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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.4 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 230 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL of 1000 mg/kg bw/day from the Combined 28-Day Repeated Dose Oral (Gavage) Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Rats is available for rats (Herberth, 2016)

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
6
Justification:
since it is a subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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:
23.3 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
7 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 1000 mg/kg bw /day from Combined 28-Day Repeated Dose Oral (Gavage) Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Rats is available for rats (Herberth, 2016) . This value was converted into the corrected dermal NOAEL taking into account the rates for absorption (oral 50 %, dermal 10 %) and exposure considerations.

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
6
Justification:
since it is a subacute study
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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:
low hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

 

Available dose descriptors:

There are data available on irritating and sensitisation potential as well as on acute toxicity (oral and dermal) of Reaction product of D-Glucopyranoside, methyl; esterified with oleic acid, methyl ester (generic name: D-glucopyranoside methyl 2,6 -dioleate).

Acute/short-term exposure – systemic effects (dermal DNEL):

There are acute studies available for the test substance. However, there are acute oral and dermal studies in rats (Weinberg, 2015 (A), Smolin, 1983, Weinberg (B)) and also dermal irritation studies in rabbits (Sanders, 2015 (B), Smolin 1983)). The results show that the substance is non-toxic by ingestion and by skin contact; no remarkable systemic toxicity is reported. Oral LD50 values LD50 > 5,000 mg/kg bw/day and dermal LD50 values LD50 > 2000 mg/kg bw/day were reported.

The DNEL for acute systemic effects by the dermal route is unnecessary since the long-term DNEL covers sufficiently the risk of short-term exposure, so no DNEL for acute systemic effects needs to be derived.

Acute/short-term exposure – systemic effects (inhalation DNEL):

No acute inhalation study is available for the substance. However, the D-glucopyranoside methyl 2,6-dioleate is not expected to pose an inhalation hazard due to its low vapour pressure (0.00627 Pa at 25 °C). Therefore, no DNEL is required.

Acute/short-term exposure – local effects (dermal DNEL):

The substance D-glucopyranoside methyl 2,6 -dioleate is not irritating to the skin of rabbits after 4-hour application of test material (Sanders, 2015 (A))). LD50 values above 2000 were reported for the

D-glucopyranoside methyl 2,6 -dioleate  in the dermal studies. Thus, the short-term dermal DNEL needs not to be derived and is sufficiently covered by the long-term DNEL for systemic and local effects.

Acute/short-term exposure – local effects (inhalation DNEL):

The D-glucopyranoside methyl 2,6 -dioleate substance does not pose an airborne hazard, due to its low vapour pressure. The long-term inhalation DNEL for systemic effects covers sufficiently local effects.

Long-term exposure – systemic effects (dermal DNEL):

No repeated dose data is available for the substance. However the long-term systemic DNEL for the dermal route has been derived from the NOAEL of an oral subacute one-generation reproductive toxicity study in rats with D-glucopyranoside methyl 2,6 -dioleate (Haas, 2015)). A NOAEL of greater than 1000 mg/kg bw/day was established. The starting point for the DNEL derivation is the oral NOAEL (route-to-route extrapolation necessary).

Long-term exposure – systemic effects (inhalation DNEL):

There are no dose-response and route-specific information on repeated dose toxicity via inhalation. The substance does not pose a hazard for humans by the inhalation route of exposure. The inhalation DNEL can be derived from the oral NOAEL of 1000 mg/kg bw established in the oral one-generation study in rats (Haas, 2015) by route-to-route extrapolation.

Long-term exposure – local effects (dermal DNEL):

No dermal DNEL for local effects is needed since the substance is not expected to be irritating or sensitising to the skin. A DNEL is not quantifiable and not relevant. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

Long-term exposure – local effects (inhalation DNEL):

No long-term inhalation DNEL for local effects is needed since the D-glucopyranoside methyl 2,6 -dioleate substance is not expected to be irritating or sensitising to respiratory system. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because no No-Observed-Effect-Level could be established from the relevant studies. However, any hazard does not exist as no classification of D-glucopyranoside methyl 2,6 -dioleate was necessary.

 

Modification of the starting point:

From all available data on the D-glucopyranoside methyl 2,6 -dioleate substance for the different human health endpoints, it is clear that the substance exert its effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target reflecting the routes, the duration and the frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.

Bioavailability (absorption):

There is no substance-specific experimental information on absorption by the oral, dermal and inhalation routes available. The absorption rates are assessed based on the physico-chemical properties and on the effects observed in treated animals in the available studies.

Oral absorption:

Due to the molecular weight of 723.07 - 1260 g/mol, a logPow of 8, low water solubility (7.68 mg/L at 20°C) together with the very slight effects found at the highest dose levels in the subacute study and in the one-generation study in rats, absorption via the oral route is considered to be slight to moderate for the substance (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). The oral absorption is set to 50% since physico-chemical properties of the substance are not in range suggestive of significant absorption from the gastro-intestinal tract. The oral absorption is considered to be the same in animals and in humans (worst-case).

Dermal absorption:

No significant dermal absorption is expected for the D-glucopyranoside methyl 2,6 -dioleate. The log Pow of 8, the water solubility of 7.68 mg/L and the molecular weight of 723.07 - 1260 g/mol point to a poor absorption through the skin. According to the TGD, Part I, Appendix IV, and ECHA guidance R.7C, 2014, 10% of dermal absorption can be considered in this case, since the criteria for molecular weight and Log Pow are met (MW above 500 g/mol and log Pow > 4). Moreover, a critical assessment of all available data (toxicity effects in the available studies and physicochemical properties) should be taken into account before using default assumptions (ECETOC, TR No. 110). The absorption after dermal exposure is generally more gradual and slower than oral absorption and a lower bioavailability is expected due to the presence of the absorption hindering outer skin layer stratum corneum and a comparatively smaller surface area. Schuhmacher et al. recommended that a low dermal penetration (< 10%) can be assumed for substances with a logPow value >5 or for substances with a Kp value <0.0001 (cm/h). (Schumacher et al., 2003). Hence a dermal absorption of 10% is assumed.

 

Dermal absorption in rats, rabbits and in humans is assumed to be the same since no information for dermal absorption of D-glucopyranoside methyl 2,6 -dioleate in humans is available.

 

Reference:

1.      Schuhmacher-Wolz U., Kalberlach F., Oppl R., van Hemmen J.J. (2003).A toolkit for dermal risk assessment: toxicological approach for hazard characterization. Ann. Occup. Hyg., Vol 47 No.8, pp. 641 -652.

 

Inhalation absorption

Absorption by inhalation is considered to be negligible (low vapour pressure of 0.00627 Pa at 25°C) and not to be higher than absorption by oral route. However, 100% absorption is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available and worst-case assumption should be made for route-to-route extrapolation according to ECHA guidance R.8, 2012.

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to obtain a long-term inhalation NOAEC for systemic effects. The following formula was used: corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

Oral-to-dermal extrapolation is performed to obtain long-term dermal NOAEL for systemic effects. The following formula was used: corrected dermal NOAEL = oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ ABSs dermal-human), where ABS is absorption.

 

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after oral administration of the test material was already assessed in respiratory volume taken for rats during 8 h (0.38m³).

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the subacute oral combined repeated dose toxicity study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral NOAEL from the subacute oral combined repeated dose toxicity study in rats , which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL from the combined repeated dose studystudy was used for the derivation of inhalation long-term DNEL. An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers for all endpoints and for all exposure routes.

Extrapolation of duration:

An assessment factor of 6 was applied for duration of exposure (subacute study).

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

A default assessment factor of 1 was applied when the NOAEL from the subacute oral one-generation reproductive toxicity study was used.

 

Calculation of DNELs:

Long-term exposure – systemic effects (dermal DNEL):

For the oral rat NOAEL of 1000 mg/kg bw the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) x (exposure of animals per week) = 1000 x (50 %/10%) x (10 %/ 10 %) x (7/5) = 7000 mg/kg bw

DNEL = 7000 mg/kg bw/(4 x 2.5 x 5 x 6 x 1 x 1) = 23.3 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (subacute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 300.

Long-term exposure – systemic effects (inhalation DNEL):

The oral rat NOAEL of 1000 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) x (exposure of animals per week) = 1000 mg/kg bw x (1/0.38 m³/kg/day) x (50%/100%) x (6.7/10) x (7/5) = 1230 mg/m³

DNEL = 1230 mg/m³/(2.5 x 5 x 6 x 1 x 1) = 16.4 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (subacute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 75.

 

Selected DNELs

DNEL systemic dermal = 23.3 mg/kg bw

DNEL systemic inhalation = 16.4 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.47 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370 mg/m³
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 1000 mg/kg bw/day from the Combined 28-Day Repeated Dose Oral (Gavage) Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Rats is available (Herberth, 2016) . This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/1.35 m³/kg/d for a 24-hour exposure and the absorption rates (oral 50 %, inhalation 100 %).

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
6
Justification:
since it is a subacute study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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:
8.33 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 1000 mg/kg bw /day from the Combined 28-Day Repeated Dose Oral (Gavage) Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Rat (Herberth, 2016) is available. This value was converted into the corrected dermal NOAEL taking into account the rates for absorption (oral 50 %, dermal 10 %).

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
6
Justification:
since it is a subacute study
AF for interspecies differences (allometric scaling):
4
Justification:
default factor for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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:
1.67 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Not applicable: oral study and oral exposure

AF for dose response relationship:
1
Justification:
(three doses were tested, using a spacing range of 2-5 fold)
AF for differences in duration of exposure:
6
Justification:
since it is a subacute study
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Bioavailability (absorption):

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

Respiratory volumes:

Adaptions in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A default respiratory volume of 1.35 m³/kg bw for rats (general poulation) was used to convert dermal NOAEL into inhalation NOAEC, referring to 24h exposure instead of 8h (worker).

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.

Calculation of endpoint-specific DNELs for general population

Long-term exposure - systemic effects (oral):

The oral NOAEL of 1000 mg/kg bw had not to be converted.

The oral NOAEL of 1000 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAEL rat = oral NOAEL human = 1000 mg/kg bw.

DNEL = 1000 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 1.67 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default).The total AF amounts to 600.

Long-term exposure - systemic effects (dermal):

For the oral rat NOAEL of 1000 mg/kg bw the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 5000 mg/kg bw

DNEL = 5000 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 8.33 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (subacute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 600.

 

Long-term exposure - systemic effects (inhalation):

The oral NOAEL of 1000 mg/kg bw was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.35 m³/kg bw/day) x (ABS oral-rat/ABS inhal-human),where 1.35 is the standard respiratory volume (m³/kg bw) of rats during 24 h exposure (according to Functionalities of IUCLID 6 DNEL calculator) , ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 1000 mg/kg bw x (1/1.35 m³/kg/day) x (50%/100%) = 370.4 mg/m³

DNEL =370.4 mg/m³/(2.5 x 10 x 6 x 1 x 1) = 2.47 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 150.

 

Selected DNELs

DNEL systemic oral = 1.67 mg/kg bw

DNEL systemic dermal = 8.33 mg/kg bw

DNEL systemic inhalation = 2.47 mg/m³