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Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
• they are manufactured from similar or identical precursors under similar conditions
• they share structural similarities with common functional groups: quaternary ammonium and saturated or unsaturated alkyl chains with comparable length (corresponding to scenario 2 of the read-across assessment framework)

The read-across hypothesis is based on structural similarity of target and source substances. Based on available experimental data, including key physicochemical properties and data from acute toxicity, irritation, sensitization (human) and genotoxicity studies, the read-across strategy is supported by a quite similar toxicological profile of all substances.

Therefore, read-across from the existing ecotoxicity, environmental fate and toxicity studies conducted with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

A justification for read-across is attached to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See justification for read-across attached to IUCLID section 13.

3. ANALOGUE APPROACH JUSTIFICATION
See justification for read-across attached to IUCLID section 13.

4. DATA MATRIX
See justification for read-across attached to IUCLID section 13.
Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Objective of study:
toxicokinetics
Type:
absorption
Results:
ca. 10% after oral administration
Type:
metabolism
Results:
omprised the oxidation of the two decyl side chains to form hydroxy and hydroxyketo derivatives; metabolism of methyl side chains was not found.
Type:
excretion
Results:
no excretion as CO2; maily excreted via faeces and to a less extent urine (mainly unmetabolized)
Metabolites identified:
no
Conclusions:
No bioaccumulation is expected based on the results. The substance is expected to have low absorption after oral administration. It is excreted in the urine and faeces and a negligible amount is retained in the body after 1 wk.
Endpoint:
dermal absorption, other
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
• they are manufactured from similar or identical precursors under similar conditions
• they share structural similarities with common functional groups: quaternary ammonium and saturated or unsaturated alkyl chains with comparable length (corresponding to scenario 2 of the read-across assessment framework)

The read-across hypothesis is based on structural similarity of target and source substances. Based on available experimental data, including key physicochemical properties and data from acute toxicity, irritation, sensitization (human) and genotoxicity studies, the read-across strategy is supported by a quite similar toxicological profile of all substances.

Therefore, read-across from the existing ecotoxicity, environmental fate and toxicity studies conducted with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

A justification for read-across is attached to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See justification for read-across attached to IUCLID section 13.

3. ANALOGUE APPROACH JUSTIFICATION
See justification for read-across attached to IUCLID section 13.

4. DATA MATRIX
See justification for read-across attached to IUCLID section 13.
Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
Administered radioactivity detected over a 72 hour-period expressed as mean +/- SEM (n=4)

- Skin test site: 88 ± 2.3%
- Skin, untreated site: 0.2% ± 0.1
- Urine: 0.15% ± 0.0
- Faeces: 0.16% ± 0.0
- Expired air: 0.27% ± 0.0
- Cage wash + cage wipe: 0.29% ± 0.0
Total recovery:
- Total recovery: 89 ± 2.4 expressed as mean +/- SEM (n=4)
Parameter:
percentage
Absorption:
< 1 %
Remarks on result:
other: Only traces of administered radioactivity were detected over a 72 h period. Dermal absorption of the substance is considered to be very low.
Conclusions:
The dermal absorption of Di-C12-18 alkyldimethyl ammonium chloride is expected to be very low (<<10%).

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
20

Additional information

No experimental in vivo or in vitro data on oral, inhalation and dermal absorption, distribution, metabolism and excretion are available for the target substance Di-C12-18 alkyldimethyl ammonium chloride. However, toxicokinetic data are available for Cetrimonium Bromide and DDAC. A justification for read-across is attached to IUCLID section 13.The toxicokinetic assessment is partially based on physicochemical properties.

 

Oral absorption

In a toxicokinetic study, female rats received a single oral gavage administration of 0.8 mg/kg [1-14C] Cetrimonium Bromide in water. After 3 days 92% of the dose was excreted in feces and about 1% in urine. About 85% of the radioactive substance excreted in feces after 3 d was the parent compound. About 2% of the administrated radioactivity was excreted in the bile during the first 12 hours after treatment. Taken together, these data indicate that about 10% of the administered dose was absorbed. Only small amounts of radioactivity were found in the blood and organs. Highest peak concentratons (at 4-8 h) were found in liver (about 0.8% of administered radioactivity) and lower levels in kidneys, spleen, heart, lung and skeletal muscle.

 

In a toxicokinetic study, rats received a single oral gavage dose of 14C-labelled DDAC. The majority (>90%) of the administered dose was excreted via the faeces. From the amount excreted in urine (<3%) and tissue residues (<1%), the report authors concluded that the oral absorption was less than 10%.

 

The physicochemical properties of the target and source substances are at least partially favourable for absorption (molecular weight < 500 g/mol,but weighted mean calculated log Kow >4). The longer chain di- and trialkyl compounds are probably absorbed to a lesser extent. The substances are quaternised, which is disadvantageous for the diffusion across the biological membranes in the gastro-intestinal tract. In general, solids with a microscale particle diameter are too large to be directly taken up by pinocytosis and have to be dissolved before they can be absorbed. The target and source substances have a similarly low water solubility, which is likely to reduce absorption.

Based on the available experimental data and on physicochemical properties, a low bioavailability after oral administration can be assumed. For chemical safety assessment, a value of 10% is considered appropriate.

 

Respiratory absorption

Both source substances and the target substances are solid at room temperature and have a low vapour pressure (<1E-05 Pa) therefore substance evaporation and uptake by inhalation as vapour is for all of them unlikely.

The extent of inhalation absorption deduced from the physico-chemical properties and from the results of oral absorption studies are expected to be low. Furthermore, the target substance Di-C12-18 alkyldimethyl ammonium chlorideas well as the source substances are quaternised ammonium compounds, and the inhalation absorption of ionic substances is generally low. For chemical safety assessment, a value of 20% is considered appropriate.

 

Dermal absorption

The physicochemical properties of the target and source substances are at least partially favourable for absorption (molecular weight < 500 g/mol,but weighted mean calculated log Kow >4). Taking into account the ionic nature of the substances (quaternary ammonium ions) a high dermal absorption is nevertheless unlikely. For chemical safety assessment, a value of 10% is considered appropriate.

 

Distribution

As small molecules a wide distribution can be expected. No information on potential target organs is available. However, as ionised molecules, the source and target substances are thought to not readily diffuse across biological membranes.

 

Metabolism/ Elimination

In a study with orally administered didecyldimethyl ammonium chloride in rat, the majority (>90%) of the dose was excreted very likely unabsorbed via the faeces. From the amount excreted in urine (<3%) and tissue residues (<1%), the report authors concluded that the oral absorption was <10%.Metabolism, which may be by microbial activity, comprised the oxidation of the two decyl side chains to form hydroxy and hydroxyketo derivatives; metabolism of methyl side chains was not found. No cleavage of the side chains (beta-oxidation) was reported.