5-Brom-2-[(3,4,5-trifluorphenoxy)-difluormethyl]-1,3-difluorbenzene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert Judgement

Adequacy of study:

key study

Study period:

2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

other: ECHA Guidance R.7c

Version / remarks:

2017

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

5-[(4-bromo-2,6-difluorophenyl)difluoromethoxy]-1,2,3-trifluorobenzene

EC Number:

610-623-5

Cas Number:

511540-64-0

Molecular formula:

C13 H4 Br F7 O

IUPAC Name:

5-[(4-bromo-2,6-difluorophenyl)difluoromethoxy]-1,2,3-trifluorobenzene

Test material form:

solid

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral route

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2017). Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4. Thus, with a logPow greater of 5.7 the substance would be expected to not passively pass biological membranes. In addition, the substance is highly insoluble in water. However, micellular formation in the gastrointestinal tract (GIT) could enable absorption processes. Moreover, the molecular weight of the substances is well below 500 g/mol and could thus contribute to a favored absorption. In addition, the substance is not expected to undergo hydrolysis based on its chemical structure. Abiotic degradation is thus not relevant for the oral route of exposure. Taken together, the physico-chemical properties of the substance indicate that intestinal absorption cannot be completely ruled out.
The above considerations are confirmed by findings of toxicity studies with the test substance. In an acute oral toxicity study with rats no mortality or other signs of toxicity were observed up to the limit dose of 2000 mg/kg bw.
The No Observed Adverse Effect Level (NOAEL) of the test item in Wistar rats was established at 300 mg/kg bw/d (highest dose tested) in a 28-day repeated dose toxicity study (OECD 407). Although no adverse effects were observed up to the highest dose tested, signs (hypertrophy in liver and thyroid gland, alterations of cholesterol, total protein, and total bile acid) of increased metabolism suggest that the substance and/or its metabolites become systemically available via the oral route.

Dermal route

The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis and possess a certain lipophilicity to cross the lipid rich environment of the stratum corneum. Considering the low water solubility of the test item (< 0.01 mg/L) and a log POW value of 5.7, the uptake into the stratum corneum will be high, however the transfer between the stratum corneum and the epidermis is limited. Thus, dermal uptake of the test item will be very low.
The above considerations are in line with findings of an acute dermal toxicity study in rats (OECD 402). No signs of toxicity were observed up to the limit dose of 2000 mg/kg bw. Moreover, no clinical signs were observed in the acute dermal irritation/corrosion study (OECD 404). However, mortality and clinical effects were observed in the Local Lymph Node Assay. Taken together, this indicates that the test item will not readily penetrate skin layers, however, small amounts may become systemically available via dermal route.

Inhalation route

Due to a very low vapor pressure of 0.052 Pa it is very unlikely that the substance becomes available as a vapor. The substance is a solid of low dustiness with a median particle size (D50) of 192 µm. Therefore, exposure via inhalation is considered not relevant for the substance.

Details on distribution in tissues:

As mentioned above, very poor bioavailability is expected for the test item via the dermal route, whereas absorption upon ingestion is considered to be likely based on physicochemical properties and as confirmed by in vivo toxicity studies. A repeated dose toxicity studies revealed signs of an increased metabolism, indicating that either the substance itself or one of its metabolites is distributed throughout the body after oral uptake and is thus systemically available.
Based on its low water solubility and high logPow value, bioaccumulating potential cannot completely be ruled out for the test item.

Details on excretion:

. Because of the tendency of reversibility of the observed effects (e.g. hyperplasia/hypertrophy), the substance is most likely eliminated from the organism.
Based on its low water solubility test item is not expected to be eliminated via the urine unless it undergoes metabolic transformation increasing its hydrophilicity. Elimination via the bile would thus be more likely.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

There is no experimental data available regarding potential metabolism of the test item.
Metabolism of the test item in the liver can be assumed because the liver was found to be a target organ the repeated dose toxicity study as a result of metabolic adaptation.

Applicant's summary and conclusion

Conclusions:

Based on the physicochemical properties, particularly water solubility, logPow and molecular weight, absorption via the gastrointestinal tract is possible for the test substance, whereas uptake following dermal exposure is considered to be very low. Based on its very low vapor pressure it is highly unlikely that the test substance will become systemically available after inhalation. Abiotic transformation e.g. hydrolysis is not expected. If absorbed, the test item would be distributed by binding to plasma protein due to its low water solubility and be eliminated via bile or the urine following metabolic transformation. Bioaccumulation cannot completely be ruled out.

Executive summary:

Toxicokinetic analysis of the test item

There are no experimental studies available on toxicokinetics of the test item. Therefore, its toxicokinetic properties are assessed based on its physico-chemical properties as well as from data available from toxicity studies and in accordance with ECHA Guidance R .7c (2017).

The test substance is an off-white powder with a yellowish tinge at room temperature. The test item, being a mono-constituent substance, has a molecular weight of 389 g/mol and a relative density of 2.0. Its melting point was determined to be 45.4 °C and whereas the boiling point is 296°C at 1013 hPa. The substance is considered highly insoluble in water, as water solubility was found to be smaller than 0.01 mg/L. Partition coefficient (logPow) of the substance was estimated to be 5.7 being the highest calibration standard of the method applied. Vapor pressure of the substance was determined to be 0.052 Pa at 25 °C. 

 

1.1 Absorption

Oral route

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2017). Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4. Thus, with a logPow greater of 5.7 the substance would be expected to not passively pass biological membranes. In addition, the substance is highly insoluble in water. However, micellular formation in the gastrointestinal tract (GIT) could enable absorption processes. Moreover, the molecular weight of the substances is well below 500 g/mol and could thus contribute to a favored absorption. In addition, the substance is not expected to undergo hydrolysis based on its chemical structure. Abiotic degradation is thus not relevant for the oral route of exposure. Taken together, the physico-chemical properties of the substance indicate that intestinal absorption cannot be completely ruled out.

The above considerations are confirmed by findings of toxicity studies with the test substance. In an acute oral toxicity study with rats no mortality or other signs of toxicity were observed up to the limit dose of 2000 mg/kg bw.

The No Observed Adverse Effect Level (NOAEL) of the test item in Wistar rats was established at 300 mg/kg bw/d (highest dose tested) in a 28-day repeated dose toxicity study (OECD 407). Although no adverse effects were observed up to the highest dose tested, signs (hypertrophy in liver and thyroid gland, alterations of cholesterol, total protein, and total bile acid) of increased metabolism suggest that the substance and/or its metabolites become systemically available via the oral route.

Dermal route

The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis and possess a certain lipophilicity to cross the lipid rich environment of the stratum corneum. Considering the low water solubility of the test item (< 0.01 mg/L) and a log POW value of 5.7, the uptake into the stratum corneum will be high, however the transfer between the stratum corneum and the epidermis is limited. Thus, dermal uptake of the test item will be very low.  

The above considerations are in line with findings of an acute dermal toxicity study in rats (OECD 402). No signs of toxicity were observed up to the limit dose of 2000 mg/kg bw. Moreover, no clinical signs were observed in the acute dermal irritation/corrosion study (OECD 404). However, mortality and clinical effects were observed in the Local Lymph Node Assay. Taken together, this indicates that the test item will not readily penetrate skin layers, however, small amounts may become systemically available via dermal route.

Inhalation route

Due to a very low vapor pressure of 0.052 Pa it is very unlikely that the substance becomes available as a vapor. The substance is a solid of low dustiness with a median particle size (D50) of 192 µm. Therefore, exposure via inhalation is considered not relevant for the substance.

 

1.3 Distribution

As mentioned above, very poor bioavailability is expected for the test item via the dermal route, whereas absorption upon ingestion is considered to be likely based on physicochemical properties and as confirmed by in vivo toxicity studies. A repeated dose toxicity studies revealed signs of an increased metabolism, indicating that either the substance itself or one of its metabolites is distributed throughout the body after oral uptake and is thus systemically available.  

Based on its low water solubility and high logPow value, bioaccumulating potential cannot completely be ruled out for the test item.

 

1.4 Metabolism and Elimination

There is no experimental data available regarding potential metabolism of the test item.

Metabolism of the test item in the liver can be assumed because the liver was found to be a target organ the repeated dose toxicity study as a result of metabolic adaptation. Because of the tendency of reversibility of the observed effects (e.g. hyperplasia/hypertrophy), the substance is most likely eliminated from the organism.

Based on its low water solubility test item is not expected to be eliminated via the urine unless it undergoes metabolic transformation increasing its hydrophilicity. Elimination via the bile would thus be more likely.