1,5,2,4-dioxadithiane 2,2,4,4-tetraoxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.056 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

540

Modified dose descriptor starting point:

NOAEC

Value:

30 mg/m³

Explanation for the modification of the dose descriptor starting point:

not applicable, as starting point is inhalation study

AF for dose response relationship:

1

Justification:

starting point is NOAEC

AF for differences in duration of exposure:

18

Justification:

assuming chronic exposure for the worker (acute to chronic extrapolation)

AF for interspecies differences (allometric scaling):

1

Justification:

no correction for caloric demand for inhalation

AF for other interspecies differences:

1

Justification:

according to guidelines

AF for intraspecies differences:

3

Justification:

according to guidelines

AF for the quality of the whole database:

10

Justification:

data on systemic effects in an acute study are limited to clinical signs, body weight and macroscopic examinations

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

18 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Value:

50 mg/m³

Explanation for the modification of the dose descriptor starting point:

not applicable, as starting point is inhalation study

AF for dose response relationship:

1

Justification:

no systemic effects were observed at the lowest dise tested

AF for interspecies differences (allometric scaling):

1

Justification:

no correction for caloric demand

AF for other interspecies differences:

1

Justification:

according to guideline

AF for intraspecies differences:

3

Justification:

according to guideline

AF for the quality of the whole database:

10

Justification:

data on systemic effects in an acute study are limited to clinical signs, body weight and macroscopic examinations

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

30 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

1

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

NOAEC for local effects

AF for differences in duration of exposure:

1

Justification:

no need for time scaling for local effects (according to guideline)

AF for interspecies differences (allometric scaling):

1

Justification:

no correction for caloric demand

AF for other interspecies differences:

1

Justification:

according to guideline

AF for intraspecies differences:

1

Justification:

according to guidelines

AF for the quality of the whole database:

1

Justification:

no local effects observed at the lowest dose tested

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

30 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

1

DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.014 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

360

Modified dose descriptor starting point:

LOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

according to guidelines; there is no evidence that route-to-route extrapolation cannot be applied

AF for dose response relationship:

5

Justification:

extrapolation from LOAEL to NOAEL

AF for differences in duration of exposure:

6

Justification:

assuming chronic exposure of the worker

AF for interspecies differences (allometric scaling):

1

Justification:

according to guideline

AF for other interspecies differences:

4

Justification:

rat to human

AF for intraspecies differences:

3

Justification:

according to guideline

AF for the quality of the whole database:

1

Justification:

reliable data available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

DNEL extrapolated from long term DNEL

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:

high hazard (no threshold derived)

Additional information - workers

Formaldehyde

 

Since exposure to formaldehyde cannot be excluded during use of MMDS, limit values for formaldehyde need to be considered in addition to limit values of MMDS. For the present evaluation, no studies on formaldehyde are available, and no read-across to formaldehyde is possible since there is no legal access to the formaldehyde dossier. However, for formaldehyde existing data from the open literature can be used. Formaldehyde is currently under evaluation by ECHA. Pending the decision by ECHA, the following data are used for formaldehyde from ECETOC Guidance 110 and Scientific Committee on Occupational Exposure Limits SCOEL/SUM/125 (2008):

CAS nr. 50-00-0; Carcinogen Cat 3; R40; T; R23/24/25; C; R34; R43; Conversion factor: 1 ppm~1.23 mg/m3

Reactivity in target tissues with direct contact with the substance, causes local irritation, acute and chronic toxicity and has genotoxic and cytotoxic properties. Studies with volunteers showed a threshold for odour perception <0.5 ppm, eye irritation 0.5-1.0 ppm and nose irritation 1 ppm. Long-term exposure of workers at the workplace induced lesions in the nasal mucosa at average exposure concentration below 1 ppm. The experimental NEL (No Effect Level) of sensory irritation in BALB/c mice is 0.3 ppm. Formaldehyde causes skin sensitization and bronchial asthma. Based on the ‘SCOEL Approach on OEL (Operator Exposure Level) Recommendations for Carcinogens”, SCOEL regards formaldehyde as a “genotoxic carcinogen, for which a practical threshold is supported”. Consequently, a health-based OEL is recommended. For the derivation of an OEL for formaldehyde, which takes the carcinogenic risk into account, the avoidance of cell proliferation is critical. The cause of cell proliferation is the irritant effect of formaldehyde on the upper respiratory tract. It is generally considered that avoidance of sensory irritation of the eye and the upper respiratory tract will provide a safety margin to avoid irritation-induced local cell proliferation. Different evaluations have been published concerning the NOAEL of eye irritation in humans. Daily exposure for 8 hours to maximum formaldehyde concentrations of 0.3 ppm “practically all workers” are protected against eye irritation. Animal data were considered supportive of this conclusion. In consequence, a concentration of 0.3 ppm formaldehyde was regarded as a practical NOAEL and was proposed as an OEL. The TWA-OEL (Time Weighted Average) of formaldehyde should be set at or below the NOAEL for sensory irritancy of the eye. In view of the limited number of persons that can be examined in a laboratory volunteer study (21 persons on the study of Lang et al. 2008), the exclusion of particularly sensitive persons with negative affectivity appears problematic. Therefore, SCOEL proposes an 8h-TWA of 0.2 ppm. This especially considers possible inter-individual differences in susceptibility to irritation by formaldehyde, which may be expected based on the entire body of data. Short-term irritation may be prevented by a 15min-STEL (Short-Term Exposure Limit) of 0.4 ppm. This STEL is set below the threshold for objective eye irritation, as outlined by Lang et al. (2007). At these levels, no systemic effect of formaldehyde is to be expected.

 

 

Starting point SCOEL and REACH TGD: local effects on the eye (0.5 ppm). AF SCOEL=2.5; AF REACH TGD=5 (intraspecies worker AF 5).

Exposure limits: IOELV SCOEL=0.2 ppm; Default DNEL long-term worker inhalation=0.1 ppm

 

For workplace exposure, existing OELs and/or the underlying information used for setting them can be used to derive DNEL values under circumstances described in the REACH TGD, Appendix R8-13. Three situations are addressed, one of them being:

           Where an EU Indicative Occupational Exposure Limit Value (IOELV) has been set, this may be taken as a DNELworker. This requires that the exposure route and duration for the DNEL is the same as that for the IOELV and no new scientific information is available that would lead to a different value being set.

Under this condition, it would not be necessary to use the REACH TGD approach and AF for defining DNELworker.

 

Summary for limit value formaldehyde (inhalation):

Based on the ‘SCOEL Approach on OEL Recommendations for Carcinogens”, SCOEL regards formaldehyde as a “genotoxic carcinogen, for which a practical threshold is supported”. For the derivation of an OEL for formaldehyde, which takes the carcinogenic risk into account, the avoidance of cell proliferation is critical. The cause of cell proliferation is the irritant effect of formaldehyde on the upper respiratory tract. It is generally considered that avoidance of sensory irritation of the eye and the upper respiratory tract will provide a safety margin to avoid irritation-induced local cell proliferation.

SCOEL Exposure Limit (worker) SCOEL /SUM/125; based on local irritation, human volunteer data; eye irritation. IOELV= 0.2 ppm; DNEL worker, long term based on REACH TGD default AF = 0.1 ppm.

As there is an EU IOELV for formaldehyde, in the absence of new scientific information, the SCOEL IOELV of 0.2 ppm (0.25 mg/m3) is considered as limit value for formaldehyde for the present risk assessment.

Considerations for dermal exposure to formaldehyde

Dermal exposure to formaldehyde cannot be excluded. A comparison of the toxicological properties of formaldehyde and MMDS for the dermal route:

Both formaldehyde and MMSDS are skin sensitizers. However the potential might differ between the two substances. Unfortunately there are no suitable skin sensitization data available, based on which a dermal DNEL can be derived, as is done for MMDS. In the CAR of formaldehyde an overall NOAEL of 0.1% is derived for local dermal effects. This overall NOAEL is used by the Dutch board for the authorization of pesticides and biocides as a dermal limit value (without further use of safety factors). For MMDS the EC3 value was established to be between 0 and 0.5%.

However the long-term dermal DNEL for MMDS was based on the oral repeated dose toxicity data, as this would result in a lower DNEL. The long-term dermal DNEL for MMDS was set at 0.014 mg/kg bw/day.

For formaldehyde a dermal limit value for systemic effects is set at 0.41 mg/kg bw/day, based on a NOAEL of 15 mg/kg bw/day and a safety factor 36. In case as a worst-case the EU-safetyfactor of 100 is used (as is normally done for biocides), a dermal limit value of 0.15 mg/kg bw/day is derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.056 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

900

Modified dose descriptor starting point:

NOAEC

Value:

50 mg/m³

Explanation for the modification of the dose descriptor starting point:

not applicable, as starting point is an inhalation toxicity study

AF for dose response relationship:

1

Justification:

starting point is NOAEC

AF for differences in duration of exposure:

18

Justification:

assuming chronic exposure of the general population (acute to chronic extrapolation)

AF for interspecies differences (allometric scaling):

1

Justification:

no correction for caloric demand for inhalation

AF for other interspecies differences:

1

Justification:

according to guideline

AF for intraspecies differences:

5

Justification:

according to guideline

AF for the quality of the whole database:

10

Justification:

acute study, data on systemic effects are limited to clinical signs, body weight and macroscopic examinations

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

50 mg/m³

Explanation for the modification of the dose descriptor starting point:

not applicable, as starting point is an inhalation toxicity study

AF for dose response relationship:

1

Justification:

no systemic effects were observed at the lowest dose tested

AF for interspecies differences (allometric scaling):

1

Justification:

no correction for caloric demand for inhalation

AF for other interspecies differences:

1

Justification:

according to guideline

AF for intraspecies differences:

5

Justification:

according to guideline

AF for the quality of the whole database:

10

Justification:

acute study, data on systemic effects are limited to clinical signs, body weight and macroscopic examinations

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

3

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

no local effects were observed at the lowest dose tested

AF for differences in duration of exposure:

1

Justification:

according to guideline

AF for interspecies differences (allometric scaling):

1

Justification:

no correction for caloric demand for inhalation

AF for other interspecies differences:

1

Justification:

according to guideline

AF for intraspecies differences:

3

Justification:

according to guideline

AF for the quality of the whole database:

1

Justification:

reliable data available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

3

DNEL extrapolated from long term DNEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.008 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

LOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

according to guidelines; there is no evidence that route-to-route extrapolation cannot be applied

AF for dose response relationship:

5

Justification:

extrapolation LOAEL to NOAEL

AF for differences in duration of exposure:

6

Justification:

assuming chronic exposure of the general population

AF for interspecies differences (allometric scaling):

1

Justification:

according to guideline

AF for other interspecies differences:

4

Justification:

rat to human

AF for intraspecies differences:

5

Justification:

according to guideline

AF for the quality of the whole database:

1

Justification:

reliable data available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

DNEL extrapolated from long term DNEL

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:

0.017 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No 110, October 2010)

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

LOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable, as route of original study is oral

AF for dose response relationship:

5

Justification:

extrapolation from LOAEL to NOAEL

AF for differences in duration of exposure:

6

Justification:

assuming chronic exposure of the general population

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human extrapolation; according to guideline

AF for other interspecies differences:

1

Justification:

according to guideline

AF for intraspecies differences:

5

Justification:

according to guideline

AF for the quality of the whole database:

1

Justification:

reliable data available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

300 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)