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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: See Discussion
Overall assessment factor (AF):
15
Modified dose descriptor starting point:
NOAEC
Value:
528.6 mg/m³
Explanation for the modification of the dose descriptor starting point:
See Discussion
AF for dose response relationship:
1
Justification:
See Discussion
AF for differences in duration of exposure:
2
Justification:
ECHA default
AF for interspecies differences (allometric scaling):
1
Justification:
See Discussion
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
3
Justification:
ECETOC default, see Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: See Discussion
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
See Discussion
AF for dose response relationship:
1
Justification:
See Discussion
AF for differences in duration of exposure:
2
Justification:
ECHA default
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
3
Justification:
ECETOC default, see Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Eye irritation

Ethylenediamine, propoxylated is classified for eye irritation. The available data do not permit a DNEL derivation. Therefore, a qualitative approach will be applied for eye irritation.

 

 

Skin sensitisation

Ethylenediamine, propoxykated not classified for skin sensitisation.

 

 

Repeated dose toxicity

 

a.      Worker-DNEL long-term dermal, systemic

 

The NOEL of 300 mg/kg bw/day from the rat 90-day repeat dose oral study with the analogue was taken as dose descriptor. In a first step a route-to-route extrapolation is made for the rat. On the assumption that, in general, dermal absorption will not be higher than oral absorption (default factor = 1) no modification of the dose descriptor is necessary to set the correct starting point when performing oral-to-dermal extrapolation

 

Oral NOEL (rat) = dermal NOEL(rat) = 300 mg/kg bw/day

 

The DNEL long-term dermal, systemic is calculated by applying assessment factors to the NOEL. Since the starting point for the DNEL calculation is a NOEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 60 was calculated as follows:

-       Intra-species differences = 3(ECETOC default, see justification below)

-       Inter-species differences (allometric) = 4(ECHA default)

-       Inter-species differences (remaining differences) = 2.5(ECHA default)

-       Exposure duration: Conversion from a subchronic study to a chronic study = 2(ECHA default)

 

Worker-DNEL long-term, dermal, systemic = 300/60 = 5 mg/kg bw/day

 

 

b.     Worker-DNEL long-term inhalation, systemic

 

The NOEL of 300 mg/kg bw/day from the rat 90-day repeat dose oral study in the analogue was taken as dose descriptor. The NAEC worker (8h) was calculated as prescribed by the guidance:

Corrected inhalatory NAEC = rat oral NOEL x (1/sRVrat) x (ABSoral rat/human inhal) x (sRVhuman/wRV)

 

-       N = 300 x (1/0.38) x 1 x (6.7/10)

-       N= 300 x 2.63 x 0.67 = 528.6 mg/m³

 

The DNEL long-term inhalation, systemic is calculated by applying assessment factors to the NAEC. Since the starting point for the DNEL calculation is a NOEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 15 was calculated as follows:

-       Intra-species differences = 3(ECETOC default, see justification below)

-       Inter-species differences (allometric) = 1(ECHA default, see route-to-route extrapolation above)

-       Inter-species differences (remaining differences) = 2.5(ECHA default)

-       Exposure duration: Conversion from a subchronic study to a chronic study = 2(ECHA default)

 

Worker-DNEL long-term inhalation, systemic = 528.6 mg/m³/15 = 35.2 mg/m³

 

 

Mutagenicity and carcinogenicity

 

The substances are not considered mutagenic. Based on the toxicological profile of the substances, carcinogenicity is not expected.

 

 

Reproduction toxicity

 

The NOAEL for reproduction and developmental toxicity of the analogue was concluded to be 1000 mg/kg bw/day (highest dose tested in OECD 421 and 414 studies). As no adverse reproductive or developmental toxic effects were observed at the highest dose tested, a DNEL for reproduction toxicity is not quantifiable. Nevertheless in case the highest dose of 1000 mg/kg bw/day will be used for a DNEL derivation this will not result in a more critical DNEL compared to the DNEL for repeated dose toxicity.

Justification for Use of ECETOC Intraspecies Assessment Factor

According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DNEL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC Technical Report No. 110 as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability.

Ethylenediamine, propoxylated, 1-5.5 moles propoxylated is an essentially non-volatile liquid at room temperature, fully miscible with water and with a log P of < 0.3 – 1.6 and a low order of toxicity. There are no toxicokinetics data for the mixed oligomers. According to Illing and Barratt (2007; 2009, both attached in Chapter 13), any toxicokinetic assessment toxicokinetics assessment is has to examine data for the repeating unit and the initiating agent, ethylenediamine, and oligomers made using ethylenediamine as initiating agent and 1-methyl-2-oxirane as the chain-lengthening agent (in ascending order of multiples of the oligomer). These are ethylene diamine (and, for comparison, its dimer) and porpane-1,2-diol and its oligomers. Conclusions for the longer oligomers are based on that data and on structure activity information. The commercially available NLP Polyols are mixtures containing several individual oligomers of different molecular weight or number of repeating units. Generally the lowest commercially available NLP polyol have at least three propoxy moieties attached to the ethylenediamine. Thus it is likely that both the amine groups will be capped, with the link as a secondary or tertiary amine rather than as an ether. This is reflected in the acute toxicity data, whereby the acute toxicity of ethylenediamine and dimer is sufficient to require classification as harmful and as a skin and eye irritant and a skin sensitiser, whereas the lowest molecular weight propoxylated material (~3-4) is essentially non-toxic. With the amine groups capped, the oligomer is likely to exhibit toxicokinetics based on the propane-1,2-diol oligomers. The lack of resemblance of ethylenediamine to glycerol or propane-1,2-diol means that NLP polyols are unlikely to interfere in fat absorption mechanisms and the absorption mechanism is likely to be passive diffusion.

The analogue, Ethylenediamine, ethoxylated and propoxylated, >1 - <8.5 moles ethoxylated, 1-8.5 moles propoxylated is an essentially non-volatile liquid at room temperature, fully miscible with water and with a log P of < 0.3-1.5 and a low order of toxicity. There are no toxicokinetic data for the mixed oligomers. According to Illing and Barratt (2007; 2009, both attached in Chapter 13), any toxicokinetic assessment has to be based on the properties of the initiator (ethylenediamine) and of propane-1,2-diol and ethane-1,2 -diol oligomers. The commercially available materials are mixtures containing several oligomers of different molecular weight or number of repeating units (propoxy- or ethoxy moeties). For most oligomers it is likely that both the amine groups will be capped, but for oligomers containing a single propane-1,2-diol or ethane-1,2-diol moiety, or capable of being biotransformed to such a moiety, free amine would be present. This is reflected in the acute toxicity data, whereby the acute toxicity of ethylenediamine and dimer is sufficient to require classification as harmful and as a skin and eye irritant and a skin sensitiser, and the there is some carry-over of eye irritancy and skin sensitisation properties to the propoxylated/ethoxylated material. However, the lack of resemblance of ethylenediamine to glycerol or propane-1,2-diol means that the oligomers are unlikely to interfere in fat absorption mechanisms and the absorption mechanism is likely to be passive diffusion.

 

Unless the ethylenediamine is hydrolysed out from the oligomer it is unlikely to be metabolised. If released it may be N-acetylated. The propoxy groups are likely to be either conjugated or hydrolysed stepwise across the ether linkage. The new oligomer is also likely to be either conjugated or hydrolysed across the ether linkage. The three carbon elements are likely to be taken into intermediary metabolism and may eventually be exhaled as carbon dioxide.

 

The repeating alkoxylate units can be hydrolyzed from the core substance releasing individual or oligomeric glycols, thus propylene glycol is expected to be a common metabolic breakdown product. The terminal hydroxyl groups and the ionizable amino groups are structural features which are susceptible to both Phase I (oxidative catabolism) and Phase II (conjugation/elimination) reactions. The terminal hydroxyls can be oxidized to carboxylic acids and/or conjugated with the glucuronide. Likewise, the freed amines of the core EDA are expected to be metabolized by N-acetylation. The substance is expected to be excreted in urine or bile. Once absorbed, it is expected to be widely distributed in body water and not expected to bioaccumulate in tissues.

 

Based on this information, it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment.

 

References for default assessment factors:

ECETOC. 2003. Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No.86. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

 

ECETOC. 2010. Guidance on Assessment Factors to Derive a DNEL. Technical Report No.110. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

 

ECHA. 2012. Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health; November 2012.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: See Discussion
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
261 mg/m³
Explanation for the modification of the dose descriptor starting point:
See Discussion
AF for dose response relationship:
1
Justification:
See Discussion
AF for differences in duration of exposure:
2
Justification:
ECHA default
AF for interspecies differences (allometric scaling):
1
Justification:
See Discussion
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
5
Justification:
ECETOC default, See Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: See Discussion
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
See Discussion
AF for dose response relationship:
1
Justification:
See Discussion
AF for differences in duration of exposure:
2
Justification:
ECHA default
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
5
Justification:
ECETOC default, See Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: See Discussion
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
AF for dose response relationship:
1
Justification:
See Discussion
AF for differences in duration of exposure:
2
Justification:
ECHA default
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
5
Justification:
ECETOC default, See Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Eye irritation

Ethylenediamine, propoxylated is classified for eye irritation. The available data do not permit a DNEL derivation. Therefore, a qualitative approach will be applied for eye irritation.

 

 

Skin sensitisation

Ethylenediamine, propoxylated is not classified for skin sensitisation.

 

 

Repeated dose toxicity

 

a. General population-DNEL long-term oral, systemic

 

The NOEL of 300 mg/kg bw/day from the rat 90-day repeat dose oral study in the analogue was taken as dose descriptor.

 

The DNEL (oral) is calculated by applying assessment factors to the NOEL. Since the starting point for the DNEL calculation is a NOEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 100 was calculated as follows:

-       Intra-species differences = 5(ECETOC default, see justification below)

-       Inter-species differences (allometric) = 4(ECHA default)

-       Inter-species differences (remaining differences) = 2.5(ECHA default)

-       Exposure duration: Conversion from a subchronic study to a chronic study = 2(ECHA default)

 

General population-DNEL long-term, oral, systemic = 300/100 = 3 mg/kg bw/day

 

 

b.     General population-DNEL long-term dermal, systemic

 

The NOEL of 300 mg/kg bw/day from the rat 90-day repeat dose oral study in the analogue was taken as dose descriptor. In a first step a route-to-route extrapolation is made for the rat. On the assumption that, in general, dermal absorption will not be higher than oral absorption (default factor = 1) no modification of the dose descriptor is necessary to set the correct starting point when performing oral-to-dermal extrapolation

 

Oral NOEL (rat) = dermal NOEL (rat) = 300 mg/kg bw/day

 

The DNEL (dermal) is calculated by applying assessment factors to the NAEL. Since the starting point for the DNEL calculation is a NOEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 100 was calculated as follows:

-       Intra-species differences = 5(ECETOC default, see justification below)

-       Inter-species differences (allometric) = 4(ECHA default)

-       Inter-species differences (remaining differences) = 2.5(ECHA default)

-       Exposure duration: Conversion from a subchronic study to a chronic study = 2(ECHA default)

 

General population-DNEL long-term, dermal, systemic = 300/100 = 3 mg/kg bw/day

 

 

c.      General population-DNEL long-term, inhalation, systemic

 

The NOEL of 300 mg/kg bw/day from the rat 90-day repeat dose oral study in the analogue was taken as dose descriptor. The NAEC general population (24 h) was calculated as prescribed by the guidance:

Corrected inhalatory NAEC = rat oral NOEL x (1/sRVrat) x (ABS oral rat/ABS inhal human)

 

-       N= 300 x (1/1.15) x 1

-       N= 300 x 0.87 = 261 mg/m³

 

The DNEL (inhalation) is calculated by applying assessment factors to the NAEC. Since the starting point for the DNEL calculation is a NOEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 25 was calculated as follows:

-       Intra-species differences = 5(ECETOC default, see justification below)

-       Inter-species differences (allometric) = 1(ECHA default, see route-to-route extrapolation above)

-       Inter-species differences (remaining differences) = 2.5(ECHA default)

-       Exposure duration: Conversion from a subchronic study to a chronic study = 2(ECHA default)

 

General population-DNEL long-term inhalation, systemic = 261 mg/m³/25 = 10.4 mg/m³

 

 

Mutagenicity and carcinogenicity

 

The substances are not considered mutagenic. Based on the toxicological profile of the substances, carcinogenicity is not expected.

 

 

Reproduction toxicity

 

The NOAEL for reproduction and developmental toxicity of the anlogue was concluded to be 1000 mg/kg bw/day (highest dose tested in OECD 421 and 414 studies). As no adverse reproductive or developmental toxic effects were observed at the highest dose tested, a DNEL for reproduction toxicity is not quantifiable.Nevertheless in case the highest dose of 1000 mg/kg bw/day will be used for a DNEL derivation this will not result in a more critical DNEL compared to the DNEL for repeated dose toxicity.

 

Justification for Use of ECETOC Intraspecies Assessment Factor

According to the ECHA guidance document, where scientific justification exists, one can deviate from the default ECHA assessment factors used in DNEL derivation. In deriving DNELS, the assessment factor chosen for Intraspecies variability (worker and general population) has been taken from the ECETOC Technical Report No, 110 as an alternative to the ECHA default. The ECETOC working group performed a detailed assessment of the many publications available on human variability as it pertains to risk assessment. As a consequence of this assessment it was determined that in the majority of cases a factor of 3 for worker or 5 for general population is sufficient to address Intraspecies variability.

 

Ethylenediamine, propoxylated, 1-5.5 moles propoxylated is an essentially non-volatile liquid at room temperature, fully miscible with water and with a log P of < 0.3 – 1.6 and a low order of toxicity. There are no toxicokinetics data for the mixed oligomers. According to Illing and Barratt (2007; 2009, both attached in Chapter 13), any toxicokinetic assessment toxicokinetics assessment is has to examine data for the repeating unit and the initiating agent, ethylenediamine, and oligomers made using ethylenediamine as initiating agent and 1-methyl-2-oxirane as the chain-lengthening agent (in ascending order of multiples of the oligomer). These are ethylene diamine (and, for comparison, its dimer) and porpane-1,2-diol and its oligomers. Conclusions for the longer oligomers are based on that data and on structure activity information. The commercially available NLP Polyols are mixtures containing several individual oligomers of different molecular weight or number of repeating units. Generally the lowest commercially available NLP polyol have at least three propoxy moieties attached to the ethylenediamine. Thus it is likely that both the amine groups will be capped, with the link as a secondary or tertiary amine rather than as an ether. This is reflected in the acute toxicity data, whereby the acute toxicity of ethylenediamine and dimer is sufficient to require classification as harmful and as a skin and eye irritant and a skin sensitiser, whereas the lowest molecular weight propoxylated material (~3-4) is essentially non-toxic. With the amine groups capped, the oligomer is likely to exhibit toxicokinetics based on the propane-1,2-diol oligomers. The lack of resemblance of ethylenediamine to glycerol or propane-1,2-diol means that NLP polyols are unlikely to interfere in fat absorption mechanisms and the absorption mechanism is likely to be passive diffusion.

The analogue, Ethylenediamine, ethoxylated and propoxylated, >1 - <8.5 moles ethoxylated, 1-8.5 moles propoxylated is an essentially non-volatile liquid at room temperature, fully miscible with water a log P of < 0.3-1.5 and a low order of toxicity. There are no toxicokinetic data for the mixed oligomers. According to Illing and Barratt (2007; 2009, both attached in Chapter 13), any toxicokinetic assessment has to be based on the properties of the initiator (ethylenediamine) and of propane-1,2-diol and ethane-1,2 -diol oligomers. The commercially available materials are mixtures containing several oligomers of different molecular weight or number of repeating units (propoxy- or ethoxy moeties). For most oligomers it is likely that both the amine groups will be capped, but for oligomers containing a single propane-1,2-diol or ethane-1,2-diol moiety, or capable of being biotransformed to such a moiety, free amine would be present. This is reflected in the acute toxicity data, whereby the acute toxicity of ethylenediamine and dimer is sufficient to require classification as harmful and as a skin and eye irritant and a skin sensitiser, and the there is some carry-over of eye irritancy and skin sensitisation properties to the propoxylated/ethoxylated material. However, the lack of resemblance of ethylenediamine to glycerol or porpane-1,2-diol means that the oligomers are unlikely to interfere in fat absorption mechanisms and the absorption mechanism is likely to be passive diffusion.

 

Unless the ethylenediamine is hydrolysed out from the oligomer it is unlikely to be metabolised. If released it may be N-acetylated. The propoxy groups are likely to be either conjugated or hydrolysed stepwise across the ether linkage. The new oligomer is also likely to be either conjugated or hydrolysed across the ether linkage. The three carbon elements are likely to be taken into intermediary metabolism and may eventually be exhaled as carbon dioxide.

 

The repeating alkoxylate units can be hydrolyzed from the core substance releasing individual or oligomeric glycols, thus propylene glycol is expected to be a common metabolic breakdown product. The terminal hydroxyl groups and the ionizable amino groups are structural features which are susceptible to both Phase I (oxidative catabolism) and Phase II (conjugation/elimination) reactions. The terminal hydroxyls can be oxidized to carboxylic acids and/or conjugated with the glucuronide. Likewise, the freed amines of the core EDA are expected to be metabolized by N-acetylation. The substance is expected to be excreted in urine or bile. Once absorbed, it is expected to be widely distributed in body water and not expected to bioaccumulate in tissues.

 

Based on this information, it is considered that the lower assessment factors proposed by ECETOC should adequately address the Intraspecies variability within the risk assessment.

 

References for default assessment factors:

ECETOC. 2003. Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No.86. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

 

ECETOC. 2010. Guidance on Assessment Factors to Derive a DNEL. Technical Report No.110. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.

 

ECHA. 2012. Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health; November 2012.

 

 

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