2,2'-oxydiethanol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

60 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor:

NOAEC

Value:

120 mg/m³

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

1

Justification:

As the POD is defined by sensory irritation observed in a human volunteer study, no additional AF is warranted according to ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110.

AF for interspecies differences (allometric scaling):

1

Justification:

No AF needed (human volunteer study).

AF for other interspecies differences:

1

Justification:

No AF needed (human volunteer study).

AF for intraspecies differences:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for intraspecies differences should be used. Since the data for DNEL derivation were obtained from a human volunteer study in which the subjects were considered to be comparable with the worker population under light activity. For this reason, a AF of 2 instead of 5 as proposed by ECHA is taken into account.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for remaining uncertainties should be used where necessary. As the approach used for DNEL derivation is conservative, no further assessment factors are required.

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:

43 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

105

Dose descriptor starting point:

NOAEL

Value:

4 440 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

4 440 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal study with MEG on dogs (BASF, 1991) was selected for DNEL derivation as it is the most relevant repeated dose study performed in accordance to OECD guideline and GLP.

In this study, the dermal NOAEL for MEG was established to be 4440 mg/kg bw/day. This value is taken in a 1:1 relation also for DEG since DEG can generate 2 molecules of MEG in a worst case assumption.

(see toxicokintetics, IUCLID section 7.1.1).

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1.4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the dog when compared with humans, namely 1.4. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of smaller animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the dog versus humans is 1.4.

AF for other interspecies differences:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability.

AF for intraspecies differences:

5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for intraspecies differences should be used. The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for remaining uncertainties should be used where necessary. Different species show a wide range of sensitivity towards DEG via the dermal route. There are human case reports on intoxication via the dermal route. Therefore, to account for these remaining uncertainties, an additional assessment factor of 2.5 has been applied.

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

Long term, local DNEL (inhalation)

The long term DEG inhalation DNEL, local effects, workers was determined to be 60 mg/m3 .

 

The internal dose obtained from such an exposure under conditions of the DNEL would be equivalent to 8.5 mg/kg bw which is at least 12-fold below the oral NOAEL from the rat (see also below).

Hence, the local DNEL should inclusively also protect from systemic effects. Nevertheless, the german AGW (national occupational exposure level) has been used as the DNEL for long-term systemic inhalation exposure.

The threshold of irritation upon inhalation exposure has, so far, not exactly been determined for DEG. No valid inhalation study is available with DEG. However, the irritation potential of DEG is considered to be lower than of MEG, hence, this read-across can be made (Greim, H., MAK-documentation).

 

The following deliberation provides a further perspective on the existing oral studies with DEG: the lowest NOAEL has been reported in a subchronic rat feeding study (128 mg/kg bw/day; 225 days; Gaunt et al., 1976). For this dose level the authors report a 13.2 % increase in urinary oxalate levels without associated histopathological findings in kidney and they did not consider this as adverse. At 230 mg/kg bw/day, the authors found an increased urinary volume which was considered to reflect a mild kidney damage (LOAEL; this latter conclusion may be debatable since DEG may show diuretic effects also on osmotic grounds). The Dutch Expert Committee stated (DEG-Health-based recommended occupational exposure limit, 2007; please also refer to IUCLID chapter 13) that for ‘oxalate’ crystaluria and increased urine volumes after concentration tests, the results were inconsistent between the male and the female rats, and no clear dose-response relationships can be observed for these effects. For example, the number of male rats with urinary ‘oxalate’ crystals was not increased at the highest dose level of 1,190 mg/kg bw/day in the 225-day study. In addition, the observed increase of urinary volumes may partly have resulted from the osmotic-diuretic effect of diethylene glycol and the ‘oxalate’ crystaluria can not be explained in view of later findings that oxalate is no or at best a minor metabolite of diethylene glycol in rats. The relevance of the ‘oxalate’ crystals found by Gaunt et al. (1976) is therefore unclear. For these considerations, the committee concluded that the NOAEL based on the histopathological findings is more relevant than the NOAEL based on the urinary ‘oxalate’ crystals and the increased urine volumes after concentration tests. In terms of the Klimisch-Code for reliability, the Gaunt study has been assigned with a 2. There is also a validity code 1 study available (28 days feeding in rats; BASF, 1988) with a NOAEL of 936 mg/kg bw/day. Combined with a time-extrapolation factor of 6 this would result in a chronic NOAEL of 156 mg/kg bw/day which is not much different from the NOAEL in the Gaunt study.

 

For an oral DNEL calculation the NOAEL of the Gaunt study may be taken as a point of departure. For the cross-species extrapolation an allometric factor of 4 is employed. The time extrapolation factor may be limited to 1.5 due to the length of the study. The intra-species factor may be confined to 3 for the workplace.

In total, an overall assessment factor of 18 would result and a systemic DNEL of 5.83 mg/kg bw/day (408 mg/person/day). This dose would be roughly equivalent to an air-borne concentration in the work place of 40 mg/m3 which would meet the proposed inhalation DNEL.

 

 

Long term, systemic DNEL (inhalation)

For the DNEL long term, systemic (inhalation) the curent german AGW (national occupational exposure level) of 44 mg/m3 has been applied.

This OEL is in the range of the local long-term inhalation exposure DNEL of 60 mg/m3 (see above) which is thought to also be protective from systemic effects as local irritation is expected to occur already at low doses before systemic effects would become prominent.

 

Long term, systemic DNEL (dermal exposure)

The key study has been done with MEG and is cross-read to DEG:

Two subsequent dermal studies have been carried out in dogs (BASF Study No.: 80SO385/8243 and 60D0366/8534, 1991) in order to evaluate the local and systemic toxicity of undiluted MEG including an ingredient, para-tert.-butylbenzoic acid (PTBBA; 1.42 % as sodium salt) which is known for a potential of testicular toxicity. The undiluted formulation was spread on 30 % of the body surface. In a first study, dose levels of 0.5, 2 and 8 mL/kg bw and day were administered. In the top dose, severe nephrotoxicity (including lethalities) was observed and also some mild testicular toxicity. The latter was considered to be more a sequel of PTBBA than of MEG-mediated renal toxicity. At 2 mL/kg bw/day (2220 mg/kg bw/day) there was an increase of urinary oxalate crystals which was considered as non-adverse due to the absence of histological findings. In the second study (BASF 60D0366/8534), 2 and 4 mL/kg bw/day were administered; with this dose design a NOAEL of 4 mL/kg bw/day (4440 mg/kg bw/day) was identified. Again, an increase of urinary oxalate crystal formation could be detected but no adverse histopathological findings.

 

This NOAEL is also supported by the results of a dermal developmental study in mice in which undilued MEG at a dose level of 3500 mg/kg bw/day was considered as a NOAEL for renal toxicity (Tyl et al., 1995).

The large difference between the NOAELs from the oral studies in rats with MEG (150 mg/kg bw/day) and the dermal studies in dogs may largely be attributed to a much lower dermal resorption rate (Sun et al., 1995).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

NOAEC

Value:

120 mg/m³

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

1

Justification:

As the POD is defined by sensory irritation observed in a human volunteer study, no additional AF is warranted according to ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110.

AF for interspecies differences (allometric scaling):

1

Justification:

No AF needed (human volunteer study).

AF for other interspecies differences:

1

Justification:

No AF needed (human volunteer study).

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for intraspecies differences should be used. The default value for general population is selected.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for remaining uncertainties should be used where necessary. As the approach used for DNEL derivation is conservative, no further assessment factors are required.

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:

21 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

210

Dose descriptor starting point:

NOAEL

Value:

4 440 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

4 440 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal study with MEG on dogs (BASF, 1991) was selected for DNEL derivation as it is the most relevant repeated dose study performed in accordance to OECD guideline and GLP.

In this study, the dermal NOAEL for MEG was established to be 4440 mg/kg bw/day. This value is taken in a 1:1 relation also for DEG since DEG can generate 2 molecules of MEG in a worst case assumption.

(see toxicokintetics, IUCLID section 7.1.1).

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1.4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the dog when compared with humans, namely 1.4. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of smaller animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the dog versus humans is 1.4.

AF for other interspecies differences:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability.

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for intraspecies differences should be used. The default value for general population is selected.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for remaining uncertainties should be used where necessary. Different species show a wide range of sensitivity towards DEG via the dermal route. There are human case reports on intoxication via the dermal route. Therefore, to account for these remaining uncertainties, an additional assessment factor of 2.5 has been applied.

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