Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

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.
Cross-reference
Reason / purpose:
reference to other study
Reference
Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010-02-12 to 2010-06-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Guideline-conform study under GLP without deviations.
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 107 (Partition Coefficient (n-octanol / water), Shake Flask Method)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method A.8 (Partition Coefficient)
Deviations:
no
Principles of method if other than guideline:
The solubility in n-octanol was determined using a simplified flask method. The solubility in water (determined in Study C71396) was found to be clearly below the solubility in n-octanol indicating a partition coefficient above 6. Hence, a main test according to OECD Guidelines 107/117 (either HPLC or flask shaking method) could not be applied. Therefore, the partition coefficient of tert-butyl-4-methoxy-4'-dibenzoylmethane was estimated using the solubility data in n-octanol from the pre-test and in the water from the main test.
GLP compliance:
yes (incl. certificate)
Type of method:
estimation method (solubility ratio)
Partition coefficient type:
octanol-water
Analytical method:
gas chromatography
Key result
Type:
log Pow
Partition coefficient:
6.1
Temp.:
20 °C
pH:
6.9
Details on results:
Neither the HPLC-method according to OECD Guideline No. 117 nor the flask-shaking method according to OECD Guideline No. 107 were applicable for the determination of the partition coefficient of Tert-Butyl-4-methoxy-4'-dibenzoylmethane. Thus, the log Pow-value for the test item was estimated from its solubility in n-octanol and in water, respectively.
In the present study, the n-octanol solubility of Tert-Butyl-4-methoxy-4'-dibenzoylmethane was determined to be 32.0 g/L.
The partition coefficient, log POW, of Tert-Butyl-4-methoxy-4'-dibenzoylmethane was calculated from the individual solubilities in n-octanol and in water, respectively, to be:
 log POW= log10 (32006.9 mg/L / 0.027 mg/L) = 6.1

Determination of test item solubility in n-octanol from two samples: 320006.9 mg/L (coefficient of variation 1.15 %)

Value of test item solubility in water of 0.027 mg/L taken from the study of Weissenfeld, 2010.

Conclusions:
The partition coefficient, log Pow, of tert-butyl-4-methoxy-4'-dibenzoylmethane was calculated from the individual solubilities in n-octanol and in water, respectively, to be 6.1.
Executive summary:

The purpose of the study is to determine or to estimate the partition coefficient of Tert-Butyl-4-methoxy-4'-dibenzoylmethane between n-octanol and water (log POW). The determination of the partition coefficient log POW of Tert-Butyl-4-methoxy-4'-dibenzoylmethane was performed using the flask shaking method as described in OECD guideline no. 117, "Preliminary estimate of the partition coefficient".

The solubility in n-octanol was determined using a simplified flask method. The solubility in water (determined in Study C71396) was found to be clearly below the solubility in n-octanol indicating a partition coefficient above 6. Hence, a main test according to OECD Guidelines 107/117 (either HPLC or flask shaking method) could not be applied. Therefore the partition coefficient of Tert-Butyl-4-methoxy-4'-dibenzoylmethane was estimated using the solubility data in n-octanol from the pre-test and in the water from the study on water solubility to be log Pow = 6.1.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
- Name of test material (as cited in study report): Butyl methoxydibenzolmethane (BMDBM)
Radiolabelling:
other: some of the studies used for toxicokinetic evaluation were performed with radiolabelled substances.

Test animals

Species:
other: Studies on different species were used for assessment.
Sex:
male/female

Administration / exposure

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.

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.