, it causes immediate tearing and vigorous
`rubbing of the eyes, whereas in rabbits the response is less vigorous and the material
`appears to remain longer in the conjunctival sac. Cats exhibit only slight conjunctival
`reddening for a day or two, whereas rabbits have been known occasionally to develop
`conjunctivitis with discharge, iritis, and temporary corneal opacification, with return to
`normal in a week or two.
`
`Ref.: 18
`
`
`
`In addition to the above GLP studies, information exists on further eye irritation studies
`performed in rabbits and Guinea pigs. In these studies the tested substance revealed either
`a no, slight or irritant effects on the eyes.
`
`N Ref.: 48, 51
`
`Skin sensitisation
`
`
`General comment
`DEGEE is moderately irritant to the eye.
`
`3.3.3.
`
`/
`Guideline:
`Humans
`Species/strain:
`24 adult volunteers (19 – 38 years old; 18 men and 6 women)
`Group size:
`Transcutol
`Test substance:
`/
`Batch:
`0.02 ml Transcutol
`Dose level:
`Epicutaneous induction: Undiluted Transcutol
`Challenge:
`Undiluted Transcutol
`Route:
`Occlusive epicutaneous
`Exposure period:
`10 days
`Observation:
`15 days
`GLP:
`In compliance
`Date:
`January 1993
`
`The Marzulli and Maibach method was used. 30 volunteers were originally selected. 25 came
`to the Institute on the day for the first treatment. One male volunteer abandoned the study
`on the 12th day.
`
`The protocol of the irritation and sensitisation study was allocated into 3 distinct periods.
`Induction period. 9 consecutive applications, to the same area, of 0.02 ml, per volunteer, of
`Transcutol by the occlusive epicutaneous route to the skin of the arm during a 3 week period.
`Rest period. 15 days without any application.
`Challenge phase. Single application of 0.02 ml Transcutol to the skin of the back.
`
`The cutaneous reaction, control of the primary and cumulative irritations, was evaluated by
`macroscopic examination of the reactions possibly observed after removal of each patch test
`
`
`
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
`___________________________________________________________________________________________
`
`SCCS/1316/10
`
`
`corresponding to the induction period. The cutaneous reaction, control of the sensitisation,
`was evaluated by macroscopic examination of the reactions possibly noted about 24 and 48 h
`after removal of the patch test corresponding to the challenge application. These
`examinations were performed for the 1st, 8th (induction) and 10th (challenge) applications, by
`comparison to the reaction possibly obtained with a patch test alone (without Transcutol).
`
`It was concluded that no pathological irritation or sensitisation reaction significant to a
`cutaneous intolerance was noted.
`
`Ref.: 19
`
`Dermal / percutaneous absorption
`
`
`General comments
`DEGEE has not been demonstrated to cause sensitisation.
`
`The SCCS considers human induction studies as unethical
`
`3.3.4.
`
`Percutaneous absorption data on rinse-off and leave-on cosmetic products (from
`Submission for SCCP Opinion in 2006)
`
`Shampoo formulations (rinse-off)
`
`Guideline:
`Test substance:
`
`OECD 428
`5% and 10% DEGEE in a shampoo considered as a rinse-off reference
`formulation. ([4-14C] DEGEE 53 mCi/mmole, Specific activity at time
`of application to the skin 81 – 83 µCi/g of formulation)
`104-272-053 from ADME BIOANALYSES (30 310 Vergeze, France)
`98.2%
`5 mg/cm² of formulation, 279.3 and 529.6 µg/cm² DEGEE
`Human skin
`37°C
`30 min
`Shampoo formulation containing 5% or 10% DEGEE
`Saline phosphate buffer (pH 7.4) containing 15 g/l bovine serum
`albumin
`TEWL measurement
`In compliance
`March 2004
`
`Batch:
`Purity:
`Dose applied:
`Skin preparation:
`Skin temperature:
`Exposure period:
`Donor chamber:
`Receptor fluid:
`
`Skin integrity:
`GLP:
`Date:
`
`Two different DEGEE concentrations 5 and 10% in a shampoo formulation were applied on
`human skin during a period of 30 minutes. At this time the skin surface was rinsed off. Then
`the diffusion was monitored until 24 hours. The receptor fluid (RF) was completely collected
`after 30 min, 3, 6, 9, 12 hours and replaced by fresh fluid, the last sampling point was 24
`hours. At the end of the 24 hr observation period, the different skin layers were separated
`(horny layer, epidermis (E) and dermis) and analysed for DEGEE remaining. Results are
`expressed in µg equivalent of DEGEE (µg/cm²) and in percentage of the applied dose for all
`the compartments analysed (see table 3.3).
`
`
`
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`Opinion on diethylene glycol monoethyl ether (DEGEE)
`___________________________________________________________________________________________
`
`SCCS/1316/10
`
`
`Table 3.3: Quantities of DEGEE analysed in the different system compartments for the 2
`tested concentrations (5 and 10 %)
`
`Batch:
`Purity:
`Dose applied:
`Skin preparation:
`Skin temperature:
`Exposure period:
`Donor chamber:
`Receptor fluid:
`
`Skin integrity:
`GLP:
`Date:
`
` A
`
`
`
`
`
` 15% DEGEE leave-on hydro-alcoholic gel formulation was tested in two experiments. The
`formulation was applied on human skin during a period of 24 hours. The receptor fluid was
`completely collected after 3, 6, 9, 12 hours and replaced by fresh fluid, the last sampling
`point was 24 hours. At the end of the 24 hr observation period, the different skin layers
`were separated (horny layer, epidermis and dermis) and analysed for DEGEE remaining.
`Results are expressed in µg equivalent of DEGEE (µg/cm²) and in percentage of the applied
`dose for all the compartments analysed (see table 3.4).
`
`Table 3.4: Quantities of DEGEE analysed in the different system compartments in two
`experiments with 15% DEGEE in a leave-on hydro-alcoholic gel formulation
`
`First experiment
`% of the applied
`µg/cm²
`dose
`
`Second experiment
`% of the applied dose
`µg/cm²
`
`6.34 ± 1.84
`425 ± 85
`
`0.77 ± 0.23
`51.0 ± 9.1
`
`7.80 ± 1.64
`385 ± 46
`
`0.91 ± 0.20
`44.9 ± 4.8
`
`Washing (W)
`Total absorbed
`(E+D+S+RF)
`Total recovery (%)
`
`The percutaneous absorption study was conducted without occlusion. The mass balance of
`the experiment was low. The low recovery at the end of the 24 hours of diffusion was
`related to the evaporation of DEGEE from the skin surface. Therefore, the test was repeated
`under occlusion (by covering the skin with a piece of Parafilm). In the new experiment the
`total absorbed was 459 µg/cm² (51.5%) with a recovery of 92 ± 6%.
`
`52 ± 9
`
`46 ± 5
`
`
`
`15
`
`
`
`
`
`Washing (W)
`Receptor fluid (RF)
`Total absorbed
`(E+D+RF)
`Total recovery (%)
`
`
`
`Hydro-Alcoholic Gel Formulation (leave-on)
`
`Guideline:
`Test substance:
`
`µg/cm²
`
`DEGEE 5%
`% of the applied
`dose
`
`DEGEE 10%
`% of the applied
`µg/cm²
`dose
`
`194 ± 4
`53.8 ± 22.3
`60.5 ± 29.8
`
`69 ± 1
`19.37 ± 8
`21.6 ± 10.6
`
`389 ± 28
`89.7 ± 19.6
`92.9 ± 20.8
`
`73 ± 5
`16.9 ± 3.0
`17.5 ± 3.9
`
`91
`
`91
`
`Ref.: 20
`
`OECD 428
`15% DEGEE in a leave-on hydro-alcoholic gel formulation. ([4-14C]
`DEGEE 53 mCi/mmole, Specific activity at time of application to the
`skin 62 – 65 µCi/g of formulation)
`104-272-053 from ADME BIOANALYSES (30 310 Vergeze, France)
`98.2%
`5 mg/cm² of formulation, about 831.4 and 859.1 µg/cm²
`Human skin
`37°C
`24 hours
`Hydro-alcoholic gel formulation containing 15% DEGEE
`Saline phosphate buffer (pH 7.4) containing 15 g/l bovine serum
`albumin
`TEWL measurement
`in compliance
`April 2004
`
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`

`Opinion on diethylene glycol monoethyl ether (DEGEE)
`___________________________________________________________________________________________
`
`SCCS/1316/10
`
`
`Ref.: 21
`
`Emulsified formulations (leave-on)
`
`Guideline:
`Test substance:
`
`Batch:
`Purity:
`Dose applied:
`Skin preparation:
`Skin temperature:
`Exposure period:
`Donor chamber:
`Receptor fluid:
`
`OECD 428
`2%, 5%, and 10% DEGEE in Oil in Water emulsion considered as
`leave-on reference formulations. ([4-14C] DEGEE 53 mCi/mmole,
`Specific activity at time of application to the skin 112 – 130 µCi/g of
`formulation)
`104-272-053 from ADME BIOANALYSES (30 310 Vergeze, France)
`98.2%
`5 mg/cm² of formulation, 100 – 571 µg/cm2
`Human skin
`37 0C
`24 hours
`Oil in Water emulsions containing 2%, 5% or 10% DEGEE
`Saline phosphate buffer (pH 7.4) containing 15 g/l bovine serum
`albumin
`TEWL measurement
`In compliance
`April 2004
`
`Skin integrity:
`GLP:
`Date:
`
`Three different DEGEE concentrations 2, 5 and 10% in an Oil in Water emulsion formulation
`were applied on human skin during a period of 24 hour. The receptor fluid was completely
`collected after 3, 6, 9, 12 hours and replaced by fresh fluid, the last sampling point was 24
`hours. At the end of the 24 hr observation period, the different skin layers were separated
`(horny lay