1-O-β-(2 ,3-di-O-alka(e)noyl-6 -O-acetyl-D-mannopyranosyl)-D-erythritol

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 July 2019 - 30 August 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study followed the expected guideline.

Justification for type of information:

Please refer to the attached justification.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Type of sensitisation studied:

skin

Study type:

study with volunteers

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: KLIGMAN, A.M. & WOODING, W.M.

Version / remarks:

KLIGMAN, A.M. & WOODING, W.M. A method for the measurement and evaluation of irritants of human skin. J. Invest.. Derm. 49: 78-94, 1967

Deviations:

yes

Remarks:

only 35 participant completed the study

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

other: FISHER's Contact Dermatitis

Version / remarks:

Fisher A, 1995. Contact Dermatitis 4th ed.

Deviations:

yes

Remarks:

Only 35 subjects completed the study

GLP compliance:

not specified

Test material

Test material information

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL:

- Source and lot/batch No.of test material: Sponsor, Ref:10444, Product code: 077314-01

- Expiration date of the lot/batch: Not stated

- Purity test date: Not stated

RADIOLABELLING INFORMATION (if applicable): N/A

- Radiochemical purity:

- Specific activity:

- Locations of the label:

- Expiration date of radiochemical substance:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL: Not stated
- Storage condition of test material:
- Stability under test conditions:
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:


TREATMENT OF TEST MATERIAL PRIOR TO TESTING: Applied undiluted
- Treatment of test material prior to testing:
- Preliminary purification step (if any): N/A
- Final dilution of a dissolved solid, stock liquid or gel: N/A
- Final preparation of a solid: N/A

FORM AS APPLIED IN THE TEST (if different from that of starting material): Not stated

OTHER SPECIFICS: N/A

Method

Type of population:

general

Ethical approval:

confirmed and informed consent free of coercion received

Subjects:

A total of 79 study subjects were recruited for this study. Out of those, 2 subjects (003 and 035) did not meet the inclusion criteria or presented any of the exclusion criteria.
The study was initiated with 77 subjects, 69 of which were female and the rest male, aged 18 – 69 years old (mean age 39 years old). This was to ensure the objective of obtaining at least a minimum of 50 responses.

Clinical history:

Inclusion Criteria
-Healthy study subjects;
-Intact skin on test site;
-Agreement to adhere to the procedures and requirements of the study and to report to the institute on the day(s) and at the time(s) scheduled for the assessments;
-Ability of giving a written consent for participating in the study;
-Aged from 18 to 70 years old;
-Study subjects of any gender;
-Phototype (Fitzpatrick): I to IV.

Non Inclusion Criteria
-Any skin marks on the test site that might interfere with the assessment of possible skin reactions (pigmentation disorders, vascular malformations, scars, increased pilosity, and great amounts of ephelides and nevus, sunburns);
-Active dermatosis (local or disseminated) that might interfere with the results of the study;
-Pregnancy or breastfeeding;
-Previous history of allergic reactions, irritation or intense feelings of discomfort to topical-use products, cosmetics or medication;
-Subjects with history of allergy to the material used in the study;
-Previous history of atopy;
-History of pathologies aggravated or triggered by ultraviolet radiation;
-Subjects suffering from immunodeficiencies;
-Intense exposure to sunlight or to sun tanning sessions up to 15 days before the initial evaluation;
-Intention of being intensely exposed to sunlight or to sun tanning sessions during the study period;
-Intention of sea bathing, going to the pool or sauna during the study;
-Subjects who practice water sports;
-Dermographism;
-Use of the following topical or systemic medications: immunosuppressive drugs, antihistamines, non-hormonal anti-inflammatory drugs, and corticosteroids within two weeks before the selection process;
-Oral or topical treatment with vitamin A acid and/or its derivatives up to 1 month before the study start;
-Aesthetic and/or dermatological treatment performed on the body within 03 weeks before selection;
-Intention of being vaccinated during the study period or up to 3 weeks before the study;
-Any conditions which the investigator finds compromising to the evaluation of the study;
-History of lack of adherence or unwillingness to adhere to the study protocol;
-Professionals who are directly involved in the performance of the current protocol as well as their relatives.

Controls:

Sterile saline solution (NaCl 0.9%)

Route of administration:

dermal

Details on study design:

Study Design
Comparative controlled clinical and single-blind study.

Materials and Equipment
-Adhesive hypoallergenic semi-occlusive hypoallergenic tape for patch testing with duly identified 1.0-cm2 filter paper discs;
-0.9% sterile physiological solution (NaCl 0.9%);
-Distilled water
Mineral oil or petrolatum;
-Gloves, masks and caps;
-Surgical marker pen;
-Cotton swab;
-Cotton;
-Weighing Scale
-Repipette;
-Heating plate;
-Beaker;
-Dropper bottle;
-Transparent bottle.

Test Site
The product was applied to the study subjects back (scapular area).

Population Size
This study was conducted with 77 approved subjects so it could be completed with at least 56 responses.

Procedures
At first the study subjects were assessed by a dermatologist in order to verify the inclusion and exclusion criteria.
The patch test methodology (KLIGMAN & WOODING, 1967), also known as contact test or epicutaneous test, was used.
Induction Period: Undiluted product (0.05g/cm²) was applied to the same duly protected area (right or left back of the subjects). The applications were made three times a week for three consecutive weeks and the product remained in contact with the subjects’ skin for 48 hours during the week and after 72 hours during the weekends.
Rest Period: There was a rest period of at least 10 days following the induction period, when no patches were applied.
Challenge period: After the rest period, a patch with the test product and control were applied to the right or left back of the subjects on a virgin area, that is, where no products had been applied before. The patch was removed by the investigators after approximately 48 hours of contact with the skin. The assessments (readings) were performed immediately (48h reading) and 24 hours (72h reading) after patch test removal. The subjects were instructed to contact the study coordinator at any time, in case they presented any complaints. In these cases, they would be sent for a evaluation and guidance by the dermatologist in charge, who would evaluated the subjects, then rate the reaction and follow the appropriate procedure (guidance and/or medication and photographic record, when necessary).
The reading (48 hours after application) were performed soon after the removal of the test product, in all cases in which no clinical signs were observed. If there were observed, the readings would be performed after at least 30 minutes and, at most, 60 minutes so that the signs, possibly caused by the removal of the test product, did not represent a false positive result.

Assessment of Clinical Signs (Readings)
In case any subject presented a contact-dermatistis adverse reaction during the study, epicutaneous tests would be carried out. The evaluation, scale published by the International Contact Dermatitis Research Group - ICDRG (FISHER, 1995) would be used (table 1).

Study Requirements:
Do not apply any other product to the test site (dorsum)
Do not change any cosmetic habits, including personal hygiene.
Do not have body aesthetic or dermatological treatment performed.
Do not change food habits
Do not change hormone treatment
If female, do not change the medicamentous contraception method
Do not wet the patches during shower, in the pools or sea, sauna or excessive sweat.
Do not remove the plasters
Do not wear tight clothes which can remove the plaster through friction or cause redness.
Do not expose to the excessive sunlight or artificial tanning

Medication and prohibited concomitant treatments:
In case the therapeutic use of any medication mentioned below is necessary, the subject would be excluded from the study;
Non-hormonal anti-inflammatory drugs of continuous use that interfere with the study, in the opinion of the investigator (the sporadic use must be evaluated by the investigator)
Antibiotics, anti-androgenic agent, antihistamine, corticoids, tetracyclines, halogens, immunosuppressants, Acid vitamin A and oral and topical derivatives (e.g. isotretinoin). Vitamin B12, B6, B1 & D2. Isoniazid, rifampicin, ethionamide (treatment of tuberculosis or leprosy). Topical medication of acne treatments such as benzoyl peroxide. Phenobarbituric, trimethadione, hydantoin, lithium, chloral hydrate (neurological and psychiatric treatment, quinine, disulfiram, thiouracil, thiourea. During the study, any aesthetic, cosmetic or dermatological treatment on the body is forbidden.

Criteria and Procedures for Study Subjects Withdrawal
he exclusion of a study subject by the investigator could have occurred due to the following reasons:
•Study subjects not included: subject who signed the ICF, but who did not meet the inclusion and non-inclusion criteria of the study;
•Subjects who would present – at the investigators’ discretion – any problem that would prevent product applications from continuing, at any time during the study;
•Consent withdrawal by the study subjects, regardless of the reason;
•Lack of adhesion of the study subject: For this study, only two absences, on alternate days, would be allowed, provided they did not coincide with the first day of the study and with the challenge period. Consecutive absences or more than two absences would also cause the exclusion of the subject;
•Subjects presenting intercurrence that affect their eligibility in the meantime between the ICF signature and the beginning of the study;
•Serious adverse event;
•Occurrent disease or treatment: any pathological process or treatment that occurred during the study period and that could interfere with the study product, such as a medication interaction or masking of results.
Those subjects removed from the study by the investigator would be supervised in case they presented any event possibly related to the study, even after their removal. Those subjects removed due to occurrence of an adverse event would be continually assessed until the case was completely resolved. Those subjects who are removed from the study after inclusion stage would not be replaced.

Adverse Events:
An adverse event is any untoward medical occurrence in a patient or clinical investigation subject administered a product and that does not necessarily have a causal relationship with this treatment. An adverse event is therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with the test product use (adapted from ICH, 1996).
According to the Good Clinical Practices (ICH, 1996), a serious Adverse Event is any untoward medical occurrence that at any dose:
•Results in death;
•Life-threatening;
•Inpatient hospitalization or prolongation of existing hospitalization.
•Persistent or significant disability /inability
•A congenital anomaly /birth defect.
Thus, any new sign, symptom or disease or clinically significant worsening compared to the condition at the first visit, should be considered an Adverse Event. Lack of clinical or self-assessment of an investigational product is not considered an Adverse Event.
Clinical sign or dermatological or systemic diseases observed during the selection process of the study subjects are not considered as Adverse Event. This information is recorded on the medical assessment form as a reason for non-inclusion and the subjects are then not included in the study.
Adverse event occurs as a result of incorrect investigational product use – such as inappropriate frequency or incorrect application – are considered as adverse event that do not interfere with the product evaluation, since the subject in this situation does not follow the correct use directions stated on the product label.
An Adverse Event Form is completed foal l events occurred. The study sponsor is notified of an adverse event through a Notification of Occurrence form sent by electronic mail r the final study report.
In case there is an adverse event with doubtful causal nexus, an investigation process is initiated in order to determine if such event is or is not related to the study or investigational product.
The procedures adopted during the event investigation are defined by the physician in charge, based on the nature of the reaction, the subject’s medical history and on factors that may interfere with the occurrence of the event such as medication or other concomitant disorders.
For the conclusion of the final diagnosis, the relation of adverse event was defined using the decision tree Colipa (2016), according to the following description:
Very likely: Only cases in which the clinical condition is considered to be evocative will be classified as very likely nexus, the following conditions occurring together (i) the temporality of the facts is compatible with the adverse reaction to cosmetics and (ii) there is a laboratory test to confirm the relationship with the test product e.g. diagnosis of contact dermatitis, without patch test, the cosmetic acne, there are no laboratory tests to confirm the relationship with the product.
Likely: The case in which the clinical condition is considered to be evocative will be classified as likely casual nexus, occurring with the following condition together: (i) the temporality of the facts is compatible with the adverse reaction to cosmetics and (ii) there is no laboratory test to confirm the relationship with the test product e.g. diagnosis of contact dermatitis, without patch test, the cosmetic acne, there are no laboratory tests to confirm the relationship with the product.
Not clearly attributable: cases in which the clinical scenario is not considered to be evocative or the chronology is not the clearly compatible or unknown, will be classified as nexus not clearly attributable.
Improbable: The following two cases are considered with improbable nexus: the clinical scenario is not considered to be evocative; the chronology is not clearly compatible or unknown and the result of the investigation with the test product is negative (patch test or re-exposure).
Excluded: the case in which the diagnosis correspond to dermatosis of well-known cause and /or known to be caused by the use of cosmetics will be classified as excluded nexus e.g. vitiligo, tineas, pityriasis rosea pityriasis versicolor, psoriasis, folliculitites, solar melanose, ephelidesm, among other, when there is no correlation between the subjects’ complaint and the use of the product e.g. muscle pain, lack of appetite, stomach pan, diarrhoea, insect bites, among others or the chronology is clearly incompatible with an adverse reaction to the cosmetic product e.g. there is no improvement in the scenario, even with the interruption of the product, there is relapse of the scenario without the reintroduction of the product. The sign and symptoms started before the start of the product use.

Results and discussion

Results of examinations:

Adherence to the study:
56 subjects completed the study but 13 subjects (010, 011, 012, 019, 029, 030, 031, 034, 042, 061, 064, 069 and 070) were absent due to personal reasons unrelated to the study and 8 subjects (013, 016, 028, 036, 038, 044, 056 and 059) were removed from the study due the following adverse events;
Subjects 036, 044 & 056 presented irritation after the continuous exposure of the skin to the adhesive tape (adhesive plaster), probably due to individual predisposition, and for this reason the applications were interrupted, and the data weren’t considered in the study evaluation. It was a case of excluded nexus, i.e. unrelated to the product.

Subjects 013, 016, 028, 038 & 059 presented adverse reaction to other test product presented in this panel. The adverse event presented by the study subjects were unrelated to the test product as confirmed through clinical investigation performed to the confirmation of the event causal nexus. The subjects were excluded from the study, their data were not considered, and subject were supervised until the regression of the scenario presented.

No other subjects presented any clinical signs in both test groups and control groups. The test product did not induce skin sensitisation reaction under the study conditions. The product was considered safe under the condition of the study and the claim dermatologically tested can be supported.

Any other information on results incl. tables

Table 4. Result of Assessment

Subject number	1^stapplication	Induction Period									Resting Period	Challenge Period
		Reading + 2^ndapplication	Reading + 3^rdapplication	Reading + 4^th application	Reading + 5^thapplication	Reading + 6^th application	Reading + 7^thapplication	Reading + 8^thapplication	Reading + 9^thapplication	Reading	No procedure made	Reading + 10^th application	Reading	Reading
001	0	0	0	0	0	0	0	0	0	0		0	0	0
002	0	0	0	0	0	0	0	0	0	0		0	0	0
003	0	0	0	0	0	0	0	0	0	0		0	0	0
004	0	0	0	0	0	0	0	0	0	0		0	0	0
005	0	0	0	0	0	0	0	0	0	0		0	0	0
006	0	0	0	0	0	0	0	0	0	0		0	0	0
007	0	0	0	0	0	0	0	0	0	0		0	0	0
008	0	0	0	0	0	0	0	0	0	0		0	0	0
009	0	0	0	0	0	0	0	0	0	0		0	0	0
010	0	0	0	F	F/R	R	R	R	R	R		R	R	R
011	F/R	R	R	R	R	R	R	R	R	R		R	R	R
012	F/R	R	R	R	R	R	R	R	R	R		R	R	R
013	0	0	EA-/R	R	R	R	R	R	R	R		R	R	R
014	0	0	0	0	0	0	0	0	0	0		0	0	0
015	0	0	0	0	0	0	0	0	0	0		0	0	0
016	0	0	EA-/R	R	R	R	R	R	R	R		R	R	R
017	0	0	0	0	F	0	0	0	0	0		0	0	0
018	0	0	0	0	0	F	0	0	0	0		0	0	0
019	F/R	R	R	R	R	R	R	R	R	R		R	R	R
020	0	0	0	0	0	0	0	0	0	0		0	0	0
021	0	0	0	0	0	0	0	0	0	0		0	0	0
022	0	0	0	0	0	0	0	0	0	0		0	0	0
023	0	0	0	0	0	0	0	0	0	0		0	0	0
024	0	0	0	0	0	0	0	0	F	0		0	0	0
025	0	0	0	0	0	0	0	0	0	0		0	0	0
026	0	0	0	0	0	0	F	0	0	0		0	0	0
027	0	0	0	0	0	0	0	0	0	0		0	0	0
028	0	0	0	0	0	0	0	0	EA-/R	R		R	R	R
029	0	0	0	0	0	F	F/R	R	R	R		R	R	R
030	0	0	0	F	F/R	R	R	R	R	R		R	R	R
031	0	0	0	0	0	0	0	0	0	0		F/R	R	R
032	0	0	0	0	0	0	0	0	0	0		0	0	0
033	0	0	0	0	0	0	0	0	0	0		0	0	0
034	F/R	R	R	R	R	R	R	R	R	R		R	R	R
036	0	EA-/R	R	R	R	R	R	R	R	R		R	R	R
037	0	0	0	0	0	0	0	0	0	0		0	0	0
038	0	0	EA-/R	R	R	R	R	R	R	R		R	R	R
039	0	0	0	0	0	F	0	0	0	0		0	0	0
040	0	0	0	0	0	0	0	0	0	0		0	0	0
041	0	0	0	0	F	0	0	0	0	0		0	0	0
042	0	0	0	0	F	F/R	R	R	R	R		R	R	R
043	0	0	0	0	0	0	0	0	0	0		0	0	0
044	0	0	0	0	0	EA-/R	R	R	R	R		R	R	R
045	0	0	0	0	0	0	0	0	F	0		0	0	0
046	0	0	0	0	0	0	0	0	0	0		0	0	0
047	0	0	0	0	0	0	0	0	0	0		0	0	0
048	0	0	0	0	0	0	0	0	0	0		0	0	0
049	0	0	0	F	0	0	0	0	0	0		0	0	0
050	0	0	0	0	0	F	0	0	0	0		0	0	0
051	0	0	0	0	0	0	0	0	0	0		0	0	0
052	0	0	0	F	0	0	0	0	0	0		0	0	0
053	0	0	0	0	0	0	0	0	0	0		0	0	0
054	0	0	0	0	0	0	0	0	0	0		0	0	0
055	0	0	0	0	0	0	0	0	0	0		0	0	0
056	0	0	0	EA-/R	R	R	R	R	R	R		R	R	R
057	0	0	0	0	0	0	0	0	0	0		0	0	0
058	0	0	0	0	0	0	0	0	0	0		0	0	0
059	0	0	0	0	0	0	0	0	0	0		R	R	R
060	0	0	EA-/R	R	R	R	R	R	R	R		0	0	0
061	0	0	0	0	0	0	0	0	0	0		F/R	R	R
062	0	0	0	0	0	0	0	0	0	0		0	0	0
063	0	0	0	0	0	0	0	0	0	0		0	0	0
064	F/R	R	R	R	R	R	R	R	R	R		0	0	0
065	0	0	0	0	0	0	0	0	0	0	0	0	0
066	0	0	0	0	0	0	0	0	0	0	0	0	0
067	0	0	0	0	0	0	0	0	0	F	0	0	0
068	0	0	0	0	0	0	F	0	0	0	0	0	0
069	0	F/R	R	R	R	R	R	R	R	R	R	R	R
070	F/R	R	R	R	R	R	R	R	R	R	R	R	R
071	0	0	0	0	0	F	0	0	0	0	0	0	0
072	0	0	0	0	0	0	F	0	0	0	0	0	0
073	0	0	0	0	0	0	F	0	0	0	0	0	0
074	0	0	0	0	0	0	0	0	0	0	0	0	0
075	0	0	0	0	0	0	0	0	0	0	0	0	0
076	0	0	0	0	0	0	0	0	F	0	0	0	0
077	0	0	0	0	0	0	0	F	0	0	0	0	0

Caption:

X = Not applied /reading not performed

F = Absence

R = Removal from the study

DK = Darkening

DY = Dryness

F/R = Absence /removal from the study

EA = Adverse event with excluded nexus

FS = Screening failure checked after the study start

0 = No reaction

1 = Mild erythema

2 = Clear erythema

3 = Erythema + edema + papules

4 = Erythema + Edema + papules + Vesicles

Applicant's summary and conclusion

Conclusions:

Under the condition of the study, the test product did not induce skin sensitisation reaction.

Executive summary:

STUDY OBJECTIVE

To prove the absence of the skin sensitisation potential of a product applied to the skin, under maximized conditions, with controlled product amount and application site, supervised by a dermatologist.

 

METHODOLOGY

Both the test product (in amount of 0.05 g/cm² of undiluted form) and control were applied to patch test filter paper discs and then applied to the right or left back (scapular area) of the study subjects. The applications were performed on Mondays, Wednesdays and Fridays, during 3 consecutive weeks. Forty-eight hours (48h) after the application, the patch test was removed by trained technicians and, approximately 30 minutes after the patch test removal, the site was assessed in order to check the presence of possible clinical signs.After this period (induction) there was a, minimum, 10 day-period when no patch was applied to the study subjects' back (rest period). Then, the challenge period started. A single application of the patch test was performed, followed by readings after 48h and 72h. The study subjects were assessed by a dermatologist at the start and at the end of the study and supervised all along the study.

 

STUDY LENGTH

6 weeks.

 

FREQUENCY OF APPLICATION

9 applications on the 3 first weeks (induction period).

1 application on the last week (challenge period).

 

APPLICATION SITE

Back (Scapular area).

 

NUMBER OF SUBJECTS

56 subjects completed the study.

 

POPULATION DESCRIPTION

Female and male, age range from 18 to 69 years old, phototype II to IV (Fitzpatrick).

 

ETHICS

This study was conducted in conformance with the Declaration of Helsinque principles, the applicable regulatory requirements, including Resolution CNS no. 466/12, and in spirit of the Good Clinical Practices (Document of the Americas and ICH E6: Good Clinical Practice).

 

RESULTS

During the study, no subjects presented skin clinical signs related to the product.

 

CONCLUSION

The product did not induce a skin sensitisation process in the study group.

The product was considered safe under the study conditions. The claim “dermatologically tested” can be supported.