1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.408 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):

50

Modified dose descriptor starting point:

NOAEC

Value:

220.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

A systemic NOAEL of 250 mg/kg bw /day from the OECD 421 Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Harlan Laboratories Ltd, 2013) was converted into the corrected inhalatory NOAEC taking into account the standard daily respiratory volume of 0.38 m³ for rats, the standard respiratory volume in workers during 8 hours: 6.7 m³ under normal conditions and 10 m³ by light activity as well as 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:

4

Justification:

Based on ECETOC Technical Report 86 (2003, page 11), a refined Assessment Factor of 4 is derived (instead of 6, relevant for sub-acute)

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling 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 (workers)

AF for the quality of the whole database:

1

Justification:

database is of high quality (GLP guideline study, Klimisch 1)

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:

6.25 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

1 250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A systemic NOAEL of 250 mg/kg bw /day from the OECD 421 Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Harlan Laboratories Ltd, 2013) was converted into the corrected dermal NOAEL taking into account the rates for absorpion (oral 50 %, dermal 10 %).Thereby the corrected dermal NOAEL is: oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ABS dermal-human) = 1250 mg/kg bw.

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:

4

Justification:

Based on ECETOC Technical Report 86 (2003, page 11), a refined Assessment Factor of 4 is derived (instead of 6, relevant for sub-acute)

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat to human)

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 (workers)

AF for the quality of the whole database:

1

Justification:

database is of high quality (GLP guideline study, Klimisch 1)

AF for remaining uncertainties:

1

Justification:

no uncertainties remaining

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

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:

1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol is not acutely toxic by oral and dermal routes of exposure if administered to rats (LD50(oral) > 10000 mg/kg bw, Reckers, 1981; LD50(dermal) > 2000 mg/kg bw, Reckers, 1981, 1982). Inhalation is not relevant route of exposure due to the low vapour pressure of the substance (0.0021 Pa at 25 °C, Atwal, 2012). The substance is non-volatile and therefore no risk of irritation or sensitisation of respiratory tract exists. The substance is not irritating or sensitising to skin (Reckers, 1982 & 1981c). Therefore, no DNELs for acute/short-term exposures (systemic and local effects) and for long-term exposures (local effects for both inhalation and dermal routes) need to be derived.

For the long-term exposure – systemic effects (inhalation and dermal DNEL), the NOAEL of 250 mg/kg bw established in the OECD 421Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Harlan Laboratories Ltd, 2013) was usedas the starting point. This is the longest test duration revealing a NOAEL known for the target substance after repeated exposures to rats. The DNELs for inhalation and dermal routes can be derived by route-to-route extrapolation applying appropriate assessment factors.

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.

Modification of the starting point:

From all available data on the 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol it is clear that the substance exert its effects by a threshold mode of action. Thus, DNELs can be calculated for the threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance and 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 (please see below).

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 rather high average molecular weight of466.84g/mol (estimated via representative structures), a logPow of 9.2 (Fox, 2012) together with the non-irritating properties of the substance and the effects found at the mid and the highest dose level in the Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Harlan Laboratories Ltd, 2012), absorption by oral route is considered to be slight to moderatefor 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‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’. The log Pow of 9.2, the water solubility of <0.1 mg/L and the molecular weight of approx. 466.84 g/molpoint to apoor absorption through the skin.According to the TGD, Part I, Appendix IV, 10% of dermal absorption can be considered in this case, since the criterion for Log Pow is met and the molecular weight is very close to the required range (MW above 500 g/mol and log Pow > 4). Additionally, the low water solubility points furthermore to the scientifically justified conclusion. Dermal absorption in rats, rabbits and in humans is assumed to be the same range since no information for dermal absorption of the target substance in humans is available.

Inhalation absorption

Absorption by inhalation is considered to be negligible (low vapour pressure of 0.0021 Pa at 25 °C) and not to be higher than absorption by oral route. However, 100 % absorption is assumed for inhalation route (in case of the route-to-route extrapolation) and considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

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/sRV_rat) x (ABS_oral-rat/ABS_inh-human) x (6.7 m³/10 m³) where sRV is the 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 dermal NOAEL for systemic effects. The following formula was used (as described in the Example B.5 of the Appendix R.8 -2):

Corrected dermal NOAEL = oral NOAEL x (ABS_oral-rat/ABS_derm-rat) x (ABS_derm-rat/ABS_derm-human) = oral NOAEL x (ABS_oral-rat/ABS_derm-human).

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 (0.38 m³).

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the oral one-generation reproductive 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 theOral-Reproduction/Developmental Toxicity Screening Study in Rats, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL 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 4 was applied for duration of exposure. Based on ECETOC Technical Report 86 (2003, page 11), a refined Assessment Factor of 4 was derived based on the 42 day exposure period in the available study (instead of 6, relevant for sub-acute). According to the ECETOC approach, "...a study duration of six months provides essentially the same value for the NOAEL as would be found after chronic exposure. Using the conservative assumption of linear accumulation of effects with time, extrapolation from one to six months would require a factor of 6 and since the NOAEL would not change between six months and two years, this should theoretically be the maximum factor necessary. Thus, an extrapolation of study duration from 1 to 6 months would suggest a default assessment factor of 6, assuming linear bioaccumulation of the substance or assuming linear accumulation of tissue damage during the six-months' exposure. This default factor should be the same for extrapolation from one month to chronic exposure based on the studies cited above. Consequently, a default factor of 2 would be assumed to be appropriate when extrapolating from studies of three to six months (6/3 =2). However, compounds, such as most industrial chemicals, that have relatively short half-lives, are not reactive to tissue components and do not deplete essential elements, might have NOAELs in 28-day studies close to those for chronic studies". Based on this knowledge, 42 -day exposure period, corresponding to 1.5 month, by extrapolation to chronic exposure (6 months/1.5 months) results in the factor of 4.

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 Oral-Reproduction/Developmental Toxicity Screening Study in Rats wasused (there was a clear dose response).

Calculation of DNELs:

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

The oral rat NOAEL of 250 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) = 250 mg/kg bw x (1/0.38 m³/kg/day) x (50%/100%) x (6.7/10) = 220.4 mg/m³

DNEL = 220.4 mg/m³/(2.5 x 5 x 4 x 1 x 1) = 4.408 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 4 – study duration, 1 – dose response, 1 – quality of data base. The total AF amounts to 50.

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

For the oral rat NOAEL of 250 mg/kg bw the following conversion was necessary:

Dermal NOAEL = oral NOAEL x (ABS_oral-rat/ABS_derm-human) = 250 x (50%/10%) = 1250 mg/kg bw

DNEL = 1250 mg/kg bw/(4 x 2.5 x 5 x 4 x 1 x 1) = 6.25 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 4 – study duration, 1 – dose response, 1 – quality of data base. The total AF amounts to 200.

Selected DNELs

DNEL systemic inhalation = 4.408 mg/m³

DNEL systemic dermal (long-term) =6.25 mg/kg bw

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.087 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):

100

Modified dose descriptor starting point:

NOAEC

Value:

108.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

A systemic NOAEL of 250 mg/kg bw /day from the Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Harlan Laboratories Ltd, 2013) was converted into the corrected inhalatory NOAEC taking into account the standard daily respiratory volume of 1.15 m³ for rats 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:

4

Justification:

Based on ECETOC Technical Report 86 (2003, page 11), a refined Assessment Factor of 4 is derived (instead of 6, relevant for sub-acute)

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling 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 (general population)

AF for the quality of the whole database:

1

Justification:

database is of high quality (GLP guideline study, Klimisch 1)

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.125 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

1 250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A systemic NOAEL of 250 mg/kg bw /day from the OECD 421 Oral-Reproduction/Developmental Toxicity Screening Study in Rats (Harlan Laboratories Ltd, 2013) was converted into the corrected dermal NOAEL taking into account the rates for absorpion (oral 50 %, dermal 10 %).Thereby the corrected dermal NOAEL is: oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ABS dermal-human) = 1250 mg/kg bw.

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:

4

Justification:

Based on ECETOC Technical Report 86 (2003, page 11), a refined Assessment Factor of 4 is derived (instead of 6, relevant for sub-acute)

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat to human)

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 (general population)

AF for the quality of the whole database:

1

Justification:

database is of high quality (GLP guideline study, Klimisch 1)

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.625 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

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:

4

Justification:

Based on ECETOC Technical Report 86 (2003, page 11), a refined Assessment Factor of 4 is derived (instead of 6, relevant for sub-acute)

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat to human)

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 (general population)

AF for the quality of the whole database:

1

Justification:

database is of high quality (GLP guideline study, Klimisch 1)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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

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 the target substance in rats and in humans is available.

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A default respiratory volume of 1.15 m³/kg bw for rats was used to convert oral NOAEL into inhalation NOAEC.

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 DNEL for general population

Long-term exposure - systemic effects (inhalation):

The oral NOAEL of 250 mg/kg bw was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day) x (ABS_oral-rat/ABS_inhal-human), where 1.15 is the standard respiratory volume (m³/kg bw) of rats during 24 h exposure, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 250 mg/kg bw x (1/1.15 m³/kg/day) x (50%/100%) = 108.7 mg/m³

DNEL = 108.7 mg/m³/(2.5 x 10 x 4 x 1 x 1) = 1.087 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 4 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 100.

Long-term exposure - systemic effects (dermal):

For the oral rat NOAEL of 250 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) = 250 x (50%/10%) =1250 mg/kg bw

DNEL = 1250 mg/kg bw/(4 x 2.5 x 10 x 4 x 1 x 1) = 3.125 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 4 – study duration, 1 –dose response, 1 – quality of data base. The total AF amounts to 400.

Long-term exposure - systemic effects (oral):

The oral NOAEL of 250 mg/kg bw had not to be converted.

The oral NOAEL of 250 mg/kg bw was not modified for differences in absorption by oral route in rats and in humans since no substance- and route specific information is available: oral absorption_rat= oral absorption_human.

DNEL = 250 mg/kg bw/(4 x 2.5 x 10 x 4 x 1 x 1) = 0.625 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 4 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default).The total AF amounts to 400.

Selected DNELs

DNEL systemic inhalation = 1.087 mg/m³

DNEL systemic dermal (long term) = 3.125 mg/kg bw

DNEL systemic oral (long-term) = 0.625 mg/kg bw