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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:
70.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
881.6 mg/m³
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 0.2% in diet is available from the 26-week feeding study in rats on the nearest structural analogue (Hine et al., 1958). In contrast, no concentration of saturated vapour atmosphere is reported in a seven-hour (50-application) inhalation study in rats (Hine et al., 1958).
AF for dose response relationship:
1
Justification:
default (three doses were tested)
AF for differences in duration of exposure:
1
Justification:
26 week study is rather a chronic 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
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:
10 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
DNEL value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A NOAEL of 0.2% in diet is available from the 26-week feeding study in rats on the nearest structural analogue (Hine et al., 1958). In contrast, no NOAEL is reported in a dermal repeated dose toxicity study (20-application) in rabbits (Hine et al., 1958). 0.2 g of test substance/animal which induced irritation is uncertain to serve as a NOAEL.
AF for dose response relationship:
1
Justification:
default (three doses were tested)
AF for differences in duration of exposure:
1
Justification:
26-week study is considered to be a chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default in case of oral-to-dermal 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 DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
125
Dose descriptor:
other: NOAEL
AF for dose response relationship:
10
Justification:
poor quality of study; no NOAEL is reported; an application of 0.2 g/animal caused severe irritating of skin. AF of 10 is to extrapolate the effect level of 0.2g to a surrogate NOAEL.
AF for differences in duration of exposure:
1
Justification:
default for local effects (duration of exposure does not influence the severity of adverse effects)
AF for interspecies differences (allometric scaling):
1
Justification:
default (local effects are considered to be of similar magnitude in animals and in humans)
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 DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

For GE-100, the following dose descriptors are available:

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

There is an acute dermal study in rats conducted with the target substance in which LD50 >2000 mg/kg bw is established (Manciaux, 1998). Therefore, DNEL for acute systemic effects by the dermal route is unnecessary since the long-term DNEL covers sufficiently the risk of short-term exposure.

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

No acute inhalation study is available. GE-100 is not expected to bear a significant hazard by inhalation due to its very low vapour pressure (0.000021/0.0392 at 25°C). Moreover, the read-across substance Polyglycidyl ether of substituted glycerine caused no deaths when rats were exposed for eight hours to saturated vapours (Hine et al., 1958). Thus, GE-100 is not classified for acute inhalation hazard and no DNEL is required.

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

The target substance was tested in the acute dermal toxicity study in which no cutaneous reactions were observed after 24 -h exposure (Manciaux, 1998). However, the read- across substance Polyglycidyl ether of substituted glycerine was irritating to the skin of rabbits after 24-hour application of test material (Hine et al., 1958). A LD50 of 14.4 mL/kg bw was reported (Pattys, 1981). However, no effect level is known without any local irritation. Thus, the short-term dermal DNEL cannot 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 substance does not bear a significant airborne hazard. The long-term inhalation DNEL for systemic effects covers sufficiently local effects.

Long-term exposure – systemic effects (dermal DNEL)

Long-term systemic DNEL for dermal route has been derived from the NOAEL of 0.2% in diet established in a 26-week feeding study in rats conducted with the read-across substance Polyglycidyl ether of substituted glycerine (Hine et al., 1958). The substance caused no treatment related mortality but significant retardation of body weight gain in the group fed with 1% was observed. In this group, the liver/body weight ratios were significantly greater than controls. No significant lesions grossly or microscopically were seen in the tissues examined after any of treatment. There was a significant increase in kidney/body weight ratio in groups fed 0.04% and 1% test material.The finding in group fed 0.04% could be of spontaneous origin since no effects were observed in the group fed 0.2%. Therefore, 0.2% substance in diet is considered to be a NOAEL. To convert the concentration in % into a dose in mg/kg bw, default values for body weights of rats and their food intake per day were used (Table R. 8-17, ECHA guidance R.8). In the feeding study, rats body weight ranged from 85 -161 g. Taking body weight of 0.35 kg for females (as worst case) and the corresponding food intake of 17.5g/day, if extrapolating linearly, the food intake of rats which body weight is 85 g (the low limit of the range body weights determined in the study) would be 4.25 g. From this amount, 0.2% corresponds to 0.085 g which is consumed by a rat with body weight of 85 g. Thus, it corresponds to 100 mg/kg bw. The starting point for the DNEL derivation can be obtained by conversion of oral NOAEL into dermal NOAEL (route-to-route extrapolation).

 

Long-term exposure – systemic effects (inhalation DNEL)

There is a repeated seven-hour vapour exposure- inhalation study in rats conducted with the read-across substance Polyglycidyl ether of substituted glycerine available (Hine et al., 1958). The series of 50 exposures to the saturated vapour of GE-100 was free of untoward effects. Unfortunately, no concentration of the test substance in the test atmosphere is reported. Since no melting point is available for GE-100, the saturated vapour concentration could not be calculated. The inhalation DNEL can be derived from the oral NOAEL of 100 mg/kg bw established in the 26 -day feeding study in rats (Hine et al., 1958) by route-to-route extrapolation.

Long-term exposure – local effects (dermal DNEL)

Long-term dermal DNEL for local effects has been derived since the read-across substance Polyglycidyl ether of substituted glycerine is reported to be highly irritating on repeated applications (Hine et al., 1958, Pattys, 1981). The DNEL can be derived from the effect dose of 0.2 g used in a dermal repeated toxicity study in rabbits (Hine et al., 1958) The neat substance was applied to the rabbits skin during 20 days (7h per day). Mortalities or health condition of animals have been not sufficiently reported (Hine et al., 1958, Pattys, 1981).

Long-term exposure – local effects (inhalation DNEL)

No long-term inhalation DNEL for local effects is needed since the substance is not 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. The controlling of risk of any hazard relevant for these endpoints should be covered qualitatively introducing appropriate RMMs and OCs. Furthermore, local effects are covered sufficiently by the DNELs for systemic effects.

 

Modification of the starting point:

From all available data on GE-100 and its structural analogues for the different human health endpoints it is clear that the substances exert their 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 substance, reflecting the routes, the duration and the frequency of exposure.

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 260.28, logPow of -1.94, and high water solubility (1000 mg/L) absorption by oral route is considered to be moderate for the target 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 substance (negative log Pow of -1.94 and water solubility of 1000 g/L point to a poor absorption through the skin). According to the TGD, Part I, Appendix VI, 100% of dermal absorption should be considered in this case, since the criterion for molecular weight is not met (MW<500). On the other hand, 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 the outer skin layer stratum corneum and a comparatively smaller surface area. Maximal dermal absorption occurs if the Log Pow is between 1 and 2, and the molecular weight above100. This test material has a log Pow of -1.94 and a molecular weight of 260.3 g/mol; logPow is the parameter, pointing to a retarded absorption rate. Schuhmacher et al. (2003) 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). Skin permeability (dermal penetration coefficient (Kp)) can be calculated using the standard approach described by Potts and Guy (Potts and Guy, 1992):

Log Kp (cm/sec) = 0.71 x logPow - 0.0061 MW – 6.3 = 0.71 x (-1.94) – (0.0061 x 260.28)-6.3 = -9.27

Kp = 5.43 x 10-10cm/sec = 1.96 x 10-6cm/h

 

Since the Kp value of 1.96 x 10-6cm/h < 0.0001 cm/h, 10% absorption is considered appropriate in this case.

Dermal absorption in rats, rabbits and in humans is assumed to be the same since no information for dermal absorption of the target chemical in humans is available.

 

References:

1. Potts, R.O., Guy, R.H., “Predicting skin permeability” Pharm Res. 1992; 9: 663–9.

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

 

Inhalation absorption

Absorption by inhalation is considered to be negligible (low vapour pressure of 0.000021/0.00392 Pa) and not to be higher than absorption by oral route. Therefore, 10% absorption is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available.

 

Route-to-route extrapolation:

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 x (ABS oral-rat/ABS dermal-human)

 

Oral-to-inhalation extrapolation is performed to obtain 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.

 

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).

 

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 26-week study, which was used to derive the dermal long-term DNEL. No allometric scaling factor was applied in the case of using rabbit’s dermal study to cover long-term local effects.

No allometric scaling factor was applied when the oral NOAEL from the 26 -week study 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.

Extrapolation of duration:

An assessment factor of 1 was applied for duration of exposure (26 week study is considered to be chronic). For the repeated dermal study in rabbits, an assessment factor of 1 was applied to the effect level causing severe irritating effects of the skin after 20 applications. A default assumption is taken in this case: “exposure duration does not increase the severity of adverse effects”.

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 NOAEL from 26-week study was used. An assessment factor of 10 for uncertainties to the quality of the dermal repeated dose toxicity study in rabbits was applied to extrapolate the dose level which was not a NOAEL to obtain a surrogate NOAEL. Furthermore, there were not sufficient information about health condition of the animals and the necropsy.

 

Calculation of DNELs:

Long-term exposure – systemic effects (dermal DNEL)

The oral rat NOEL of 100 mg/kg bw was converted into the dermal NOEL:
Dermal NOEL = oral NOEL x (ABS oral-rat/ABS dermal-human) = 100 mg/kg bw x (50%/10%) = 500 mg/kg bw.

DNEL = 500 mg/kg bw/(4 x 2.5 x 5 x 1 x 1 x 1) = 10 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 50.

 

Long-term exposure – local effects (dermal DNEL)

The effect level of 0.2 g/rabbit which corresponds to 0.1g/kg bw (a default weight of rabbits is 2 kg (OECD TG 410) was used for the DNEL derivation. No modification of the starting point necessary (example A.1 in ECHA Guidance R.8)

DNELlocal= 100 mg/kg bw/ (1 x 2.5 x 5 x 1 x 10) = 0.8 mg/kg bw. Assessment factors are: 1 – interspecies (local effects), 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (local effects), 10 – dose response (poor quality of study; extrapolation to a surrogate NOAEL), 1 – quality of data base. The total AF amounts to 125.

 

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

The oral rat NOEL of 100 mg/kg bw was converted into the inhalation NOEC:

Inhalation NOEC = oral NOEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 100 mg/kg bw x (1/0.38 m³/kg/day) x (50%/10%) x (6.7/10) = 881.6 mg/m³

DNEL = 881.6 mg/m³/(2.5 x 5 x 1 x 1 x 1) = 70.5 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 12.5.

 

Selected DNELs

The DNEL of 0.8 mg/kg bw for dermal local effects is based on an effect level which is not a NOAEL and which induced severe irritating effects in animals and, in principle, is not sufficient to cover systemic effects due to the high uncertainty around selection of assessment factor for dose-response. DNELlocalof 0.8 mg/kg bw is considered to be a specific DNEL only for local effects.

DNEL systemic dermal =10 mg/kg bw

DNEL systemic inhalation =70.5 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard 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:
no hazard 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:
no hazard 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:
no hazard identified

Additional information - General Population

There are no consumer uses therefore no DNELs are required.