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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
Objective of study:
absorption
excretion
Qualifier:
no guideline available
Principles of method if other than guideline:
Healthy human subjects are exposed to two UV filters (Ethylhexyl Methoxycinnamate and Butyl Methoxydibenzoylmethane), investigating the absorption and excretion of the substances.
GLP compliance:
no
Specific details on test material used for the study:
4 % w/v of unlabelled material in solution
Radiolabelling:
yes
Remarks:
14C
Species:
human
Sex:
male
Route of administration:
dermal
Vehicle:
other: carbitol
Duration and frequency of treatment / exposure:
8 hours single treatment
Dose / conc.:
25 other: μCi
Remarks:
Doses / Concentrations: 4 %
No. of animals per sex per dose:
4 subjects, of which 1 for pilot study
Control animals:
no
Preliminary studies:
Recovery Ethylhexyl Methoxycinnamate from subject 1:
Skin (by stripping): 0.18 µCi = 0.72 %
Plasma: not detectable
Urine: 0.170 µCi = 0.16 %
Faeces: not detectable
Details on absorption:
Skin (stripping):
Subject 2: 1 %
Subject 3: 0.28 %
Subject 4: 0.48 %
Details on distribution in tissues:
Plasma: not detectable
Details on excretion:
Urine:
Subject 2: 0.16 %
Subject 3: 0.2 %
Subject 4: 0.12 %

Faeces:
Subject 2: not detectable
Subject 3: not detectable
Subject 4: not detectable
Metabolites identified:
not measured
Details on metabolites:
Not relevant

Total recovery for both the pilot and main study:

- Subject 1 (pilot): 92.3 %

- Subject 2: 90.6 %

- Subject 3: 98.2 %

- Subject 4: 93.0 %

According to OECD 427, 100 ± 10 % of test substance should be recovered in an in vivo (animal) study, this human study fulfills that requirement.

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

Occlusion (pilot study) did not appear to increase the absorption of tracer from the combined substances.

There were no clinically significant adverse reactions.

Recovery of labeled Ethylhexyl Methoxycinnamate (with unlabeled Butyl Methoxydibenzoylmethane 1789) from urine was significantly higher than that of labeled Butyl Methoxydibenzoylmethane 1789 (with unlabeled Ethylhexyl Methoxycinnamate 1789), but still extremely low.

Conclusions:
Ethylhexyl Methoxycinnamate (containing Butyl Methoxydibenzoylmethane) shows a very low percutaneous absorption, that is indicated by very 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. Therefore, it can be concluded that Ethylhexyl Methoxycinnamate does not bioaccumulate in human under the study conditions.
Executive summary:

1 healthy subject was treated with Ethylhexyl Methoxycinnamate (containing unlabelled 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 UV-Filter) was determined in skin (upper layer), plasma, urine and faeces.

No adverse effects were found after treatment in any of the subjects. Occlusion did not seem to have effect on the percutaneous absorption. In skin and urine only a very low amount of the radioactivity was recovered (maximum 1 %). In plasma and faeces no radioactivity was detectable. Therefore it is concluded that Ethylhexyl Methoxycinnamate shows only slight absorption into skin, and does not bioaccumulate.

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
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 (Ethylhexyl Methoxycinnamate), evaluating the percutaneous absorption and excretion of the substance.
GLP compliance:
no
Remarks:
human study
Specific details on test material used for the study:
10 % w/v unlabelled material and 125 μCi/mL 14C
Radiolabelling:
yes
Remarks:
14C
Species:
human
Strain:
other: not relevant
Sex:
male
Route of administration:
dermal
Vehicle:
other: carbitol
Duration and frequency of treatment / exposure:
8 hours single treatment
Dose / conc.:
25 other: μCi
Remarks:
Doses / Concentrations: 10 %
No. of animals per sex per dose:
4 subjects, of which 1 for pilot study
Control animals:
no
Preliminary studies:
Recovery Ethylhexyl Methoxycinnamate from subject 1:
Skin (by stripping): 0.15 µCi = 0.6 %
Plasma: not detectable
Urine: 0.170 µCi = 0.68 %
Faeces: not detectable
Details on absorption:
Skin (stripping):
Subject 2: 0.28 %
Subject 3: 0.16 %
Subject 4: 0.2 %
Details on distribution in tissues:
Plasma: not detectable
Details on excretion:
Urine:
Subject 2: 0.28 %
Subject 3: 0.24 %
Subject 4: 0.08 %

Faeces:
Subject 2: not detectable
Subject 3: not detectable
Subject 4: not detectable
Metabolites identified:
not measured
Details on metabolites:
Not relevant

Total recovery percentages of pilot and main study:

- Subject 1 (pilot): 94.1 %

- Subject 2: 101.1 %

- Subject 3: 96.4 %

- Subject 4: 99.0 %

OECD guideline 427 states that 100 ± 10 % of the dose should be recovered (for in vivo tests), which is achieved in this human 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:
Ethylhexyl Methoxycinnamate shows a very low percutaneous absorption, that is indicated by very 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. Therefore, it can be concluded that Ethylhexyl Methoxycinnamate does not bioaccumulate in human under the study conditions.
Executive summary:

1 healthy subject was treated with Ethylhexyl Methoxycinnamate 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 Ethylhexyl Methoxycinnamate) was determined in skin (upper layer), plasma, urine and faeces.

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 %). Therefore it is concluded that Ethylhexyl Methoxycinnamate shows only slight absorption into skin, and does not bioaccumulate.

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study was conducted according to an equivalent of OECD guideline 428, but not under GLP conditions.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Deviations:
yes
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14C
Species:
other: naked rat
Strain:
not specified
Sex:
not specified
Type of coverage:
other: Closed system
Vehicle:
other: Carbitol
Duration of exposure:
1, 6, 16 and 24 hours
Doses:
- Nominal doses: 1, 3 and 10 % in carbitol
- Actual doses: 120, 360, 1200 µg substance/cm² respectively
Control animals:
no
Dose:
1 % in carbitol
Parameter:
percentage
Absorption:
1.7 %
Remarks on result:
other: 1 hr
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
1 % in carbitol
Parameter:
percentage
Absorption:
21.3 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
1 % in carbitol
Parameter:
percentage
Absorption:
39.7 %
Remarks on result:
other: 16 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
3 % in carbitol
Parameter:
percentage
Absorption:
1.9 %
Remarks on result:
other: 1 hr
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
3 % in carbitol
Parameter:
percentage
Absorption:
13.6 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
3 % in carbitol
Parameter:
percentage
Absorption:
33.2 %
Remarks on result:
other: 16 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
10 % in carbitol
Parameter:
percentage
Absorption:
2.1 %
Remarks on result:
other: 1 hr
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
10 % in carbitol
Parameter:
percentage
Absorption:
12.8 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
10 % in carbitol
Parameter:
percentage
Absorption:
22.8 %
Remarks on result:
other: 16 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid

Percentage of substance absorbed after 24 hrs:

1 % in carbitol: 44.3 %

3 % in carbitol: 35.6 %

10 % in carbitol: 22.7 %

About 70 - 90 % of the applied dose of Ethylhexyl Methoxycinnamate was found on the skin surface during the first 6 hours after application

The amount recovered from the stratum corneum was low and reached its maximum 24 hours after application. The steady state was attained within 6 hours.

The portion of Ethylhexyl Methoxycinnamate found in the stripped skin increased to its maximum within 16 hours. Lower levels of the test material were found 24 hours after application.

A significant part of the applied dose was found in the chamber liquid (7 - 17 %) after longer times of exposure.

Conclusions:
In an in vitro system using naked rat skin, the skin penetration potential and resorption capacity of Ethylhexyl Methoxycinnamate were significant after longer times of exposure, based on the high amount of Ethylhexyl Methoxycinnamate found in the stripped skin, the low levels in the stratum corneum and the amount of activity recovered from the chamber liquid.
Executive summary:

Skin penetrating potential of Ethylhexyl Methoxycinnamate in naked rat skin was determined in a study using an in vitro system. The study was performed according to an equivalent of OECD guideline 428. Three concentrations of Ethylhexyl Methoxycinnamate in carbitol (1, 3 and 10 %) were applied and skin absorption rates were determined by the activity of the 14C-labelled test article.

It was found that the higher amount of Ethylhexyl Methoxycinnamate is absorbed into the upper layer of the skin (stripped skin). The low levels in the stratum corneum and the amount of activity recovered from the chamber liquid indicate significant penetration and resorption capacities of Ethylhexyl Methoxycinnamate through the intact skin of the naked rat after longer times of exposure.

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to an equivalent of OECD guideline 428, but not under GLP conditions. Report is concise but clear.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Deviations:
yes
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14C
Species:
other: mini pig
Strain:
not specified
Sex:
not specified
Type of coverage:
other: Closed system
Vehicle:
other: O/W lotion, O/W cream and W/O cream
Duration of exposure:
6 hours
Doses:
- Nominal doses:
In three vehicles (1 lotion, 2 creams):
7.5% Ethylhexyl Methoxycinnamate
2% Ethylhexyl Methoxycinnamate 1789 + 7.5% Ethylhexyl Methoxycinnamate (14C)
- Actual doses:
Ethylhexyl Methoxycinnamate in O/W lotion: 67.35 ug/cm2
Ethylhexyl Methoxycinnamate in O/W cream: 58.9 ug/cm2
Ethylhexyl Methoxycinnamate in W/O cream: 58.9 ug/cm2
- Rationale for dose selection: Based on studies of consumer's application habits (Doskoczil et al)
No. of animals per group:
Not relevant
Control animals:
no
Remarks:
not relevant
Dose:
7.5% Ethylhexyl Methoxycinnamate (14C) in O/W lotion
Parameter:
percentage
Absorption:
2.8 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
2% Ethylhexyl Methoxycinnamate 1789 and 7.5% Ethylhexyl Methoxycinnamate (14C) in O/W lotion
Parameter:
percentage
Absorption:
2.8 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
7.5% Ethylhexyl Methoxycinnamate (14C) in O/W cream
Parameter:
percentage
Absorption:
3.5 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
2% Ethylhexyl Methoxycinnamate 1789 and 7.5% Ethylhexyl Methoxycinnamate (14C) in O/W cream
Parameter:
percentage
Absorption:
3.1 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
7.5% Ethylhexyl Methoxycinnamate (14C) in W/O cream
Parameter:
percentage
Absorption:
3.9 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Dose:
2% Ethylhexyl Methoxycinnamate 1789 and 7.5% Ethylhexyl Methoxycinnamate (14C) in W/O cream
Parameter:
percentage
Absorption:
3.5 %
Remarks on result:
other: 6 hrs
Remarks:
Based on amount of test material in stripped skin and chamber liquid
Conversion factor human vs. animal skin:
Not relevant

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 Ethylhexyl Methoxycinnamate in all three vehicles was recovered as rest material (remains onto skin).

The penetration rate of Ethylhexyl Methoxycinnamate from all 3 vehicles is less than 4% of the applied dose.

No alteration of the penetrating capability of Ethylhexyl Methoxycinnamate 1789 and Ethylhexyl Methoxycinnamate was noted when samples containing both UV-filters are used for penetration studies, as compared to a previous study.

Conclusions:
There were no significant differences between the penetration rate values of Ethylhexyl Methoxycinnamate applied in different vehicles. No more than 4% of Ethylhexyl Methoxycinnamate was found to be absorbed in mini pig skin when applied in a concentration of 7.5% under the study conditions.
Executive summary:

The effect of 3 cosmetic vehicles (1 lotion, 2 creams) on the penetration rate of the chemical UV-filter Ethylhexyl Methoxycinnamate through the excised skin of mini pigs was investigated in this study.

The data presented here indicate that the penetration rate of Ethylhexyl Methoxycinnamate can be classified as low (less than 4% after 6 hours). The authors used this data to calculate the approximate penetration rate of Ethylhexyl Methoxycinnamate in these 3 vehicle types into and through the human skin. Based on consumer habits (Doskoczil et al.), it can be assumed that at maximum 0.8 mg/kg of Ethylhexyl Methoxycinnamate will be resorbed after application to the intact skin surface.

Description of key information

In conclusion, ethylhexyl methoxycinnamate has a low absorption when applied to the skin. A very low amount is excreted in urine (<0.5 %). The absence of effects in toxicological studies and the physical/chemical properties of ethylhexyl methoxycinnamate indicate low oral absorption, or low toxicity of the compound and its metabolites.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Background

The UV-absorbing substance ethylhexyl methoxycinnamate is used in protective sun screen cream and has been on the market for many years. Available toxicokinetic information on ethylhexyl methoxycinnamate is therefore focussed on dermal absorption. Two in vitro studies were available in which the dermal absorption in naked rat skin and mini pig skin were determined. Furthermore, two studies with human volunteers are available, in which the dermal absorption and excretion was determined. Additional information from public literature and other toxicology studies is also discussed to describe the behaviour of ethylhexyl methoxycinnamate for the dermal and oral route. The inhalation route is not discussed as inhalation exposure is not expected.

 

Studies on toxicokinetics in the dossier

The in vitro dermal absorption of ethylhexyl methoxycinnamate in the mini pig skin is relatively low (Klecak et al., 1982). In this study, 14C-ethylhexyl methoxycinnamate was tested in two different creams and a lotion at a concentration of 7.5 %, and absorption did not exceed 4 % after 6 hours. With the availability of dermal absorption studies with minipig skin and from human volunteer studies (see below), known dermal absorption data for ethylhexyl methoxycinnamate in rat skin (DSM, 1979) is considered obsolete as rat skin is typically two to ten times more permeable than human (ECETOC 1993).

The in vivo dermal absorption and excretion was studied in healthy human volunteers (Davragh and Lambe, 1980). A solution of 14C-ethylhexyl methoxycinnamate in carbitol, at a concentration of 10 %, was applied onto a piece of gauze taped onto the human skin without occlusion, and radioactivity was determined in the piece of gauze, on the skin, in the stratum corneum (by skin stripping), in blood plasma, urine, and faeces. Results show that a very high percentage of the dose was recovered from the application site, whereas radioactivity was not detectable in blood plasma and faeces. A very low percentage of the applied dose was recovered from the skin after stripping (0.16 - 0.28 %) and from urine (0.08 - 0.68 %). The total recovery of radioactivity was high in all subjects (94.1 - 101.1 %). Based on these results, and the results obtained in the in vitro studies, it can be concluded that ethylhexyl methoxycinnamate has a low dermal absorption potential.

 

Information from public literature

From the use of ethylhexyl methoxycinnamate as UV filter in sunscreen cream, it is obvious that the most likely route of exposure will be via the skin. In literature, several publications are available concerning dermal absorption of ethylhexyl methoxycinnamate, most of them focussing on the influence of different kinds of vehicle (sunscreen cream). Depending on the vehicle, ethylhexyl methoxycinnamate has a low dermal absorption potential. Information on other toxicokinetics properties were not found in literature.

 

Information from other studies

Physical/chemical parameters such as log Pow, water solubility, and molecular weight, as well as parameters like hydrolysis rate can provide useful information regarding the behaviour of a substance in the body. Ethylhexyl methoxycinnamate has a log Pow of > 6 and is slightly soluble (0.22 - 0.75 mg/L). The molecular weight is 290.4. Furthermore, information from a hydrolysis study is available.

The combination of a high log Pow and low water solubility confirms the findings of the dermal penetration studies described above. Furthermore, in a dermal repeated dose toxicity study, no clear toxic effects were observed, indicating that ethylhexyl methoxycinnamate may not be taken up in the body via the dermal route.

Concerning the oral route, the highly lipophilic nature of ethylhexyl methoxycinnamate and its poor water solubility indicate poor absorption. However, according to the Guidance on information requirements, lipophilic compounds such as ethylhexyl methoxycinnamate may be taken up by micellular solubilisation, (of particular importance when log Pow > 4 and water solubility < 1 mg/L). More information on the toxicokinetics of ethylhexyl methoxycinnamate via the oral route may be obtained via the toxicity studies. In the dossier, studies are available concerning acute toxicity, skin and eye irritation, skin sensitization, mutagenicity, oral repeated dose toxicity, and developmental toxicity. None of the studies show a clear toxic effect of ethylhexyl methoxycinnamate, indicating poor absorption of the substance, or low toxicity of parent compound and metabolites.

In a hydrolysis study, a DT50 of more than one year was observed, which indicates that ethylhexyl methoxycinnamate is not expected to degrade in the GI-tract. Furthermore, from the structure of the compound ethylhexyl-methoxycinnamate it can be concluded that under normal to foreseen (physiological) conditions the compound is stable. The ester-bond is of a rigid type and will only tend to decompose under vigorous conditions. However, in the human body biotransformation of ethylhexyl methoxycinnamate may occur, as ester-bonds can be hydrolysed by esterases.

 

Conclusions

In conclusion, ethylhexyl methoxycinnamate has a low absorption when applied to the skin. A very low amount is excreted in urine (<0.5 %). The absence of effects in toxicological studies and the physical/chemical properties of ethylhexyl methoxycinnamate indicate low oral absorption, or low toxicity of the compound and its metabolites.

 

References

ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals), (1993). Percutaneous absorption. Monograph n° 20, ECETOC, Brussels, Belgium

European Chemicals Agency, (2008). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.