Ethylene dinitrate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.06 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):

62.5

Dose descriptor starting point:

NOAEL

Value:

3.04 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

3.75 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

A NOAEL was used as the starting point for the DNEL and there were no unusual dose-response issues (as described in ECHA, 2008).

AF for differences in duration of exposure:

1

Justification:

A chronic study was used as the starting point for the DNEL resulting in a default factor of 1 (ECHA, 2008).

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

ECHA (2008) recommends a factor of 2.5 to account for “remaining differences”.

AF for intraspecies differences:

5

Justification:

ECHA (2008) recommends a factor of 5 for workers given that this subpopulation does not cover very young, very old and very ill.

AF for the quality of the whole database:

5

Justification:

Given that the only inhalation study available for review was conducted in 1942 and there are no other inhalation studies for either EGDN or NG against which to compare the corrected inhalatory NOAEC, a factor of 5 was selected which is based upon professional judgement.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

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:

0.15 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):

100

Dose descriptor starting point:

LOAEL

Value:

15 mg/kg bw/day

AF for dose response relationship:

10

Justification:

A LOAEL was used as the starting point for the DNEL and there were no unusual dose-response issues (as described in ECHA, 2008) resulting in an assessment factor of 10.

AF for differences in duration of exposure:

1

Justification:

A chronic study was used as the starting point for the DNEL resulting in a default factor of 1 (ECHA, 2008).

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not conducted when the starting point is based on local effects (ECHA, 2008).

AF for other interspecies differences:

1

Justification:

There is no evidence for species differences in the general mode of action or kinetics in case of local effects.

AF for intraspecies differences:

5

Justification:

ECHA (2008) recommends a factor of 5 for workers given that this subpopulation does not cover very young, very old and very ill.

AF for the quality of the whole database:

2

Justification:

Lower doses have been reported to be delivered via transdermal patches; however, this is considered to be associated with therapeutic effects. Thus, the chronic LOAEL value applied was considered to be reasonably conservative given other chronic values available for dermal toxicity. However, the only reliable dermal chronic toxicity study was available for the analogue compound (NG) and not for EGDN. An AF value of 2 was considered appropriate based upon professional judgement.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

General

DNEL derivation for the substance is performed under consideration of the recommendations of ECHA REACH Guidance (2010). In view of the data used for evaluation, the “factor for remaining uncertainties“ is considered to amount to a value of 1.

Short-term, local DNEL

A LOAEL of 15 mg/kg bw/d from a repeated dermal toxicity study with NG was used to derive the systemic long-term DNEL. At this concentration only local effects were observed. No DNEL, local, short-term was derived since local exposure is sufficiently covered by the long-term systemic DNEL

Short-term, systemic DNEL

The guidance on dose/concentration response regarding human health (Appendix 8-8 of chapter R.8 of the Guidance on Information Requirements and Chemical Safety Assessment) recommends a qualitative risk characterisation in case a substance is being acutely very toxic. EGDN has a harmonised classification as oral and inhalative Acute Tox. 2 (H300 and H330) and dermal Acute Tox. 1 (H310) according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk characterisation is conducted.

 

Long-term, sytemic DNEL

Inhalation exposure

With respect to the inhalation pathway, EGDN would be expected to exist in the vapour-phase if exposed to the environment; however, it is understood that the production workers are unlikely to be exposed via inhalation given use of engineering controls to mitigate vapour-phase EGDN from entering the areas where workers may become exposed and use of appropriate RMM. In the case of an accidental release, it is understood that this pathway is not considered to be a significant source of exposure for workers given that personal-protective equipment (e.g. respirators) are applied in the event of an emergency to prevent workers from becoming exposed to volatile chemicals via inhalation.

A chronic inhalation study in cats is available which provides data for both EGDN and NG (Gross et al. 1942; not included in IUCLID section 7.6). Adverse effects including methemoglobinemia were reported in response to both EGDN and NG at all dose levels and exposure durations tested, which were as low as 13 mg/m3 air for 1000 days and 5 mg/m3 air for 156 days for EGDN and NG, respectively. However, the Klimisch rating for this study was Category 3 “not reliable” and as such was not relied upon in the derivation of the DNEL. This study was conducted in 1942 and the reliability of the reported exposure concentrations was therefore considered to be questionable, particularly as the quantitative basis of a DNEL. However, toxic effects were reported in this study and included methemoglobinemia, which is also seen in response to oral or dermal challenge with EGDN and NG. Given that it is likely that the same toxic effect (i.e., methemoglobinemia) results from exposure to EGDN and NG via any of these exposure routes, it was considered defensible to base the inhalation DNEL on oral toxicity data.

The starting point for the estimation of the DNEL for repeated dose inhalation toxicity for systemic effects under worker exposures was the chronic NOAEL of 3.04 mg/kg-day for NG that was derived in a repeated dose oral toxicity study with rats (see IUCLID section 7.6). At doses above this level (31.5 mg/kg/day), methemoglobinemia, several histopathologic effects (e.g. enlarged livers and hepatocellular carcinoma) and moderate depression of weight gain were observed. It is unlikely that this study was conducted according to GLP given that the study was conducted prior to the implementation of GLP practices; however, based on a review of the study, it was considered Klimisch Category 1 (Reliable Without Restrictions).

As described above, this chronic NOAEL of 3.04 mg/kg-day was considered to be a suitable basis for the derivation of the DNEL.

 

Modification into a correct starting point:

Relevant dose descriptor (NOAEL): 3.04 mg/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50/100

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/day

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

 

Corrected NOAEC (inhalation) for workers:

= 3.04 mg/kg bw/day× 0.5 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × 1.4

= 3.75 mg/m³

 

Overall Assessment Factor = 62.5

Interspecies: According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF is needed when route (oral)-to route (inhalation) is applied.

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF (chronic): 1

Whole database AF: 5

 

Given that the only inhalation study available for review was conducted in 1942 and there are no other inhalation studies for either EGDN or NG against which to compare the corrected inhalatory NOAEC, a factor of 5 was selected which is based upon professional judgement.

Taking the above mentioned assessment factors into account, the following worker long- term inhalation DNEL for systemic effects is:

3.75 mg/kg bw/d / (1 x 5 x 2.5 x 1 x 1 x 5) = 3.75 mg/kg bw/day / 62.5

= 0.06 mg/kg bw/day

This DNEL is congruent with the German MAK value that was set to 0.063 mg/m³ in 2018 (The MAK Collection for Occupational Health and Safety 2018, Vol 3, No 4).

 

Dermal exposure

There are no repeated dose dermal toxicity studies available for EGDN. However, one such study is available for NG and as such, the key study for the derivation of the DNEL for worker exposures was based upon dermal toxicity data for NG. The starting point for the estimation of the DNEL for repeated dose dermal toxicity for dermal effects associated with worker exposures was a chronic LOAEL of 15 mg/kg-day for NG for dermal effects that was derived in a 26-week dermal toxicity study with rabbits (Imoto et al. 1986). At this lowest dose tested, dermal effects included erythema, edema, papules, scales, and thickening of the skin. Systemic effects were also observed, but only at the highest dose level of 240 mg/kg-day and not at the other two dose levels of 15 and 60 mg/kg/day. Therefore, the NOAEL for systemic effects was 60 mg/kg and no NOAEL was identified for dermal effects. It was considered protective of both local and systemic effects to use a LOAEL of 15 mg/kg/day as a starting point for the derivation of the dermal DNEL. This study was not summarized by HPVIS, but was partially reviewed (most of the text was in Japanese but tables and abstract were in English) and was rated as Klimisch Category 2 “reliable with restrictions”.

Overall Assessment factor: 100

Dose response relationship AF: 10

Exposure duration AF (chronic): 1

Interspecies AF (allometric scaling): 1

Interspecies AF, remaining differences: 1

Intraspecies AF (worker): 5

Whole database AF: 2

Taking the above mentioned assessment factors into account, the following worker long- term dermal DNEL for local effects is:

15 mg/kg bw/d / (10 x 1 x 1 x 1 x 5 x 2) = 15 mg/kg bw/day / 100

= 0.15 mg/kg bw/day

Note that while most of the AFs are based on the values prescribed by ECHA (2008), the AF for quality of database was based primarily on professional judgement. ECHA (2008) does not prescribe values for quality of database but recommends that quality of database be considered when deriving the DNELs. Selection of the value of 2 for quality of database is intermediate between the following two situations described by WHO/IPCS (1994):

Minor deficiencies in the data exist with respect to quality, quantity or omission; and

Database considered complete for the evaluation of the compound under consideration.

It was considered to provide an appropriate balance between the lack of a repeated dose dermal toxicity study for EGDN, and the good quality of the studies provided for NG. The uncertainty in the quality of database would be reduced if a repeated dose dermal toxicity study were available for EGDN.

Long-term, local DNEL

Inhalation exposure

The substance did not show any local effects in the available chronic inhalation toxicity studies. Thus, no hazard was identified for long-term local effects.

Dermal exposure

A LOAEL of 15 mg/kg bw/d was used to derive the systemic dermal DNEL. At this concentration only local effects were observed. Therefore no DNEL, local, long-term was derived for dermal exposure. The local exposure is sufficiently covered by the long-term systemic DNEL.

 

References

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.

- ECHA (2016). Guidance on Information Requirements and Chemical Safety Assessment Part E: Risk Characterisation. Version 3. ECHA-2016-G-04-EN

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