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Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
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 (corresponding to scenario 2 of the read-across assessment framework): both, the target and source substance, are aliphatic amines with C8-18 alkyl chains and acetate functions
- Two thirds (w/w) of the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid (excluding the solvent water) are composed of the source substance DOPA-Glycinate. The remaining third of Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid consists of other aliphatic amines and derivatives which are considered as structural analogues to those constituting the source substance DOPA-Glycinate and may therefore be expected to elicit comparable (eco)toxicological effects.

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, repeated dose toxicity, genotoxicity and short term ecotoxicity studies, the read-across hypothesis is supported by a quite similar toxicological profile of both substances.

(Eco)toxicological, physicochemical and environmental fate data are summarised in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

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.

Further details are attached to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
For further details refer to IUCLID section 13.

3. ANALOGUE APPROACH JUSTIFICATION
For further details refer to IUCLID section 13.

4. DATA MATRIX
For further details refer to IUCLID section 13.

Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Preliminary studies:
The following no-effects levels were determined in an orientating experiment:
NOEL rat, i.v. = 125 mg/kg bw; NOEL rat, p.o = 400 mg/kg bw.
The administered radioactivity was distributed as follows: Approximately 55 %/19 % (p.o./i.v.) in the faeces, 6 %/23 % in urine, 0.6 %/0.9 % in cage wash, and 12 % (p.o.) in expired air. The mean of the highest plasma concentration was 0.04 %/0.25 % (p.o./i.v.). The fraction of radioactivity excreted in expired air indicated that this route of elimination is relevant.
Type:
absorption
Results:
34% oral absorption
Type:
distribution
Results:
throughout the body, with the highest levels in the residual carcass, in the liver, the kidneys, and the adipose tissue
Type:
metabolism
Results:
mainly oxidation (hydroxylation), to a minor extent dehydrogenation and acetylation
Type:
excretion
Results:
excreted rapidly within 24 hours; main elimination pathway: via the faeces, followed by expired air and urine
Metabolites identified:
yes
Details on metabolites:
In urine, the parent compounds N-C12 Gly, N’-C12 Gly, N’-C12 di Gly, C12 PDA and several metabolites were identified by mass spectrometry. Oxidation (hydroxylation) of the parent and some other metabolites like dehydrogenated and acetylated compounds, especially for C12 PDA, were identified. The most abundant compounds in urine were the oxidation products.
In plasma, only the unchanged parent compounds N-C12 Gly, N’-C12 Gly, N’-C12 di Gly, C12 PDA could be identified by mass spectrometry. For the radioactivity counting only N-C12 Gly, N’-C12 Gly were identified. The most abundant compounds in plasma were the parent substance N-C12 Gly and N’-C12 Gly.
In faeces, N-C12 Gly, N’-C12 Gly, N’-C12 di Gly, C12 PDA and several metabolites were identified by mass spectrometry. Oxidation (hydroxylation) of the parent and some other metabolites, like dehydrogenated and acetylated modifications, was demonstrated. The most abundant compounds in faeces were the oxidation products.
Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
The systemic bioavailability: 34% following oral administration.
The substance is mainly metabolised by oxidation (hydroxylation), and to a minor extent dehydrogenation and acetylation.
The vast majority of the administered radioactivity was excreted rapidly within 24 hours. The main elimination pathway was via the faeces, followed by expired air and urine.
Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
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 (corresponding to scenario 2 of the read-across assessment framework): both, the target and source substance, are aliphatic amines with C8-18 alkyl chains and acetate functions
- Two thirds (w/w) of the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid (excluding the solvent water) are composed of the source substance DOPA-Glycinate. The remaining third of Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid consists of other aliphatic amines and derivatives which are considered as structural analogues to those constituting the source substance DOPA-Glycinate and may therefore be expected to elicit comparable (eco)toxicological effects.

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, repeated dose toxicity, genotoxicity and short term ecotoxicity studies, the read-across hypothesis is supported by a quite similar toxicological profile of both substances.

(Eco)toxicological, physicochemical and environmental fate data are summarised in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

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.

Further details are attached to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
For further details refer to IUCLID section 13.

3. ANALOGUE APPROACH JUSTIFICATION
For further details refer to IUCLID section 13.

4. DATA MATRIX
For further details refer to IUCLID section 13.

Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Signs and symptoms of toxicity:
not examined
Dermal irritation:
no effects
Total recovery:
Test preparation 1, 20 % (w/w): 101.69 % (SD = 3.04%)
Test preparation 2, 0.2 % (w/w): 97.10 % (SD = 2.99%)

Time point:
24 h
Dose:
20%
Parameter:
percentage
Remarks:
potentially absorbable dose (sum of the absorbed dose, exposed skin and stratum corneum tape strips 3–20)
Absorption:
1.1 %
Time point:
24 h
Dose:
0.2%
Parameter:
percentage
Remarks:
potentially absorbable dose (sum of the absorbed dose, exposed skin and stratum corneum tape strips 3–20)
Absorption:
15.1 %
Key result
Time point:
24 h
Dose:
20%
Parameter:
percentage
Remarks:
Dermal delivery (exposed skin + absorbed dose)
Absorption:
0.6 %
Key result
Time point:
24 h
Dose:
0.2%
Parameter:
percentage
Remarks:
Dermal delivery (exposed skin + absorbed dose)
Absorption:
5 %

Test preparation 1, 20 % (w/w):99.76 % of the applied dose was removed by washing at 6 h post application. At 24 h post application, the total dislodgeable dose was 100.35 % of the applied dose. The stratum corneum retained 0.72 % of the applied dose, 0.37 % was removed with the first 5 tape strips.

Absorbed dose: 0.01 % (0.18 ng equivalent/cm²)

Dermal delivery: 0.62 % (13.17 ng equivalent /cm²)

Potentially absorbable dose: 0.97 % (20.53 ng equivalent /cm²)

Test preparation 2, 0.2 % (w/w):73.66 % of the applied dose was removed by washing at 6 h post application. At 24 h post application, the total dislodgeable dose was 75.30 % of the applied dose. The stratum corneum retained 16.08 % of the applied dose, 9.71 % was removed with the first 5 tape strips.

Absorbed dose: 0.11 % (0.02 ng equivalent /cm²)

Dermal delivery: 5.04 % (1.01 ng equivalent /cm²)

Potentially absorbable dose: 11.42 % (2.28 ng equivalent /cm²)

 

 

Table A6.2-4:Details on human skin.

Donor no.

Sex/age of donor

Site of sampling

Supplier

Membrane full-thickness (µm)

Membrane split-thickness (µm)

0164

F/28Y

Breast

St. Johns Hospital

1010–1150

380–390

0161

F/36Y

Abdomen

BUPA

1020–1080

390–400

0162

F/35Y

Abdomen

BUPA

700–1190

390–400

0179

F/84Y

Breast

Nottingham

1130

400

0169

F/82Y

Breast

Nottingham

1000

400

0180

F/74Y

Breast

Nottingham

940–1000

400

0166

F/33Y

Abdomen

Transkin

1240

400

 

 

Table A6.2-5:Summary of the results (mean values).

Test preparation

1

2

Target concentration of active substance

20 % (w/w)

0.2 % (w/w)

Active substance concentration in test preparation by radioactivity

21.016 % (w/w)

0.199 % (w/w)

Application rate of Test preparation

10.06 mg/cm²

10 µl/cm²

Application rate of test item

2114 µg equivalent/cm²

19.94 µg equivalent/cm²

Distribution

% applied dose

ng equivalent /cm²

% applied dose

ng equivalent /cm²

Dislodgeable dose 6 h
(skin wash+tissue swab+pipette tips)

99.76

2108.47

73.66

14.69

Total dislodgeable dose
(dislodgeable dose 6 h +stratum corneum + unexposed skin + cell wash)

100.35

2120.83

75.30

15.02

Unabsorbed dose

101.07

2136.17

92.06

18.36

Absorbed dose
(cumulative receptor fluid + receptor rinse)

0.01

0.18

0.11

0.02

Dermal delivery
(exposed skin + absorbed dose)

0.62

13.17

5.04

1.01

Potentially absorbable dose
(dermal delivery + stratum corneum tape strips)

0.97

20.53

11.42

2.28

Mass balance
(unabsorbed dose + dermal delivery)

101.69

2149.34

97.10

19.36

 

According to EFSA Guidance on Dermal Absorption (2012) as well as the EU Guidance Document

on Dermal Absorption (2004) only the first 2 tape strips should be discarded. On that basis dermal absorption for both low and high doses have been re-calculated.  

 

Recalculation disregarding 2 rather than 5 tape strips:

 

Prep 1 (20% a.i.)

 

Cell 1

Cell 2

Cell 3

Cell 4

Cell 8

Cell 9

Cell 10

Cell 12

Cell 13

Cell 14

Mean

STDEV

1

0.008

0.019

0.08

0.068

0.18

 

0.282

0.12

0.023

0.144

0.103

0.090

2

0.003

0.011

0.141

0.099

0.093

 

0.295

0.063

0.01

0.201

0.102

0.098

Stratum total

0.04

0.1

0.99

0.69

0.95

 

1.58

0.62

0.16

1.33

0.718

0.549

minus 1+2

0.029

0.07

0.769

0.523

0.677

 

1.003

0.437

0.127

0.985

0.513

0.378

Dermal delivery

0.02

0.09

0.77

0.27

1.35

 

1.73

0.82

0.15

0.41

0.623

0.597

Absorbable Dose

0.049

0.16

1.539

0.793

2.027

 

2.733

1.257

0.277

1.395

1.137

0.907

 

Prep 2 (0.2% a.i.) 

 

Cell 16

Cell 17

Cell 18

Cell 19

Cell 24

Cell 25

Cell 26

Cell 28

Cell 29

Cell 30

Mean

STDEV

1

3.11

2.24

2.84

4.42

3.36

3.89

4.82

3.78

4.87

6.06

3.939

1.131

2

1.66

1.8

1.71

2.33

1.73

2.53

2.19

2.26

2.5

2.26

2.097

0.338

Stratum total

12.02

13.59

14.46

19.48

15.39

15.49

20.79

16.73

14.73

18.17

16.085

2.718

minus 1+2

7.25

9.55

9.91

12.73

10.3

9.07

13.78

10.69

7.36

9.85

10.049

2.052

Dermal delivery

2.56

2.52

3.84

3.15

8.21

9.37

6.12

7.47

3.15

4.02

5.041

2.538

Absorbable Dose

9.81

12.07

13.75

15.88

18.51

18.44

19.9

18.16

10.51

13.87

15.090

3.611
Conclusions:
The systemically available dose (= dermal delivery: exposed skin + absorbed dose): 0.6±0.6% for the high exposure scenario (20% a.i.), and 5.0±2.5% for the low exposure scenario (0.2% a.i.), respectively.
The potentially absorbable dose: 1.1±0.9% for the high exposure scenario (20% a.i.), and 15.1±3.6% for the low exposure scenario (0.2% a.i.), respectively.

Description of key information

The oral bioavailability was determined to be 34% (OECD guideline 417, GLP; rat).

The systemically available dose after dermal administration was determined to be 0.6±0.6% for the high exposure scenario (20% a.i.), and 5.0±2.5% for the low exposure scenario (0.2% a.i.), respectively (OECD guideline 428, GLP; human skin).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
5
Absorption rate - inhalation (%):
100

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 Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid. However, toxicokinetic data are available for the source substance DOPA-Glycinate. A justification for read-across is attached to IUCLID section 13. Additionally, the toxicokinetic assessment is partially based on physicochemical properties.

 

Oral absorption

The physicochemical properties of the target substance are favourable for absorption (molecular weight < 500 g/mol, log Kow -0.55).

 

The systemic bioavailability of the source substance DOPA-Glycinate was 34% following oral administration. Based on the available experimental data and on physicochemical properties, the bioavailability after oral administration is set to 50% in accordance with the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance.

 

Respiratory absorption

The extent of inhalation absorption deduced from the physico-chemical properties are expected to be high. For chemical safety assessment, a value of 100% is considered appropriate according to the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance.

 

Dermal absorption

The physicochemical properties of the target substance are only partially favourable for dermal absorption (molecular weight < 500 g/mol, log Kow -0.55); the substance is expected to be too hydrophilic to easily cross the stratum corneum. On the other hand, the substance is corrosive, which may enhance penetration.

Experimental data are available for the source substance DOPA-Glycinate supporting the assumption of low dermal penetration.

The percutaneous absorption of [14C]-DOPA-Glycinate was tested according to OECD 428: Skin Absorption: In Vitro Method (2004).

The systemically available dose of DOPA-Glycinate (= dermal delivery: exposed skin + absorbed dose) was 0.6±0.6% for the high exposure scenario (20% a.i.), and 5.0±2.5% for the low exposure scenario (0.2% a.i.), respectively. For chemical safety assessment, a value of 5% is considered appropriate in accordance with the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance.

 

Distribution

As a small molecule with high water solubility, a wide distribution of substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid can be expected. This assumption is further supported by in vivo data on the source substance DOPA-Glycinate.

DOPA-Glycinate was distributed throughout the body, with the highest levels in the residual carcass, in the liver, the kidneys, and the adipose tissue.

The recovery of radioactivity was greatest in the residual carcass (12–19 %), followed by the liver (approx 4 %). In all other tissues the radioactive recovery was low (≤ 1.00 %) and quite uniformly distributed, with no tissue storage in brain, heart, ovaries and spinal cord. There was no relevant difference in the tissue distribution of radioactivity between animals treated orally or intravenously with a single or repeated dose of the test substance.

A similar distribution can be assumed for the target substance, based on comparable physicochemical properties.

 

Metabolism/ Elimination

No experimental data are available or the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid. An ADME study was conducted with the closely related substance DOPA-Glycinate. In plasma, only parent substances but no transformation products could be identified. A first-pass effect following intestinal absorption is therefore unlikely. In urine and faeces, parent substances as well as transformation products were detected. Metabolites in both urine and faeces were characterised by oxidation (hydroxylation) of the parent and some other metabolites like dehydrogenated and acetylated compounds. The most abundant compounds in urine were the oxidation products.

Upon oral administration, radioactivity was predominantly eliminated via faeces (approx. 60 %) and via expired air (approx. 18 %). A lower proportion was excreted via urine (approx. 9 %) and less than 20 % of the administered dose was found in the carcass.

Based on close structural similarity, similar metabolism is expected for the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid.