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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: human study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Objective of study:
absorption
excretion
Qualifier:
no guideline available
Principles of method if other than guideline:
Healthy human volunteers are exposed to the UV filter Butyl Methoxydibenzoylmethane (BMDBM), evaluating the percutaneous absorption and excretion of the substance.
A total of eight healthy volunteers were studied. They were divided into two groups of four, one group (subjects 1-4) receiving the solution containing 14C-OMC, the other (subjects 5-8) the solution containing 14C- butyl methoxydibenzoylmethane (14C-BMDBM). One subject in each group (subjects 1 and 5) was studied in a preliminary pilot study in order to establish if 25 µCi was an appropriate dose to employ in the main study.
In the pilot study (subjects 1 and 5) the doses were maintained in position using small watch glasses having an area of 10 cm2. In the principal study, occlusion was not used (subjects 2-4 and 6-8) and the dose was applied to a small square of gauze (10 cm2) taped to the skin.
For all eight subjects the period of exposure was eight hours. At the end of this period the dose was removed and the treated area was wiped with Q-tips moistened with ethanol, employing 20 Q-tips per area. The treated area was then stripped 10 times with sections of Scotch tape.
The clock glasses or gauze sections were soaked overnight in toluene which was then transferred with several rinses to a volumetric flask and diluted to 500 mL. Duplicate 1 mL aliquots were counted. A similar procedure was employed for evaluating the radioactivity on the Q-tips. The sections of Scotch Tape were transferred to counting vials, soaked overnight, with occasional shaking, in a toluene based scintillator and counted directly.
Blood (10 ml) was collected into heparinised containers at the following times: Pre dose and 2, 4, 6, 8, 12, 24, 48, 96 and 120 hours post administration. The plasma was separated and frozen.
All urine excreted over the following time periods was collected: Pre treatment Control and 0-2, 2-4, 4-8, 8-12, 12-24, 24-48, 48-72, 72-96 and 96-120 hours following dose application.
All faeces excreted over the following time intervals were collected: 0-24, 24-48, 48-72, 72-96 and 96-120 hours.
Radioactivity in plasma and urine was determined by direct counting of duplicate 1 mL aliquots in Insta Gel (10 mL). Radioactivity in faeces was determined in aliquots of aqueous homogenates by a combustion procedure employing the "ImDex" Biological Oxidiser.
GLP compliance:
no
Remarks:
human study
Radiolabelling:
yes
Remarks:
14C
Species:
human
Strain:
other: not relevant
Sex:
male
Route of administration:
dermal
Vehicle:
other: Carbitol (diethylene glycol monoethyl ether)
Duration and frequency of treatment / exposure:
8 hours single treatment
Remarks:
Doses / Concentrations:
10% / 25 µCi per subject total dose in 200 µL Carbitol
No. of animals per sex per dose:
4 subjects, of which 1 for pilot study.
Control animals:
no
Preliminary studies:
Recovery Butyl Methoxydibenzoylmethane from subject 5 (occluded dose):
Skin (by stripping): = 0.48%
Plasma: not detectable
Urine: = 0.08%
Faeces: not detectable
Details on absorption:
Skin (stripping):
Subject 6: 0.02 µCi = 0.08 %
Subject 7: 0.04 µCi = 0.16 %
Subject 8: 0.07 µCi = 0.28 %
Details on distribution in tissues:
Plasma: not detectable
Details on excretion:
Urine:
Subject 6: 0.003 µCi = 0.012%
Subject 7: 0.004 µCI = 0.016%
Subject 8: 0.003 µCi = 0.012%

Faeces:
Subject 6: not detectable
Subject 7: not detectable
Subject 8: not detectable
Metabolites identified:
not measured
Details on metabolites:
Not relevant

Table 1: Overall recovery of radioactivity within 5 days after dermal application of 25 µCi14C-butyl methoxydibenzoylmethane (14C-BMDBM) in Carbitol to human male volunteers.

 

 

Subject 5a)

Subject 6

Subject 7

Subject 8

Total dose

µCi

25.00

25.00

25.00

25.00

%

100.0

100.0

100.0

100.0

Watch glass or gauze patch

µCi

24.08

24.05

23.42

24.02

%

96.3

96.2

93.7

96.1

Q-tips skin

µCi

1.27

1.19

1.91

1.65

%

5.08

4.76

7.64

6.60

Tape strippings

µCi

0.12

0.02

0.04

0.07

%

0.48

0.08

0.16

0.28

Urine

µCi

0.02

0.003

0.004

0.003

%

0.08

0.01

0.02

0.01

Total recovery

µCi

25.49

25.26

25.37

25.74

%

102.0

101.0

101.5

103.0

a)Preliminary study

In the preliminary study an occlusive application method was used. In the main study occlusion was not used.

No adverse reactions were seen in any of the subjects.

Occluded doses initiate a greater absorption of radioactivity than non-occluded doses.

Conclusions:
Butyl Methoxydibenzoylmethane shows a very low percutaneous absorption, that is indicated by high recovery of the dose from the skin,
undetectable radioactivity in plasma and faeces and a very low percentage of applied dose excreted in the urine.
Executive summary:

1 healthy subject was treated with Butyl Methoxydibenzoylmethane for 8 hours in a preliminary study (for determination of activity to be applied), 3 healthy subjects were used in the main study. The preliminary study used occlusive application, in the main study no occlusion was applied. Subjects were screened (physical examination) and tested for derivations of haematology, serum chemistry and urinanalysis. Radioactivity (= amount of Butyl Methoxydibenzoylmethane) was determined in skin (upper layer), plasma, urine and faeces. The amounts of radioactivity found in the skin by tape stripping was 0.48% and 0.08-0.28% of the applied dose in the occlusive and non-occlusive experiment, respectively.

No adverse effects were found after treatment in any of the subjects. In plasma and faeces no radioactivity was detectable. In skin and urine only a very low amount of the radioactivity was recovered (<1% and <0.1%, respectively).

Occlusion did not appear to increase the absorption, as the results of the preliminary study are reflected by the main study.

It can therefore be stated that the dermal resorption of the test item BMDBM by human skin is very low.

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2009-11-15
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
Procedure in accordance with generally accepted scientific standards and described in sufficient detail.
Reason / purpose:
reference to other study
Objective of study:
toxicokinetics
Qualifier:
no guideline followed
GLP compliance:
no
Radiolabelling:
other: some of the studies used for toxicokinetic evaluation were performed with radiolabelled substances.
Species:
other: Studies on different species were used for assessment.
Sex:
male/female
Route of administration:
other: The three major routes of administration (oral, dermal, inhalation) were considered in the assessment.
Vehicle:
not specified
Details on study design:
An evaluation of toxicokinetic behavior of BMDBM based on data from DSM toxicity studies, physico chemical data, ADME data and DSM skin penetration data (for pig and human skin) has been undertaken. Metabolism in mammals was evaluated using METEOR, Program Version 11.0.0, Lhasa Ltd.
Metabolites identified:
not measured

Data from toxicity studies

Available toxicity studies (90 day oral, 21 day dermal rabbit studies) with BMDBM did not include plasma level measurements of the test substance. Therefore, there is no direct data to clarify the extent of systemic availability of the parent molecule.

 

Physico-chemical data

Molecular weight: 310.38 g/mol (D)

Physical form at room temperature: solid (powder).

Water solubility: 0.01 mg/L (20 °C)

Partition coefficient, log Pow = 6.1 measured.

Vapour pressure, 1.36 x 10-6mmHg (25 °C) (EPIWIN)

 

ADME data

No specific metabolism studies have been performed with BMDBM or could be located in the literature (SciFinder search, Aug 2009).

In silico prediction of the BMDBM metabolism in mammals (using METEOR, Program Version 11.0.0, Lhasa Ltd) indicated that terminal O-demethylation and terminal methyl hydroxylation are probable. Subsequent sulphation and glucronidation are also predicted at a probable level. Such metabolic steps will result in more polar molecules that can be readily excreted via the urinary system. Therefore, although BMBDM has a log Pow value above 3 that may favour fat deposition, in the event of systemic penetration it will be metabolised to more water soluble molecules that can be excreted. Overall therefore, systemic accumulation of BMBDM is considered to be very unlikely.

 

Oral /GI Absorption

A systemic biological effect involving the liver was seen in the oral 13 week rat study (DSM,1983) at the high dose of 1000 mg/kg bw/day. This indirectly indicates there is bioavailabilityof parent or of metabolites following oral intake at high dosage but gives no indication of the amount absorbed.

The molecular weight of BMDBM is in the range (MW < 500 D) where skin penetration can occur but the log Pow is slightly above the range favouring penetration (log Pow in range -1 to +4). The water solubility is however low. Therefore, based on these physico-chemical data, some oral absorption may be expected.

 

Respiratory Absorption - Inhalation

The vapour pressure of BMDBM is very low and therefore negligible exposure to vapour is expected from exposure in the work place or during transportation.

Potential use of BMBDM in consumer skin spray formulations, which could lead to inhalation exposure, is outside the remit of this evaluation.

 

Dermal absorption

In a 21 day dermal rabbit toxicity study (Keller, 1980), in the absence of a biological response (no adverse effects were observed in rats up to the high dose of 360 mg/kg bw/day, both in groups with intact skin or with abraded skin), there was no indication of systemic bioavailability following dermal exposure.

The molecular weight of BMBDM is in the range (MW < 500 D) where skin penetration can occur but the log Pow is slightly above the range favouring penetration (log Pow in range -1 to +4). Also the water solubility is very low. Therefore, based on these physico-chemical data, only low dermal penetration is expected.

Several different studies for percutaneous absorption have been performed. These are summarized in the opinion of the SCC (SCC: Evaluation and Opinion on: 4-tert.-butyl-4'-methoxydibenzoylmethane, adopted by Scientific Committee Cosmetology 2-June-1992). These studies are concerned primarily with dermal penetration from cosmetic formulations. Here, only the studies conducted with pig skin and the human in vitro and in vivo studies are taken into account. Data for rat skin is not considered as pig skin is considered a better model for human skin penetration. In vitro studies with isolated pig skin (DSM, 1982) using 14C-labelled BMBDM at a concentration of 2 % in cream formulations, showed only a low penetration rate (up to 1.5 % of applied radioactivity 6 h post application). Dermal penetration in pig skin was not influenced by UV light (DSM, 1986). In a study (DSM, 1982) with 14C-labelled BMDBM using isolated human abdominal cadaver skin, up to 2.7 % of the applied radioactivity was observed in the epidermis, 7.3 % in the dermis 18 hr post dose but no activity was found in the collection fluid at any time and lower skin corium contained only 0.34 % after the longest exposure period. In a human in vivo study (DSM, 1980), subjects were treated with a 10 % solution of 14C-labelled BMBDM in carbitol with an 8 hour exposure. The amounts of BMDBM found in the urine were 0.08 and 0.016 % for the occluded and non-occluded experiment, respectively. No radioactivity was found in the blood or faeces in any subject. Therefore, these data confirm only a very low level of systemic penetration of BMDBM or its metabolites.

Conclusions:
Results from oral toxicity studies in rats with up to 3 months exposure indicated based on indirect evidence that there is systemic availability of BMDBM or metabolites at a high oral dosage. Direct evidence in the form of plasma data is not available. The predicted phase I and phase II metabolism of BMDBM indicates metabolism that will enable excretion and hence the lack of systemic accumulation. Therefore, there is no expectation of greater systemic toxicity following longer term exposure. The level of systemic exposure from dermal contact is determined to be low. The expected level of inhalation exposure is negligible due to the low vapour pressure.
Executive summary:

Results from oral toxicity studies in rats with up to 3 months exposure indicated based on indirect evidence that there is systemic availability of BMDBM or metabolites at a high oral dosage. Direct evidence in the form of plasma data is not available. The predicted phase I and phase II metabolism of BMDBM indicates metabolism that will enable excretion and hence the lack of systemic accumulation. Therefore, there is no expectation of greater systemic toxicity following longer term exposure. The level of systemic exposure from dermal contact is determined to be low. The expected level of inhalation exposure is negligible due to the low vapour pressure.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Well conducted study, meets generally accepted scientific principles.
Objective of study:
absorption
Qualifier:
equivalent or similar to
Guideline:
other: OECD 428 skin-in vitro
Principles of method if other than guideline:
Excised skin samples from mini pigs (approximately 20 cm²) are mounted in an exposure chamber and penetrated on a surface area of 5 cm² for 6 h with the radio-labelled test item in three different standard cosmetic vehicles. The basal part of the skin sample is in constant contact with the physiological salt solution, which is constantly stirred.
For the determination of dermal penetration, the average activity in the penetration chamber liquid is determined.
For the determination of unabsorbed test material, the skin is wiped off with cotton wool which is then extracted in toluene. The average activity of the extraction solution is determined.
The amount of adsorbed material in the stratum corneum is determined by measurement of the total activity of the tape strips after the "tape stripping" procedure (15 ± 6 strippings performed).
The activity in the resulting stripped skin is measured to determine the amount of absorbed test substance.
GLP compliance:
no
Radiolabelling:
yes
Species:
miniature swine
Strain:
not specified
Sex:
not specified
Route of administration:
dermal
Vehicle:
other: three different vehicles were used: O/W lotion, O/W cream, and W/O cream
Duration and frequency of treatment / exposure:
The contact time of the test samples to the skin was limited to 6 hours, simulating the duration of exposure of the sunscreen to the skin under user conditions.
Remarks:
Doses / Concentrations:
Formulations contained 2 % and 7.5 % of the test substance butyl methoxydibenzoylmethane (BMDBM), which is equivalent to doses of 120 and 450 µg/cm² or absolute amounts of 600 and 2250 µg, respectively (using a test surface of 5 cm²).
No. of animals per sex per dose:
1 skin sample was used per concentration and formulation.
Control animals:
no
Details on absorption:
Based on the data listed in table 1 the following conclusions can be made:
1. After an exposure time of 6 hours to the intact surface of the mini pig skin the majority of the applied dose per cm2 of BMDBM was recovered as rest material, i.e. at minimum 97.1 % of BMDBM.
2. The total penetration rate value of BMDBM from all vehicles is generally very low, between 0.9 % and 3.9 %.
3. No significant differences were noted when values of the penetration rate of BMDBM from the 3 vehicles used were compared.
Metabolites identified:
not measured

Table 1: Penetration studies with 14C-labelled BMDBM formulations in different vehicles. Given is the relative activity in the different compartments after 6h topical application of the test item in %.

 

Horny layer

Stripped skin

Chamber liquid

Residual material

O/W lotion

BMDBM 14C 2 %

1.7

0.9

0

97.3

BMDBM 14C 7.5 %

1.1

2.4

0.4

96.1

O/W cream

BMDBM 14C 2 %

1.5

1.2

0

97.3

BMDBM 14C 7.5 %

1.0

3.1

0.4

95.5

W/O cream

BMDBM 14C 2 %

1.4

1.5

0

97.1

BMDBM 14C 7.5 %

1.2

3.4

0.5

94.9

BMDBM 2 % = 120 µg BMDBM/cm² (total dose applied: 600 µg per 5 cm²)

BMDBM 7.5 % = 450 µg BMDBM/cm² (total dose applied: 2250 µg per 5 cm²)

Conclusions:
Results showed that almost the whole part of topically applied BMDBM (= 95 %) remained on the skin surface. 1.0 - 1.7 % were adsorbed on the stratum corneum, 0.9 - 3.4 % absorbed in the skin and only a minimum (<=0.5 %) was found to pass the skin. Skin absorption/penetration was not affected by the different vehicles.
Executive summary:

The effect of 3 cosmetic vehicles on the penetration rate of chemical UV-filter butyl methoxydibenzoylmethane (BMDBM) through the excised skin of mini pigs was investigated in these studies. The data presented here indicate that the penetration rate of BMDBM from all 3 vehicles used is very low. Almost the whole part of topically applied BMDBM (= 95 %) remained on the skin surface. 1.0 - 1.7 % were adsorbed on the stratum corneum, 0.9 - 3.4 % absorbed in the skin and only a minimum (<=0.5 %) was found to pass the skin. Skin absorption/penetration was not affected by the different vehicles.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Well conducted study, meets generally accepted scientific principles.
Objective of study:
absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
Human cadaver abdominal skin samples are mounted in an exposure chamber and treated on a surface area of 2 cm² for 1, 6, and 18 h with the radio-labelled test item in a W/O cream. The basal part of the skin sample is in constant contact with the physiological salt solution, which is constantly stirred.
For the determination of dermal penetration, the average activity in the penetration chamber liquid is determined.
For the determination of unabsorbed test material, the skin is wiped off with cotton wool which is then extracted in toluene. The average activity of the extraction solution is determined.
The amount of adsorbed material in the stratum corneum is determined by measurement of the total activity of the tape strips after the "tape stripping" procedure.
The activity in epidermis, dermis and subcutaneous fat is measured to determine the amount of absorbed test substance.
GLP compliance:
no
Radiolabelling:
yes
Species:
human
Strain:
not specified
Sex:
not specified
Route of administration:
dermal
Vehicle:
other: W/O cream
Duration and frequency of treatment / exposure:
1, 6, and 18 h
Remarks:
Doses / Concentrations:
2.5 mg/cm² of a formulation containing 2 % BMDBM were applied to the skin samples, equivalent to a dose of 50 µg/cm² or a total amount of 100 µg BMDBM.
No. of animals per sex per dose:
1 skin sample per dose and exposure time.
Control animals:
no
Details on absorption:
Butyl methoxydibenzoylmethane (BMDBM) penetrates very uniformly to about 600 - 800 µm, i.e. into the epidermis and the upper corium, and its concentration in this region increases as a function of time. Further penetration into the deeper layers then occurs very slowly, as can be seen in Table 1.
No radioactivity was detected in the penetration chamber water at any time.
Metabolites identified:
not measured

Table 1: Distibution [%] of the applied dose (100 µg) of butyl methoxydibenzoylmethane (BMDBM) in the single skin layers

Time

Horny layer

Epidermis

Uppercorium

Lower corium

Subcutaneous fat

Total 1)

 

Strippings

%

µm

%

µm

%

µm

%

µm

%

 

1 h

12

4.23

160

0.08

640

0.18

1600

0.02

240

0

0.28

6 h

15

6.37

160

0.29

640

0.37

800

0

720

0

0.66

18 h

12

5.92

160

2.74

640

6.96

1120

0.34

720

0.10

10.14

1) Total Epidermis + Dermis + Fat

 

Conclusions:
After dermal application of the test substance butyl methoxydibenzoylmethane (BMDBM) as 2 % formulation in W/O cream, no accumulation in the penetration chamber water was measured. Dermal absorption increased with exposure time from 0.3 % (1 h) over 0.7 % (6 h) to 10.1 % (18 h) with the majority penetrating into the upper part of the dermis.
Executive summary:

After dermal application of the test substance butyl methoxydibenzoylmethane (BMDBM) as 2 % formulation in W/O cream, no accumulation in the penetration chamber water was measured. Dermal absorption increased with exposure time from 0.3 % (1 h) over 0.7 % (6 h) to 10.14 % (18 h) with the majority penetrating into the upper part of the dermis.

Description of key information

The available studies show a very low dermal penetration rate of the test item.

Key value for chemical safety assessment

Additional information

To date, three different studies (two in-vitro; 1 in-vivo) describing dermal absorption of the test item butyl methoxydibenzoylmethane (BMDBM) are available:

Darragh 1980: Radioactivity from radio-labelled BMDBM was detected only on skin surface. Minor proportions (<1 %) were adsorbed in the stratum corneum. In plasma and feces no radioactivity and in urine a very low percentage (<0.1 %) could be recovered.

Kleczak 1982: Results showed that almost the whole part of topically applied BMDBM (95 %) remained on the skin surface. 1.0 - 1.7 % were adsorbed on the stratum corneum, 0.9 - 3.4 % absorbed in the skin and only a minimum (<=0.5 %) was found to pass the skin. Skin absorption/penetration was not affected by the different vehicles.

Stuttgen 1982: After dermal application of BMDBM, no penetration into the receptor fluid was observed. Dermal absorption increased with exposure time. From this it follows that more than 84 % of the applied dose remained on the skin surface.

 

In these three studies only minimal dermal penetration of BMDBM after topical administration was observed. In all studies, the majority of the applied dose remained on the skin surface and only a minor percentage was absorbed into epidermis or dermis. Systemic uptake and excretion of BMDBM in the body was only evaluated by Darragh et al. (1980). They found a minor proportion in urine but no BMDBM in plasma or feces.

Edwards 2009: in this key study was discussed, that the molecular weight of BMDBM is in the range (MW<500 D) were skin penetration can occur but the log Pow is slightly above the range favoring penetration (log Pow in range -1 to +4), i.e. 4.5 as calculated by EPIWIN. Meanwhile, a log Pow value of 6.1 was determined experimentally for BMDBM (Weissenfeld, 2010), but this result does not change the interpretation of percutaneous absorption since the value is above of the optimal penetration range. This finding could be confirmed the in vitro study results where majority of the applied dose remained on the skin surface.