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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
47.02 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):
37.5
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 763.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
A systemic NOAEL of 1000 mg/kg bw /day from the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422) (Dunster, 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 100 %, inhalation 100 % (worst-case)).
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:
3
Justification:
the default assessment factor was adjusted taking into account study duration of 56 days (see Discussion)
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 for workers
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are 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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.33 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):
150
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A systemic NOAEL of 1000 mg/kg bw /day from the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422) (Dunster, 2013) was converted into the corrected dermal NOAEL taking into account the rates for absorpion (oral 100 %, dermal 50 %).Thereby the corrected dermal NOAEL is: oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 2000 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:
3
Justification:
the default assessment factor was adjusted taking into account study duration of 56 days (see Discussion)
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats 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 (GLP guideline study)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are 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

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 on Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

Available dose descriptors:

The target substance 1-(3-sulphonatopropyl)pyridinium is not acutely toxic by oral and dermal routes of exposure (oral LD50 is > 5000 mg/kg bw, Ullmann and Sacher, 1983; dermal LD50 > 2000 mg/kg bw, Driscoll, 2001). Inhalation is not a relevant route of exposure due to the low vapour pressure of the substance (4.24E-5 Pa at 25 °C, EPIWIN). The target substance is non-volatile and therefore no risk of irritation or sensitisation of respiratory tract exists. The substance is not irritating to skin and eyes and not sensitising to skin (Clauss and Ullmann, 1982; Ullmann and Suter, 1982; Driscoll, 2001). 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 1000 mg/kg bw established in the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422, Dunster, 2013) was used as the starting point. This is the lowest 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 a No-Observed-Effect-Level could not be established from the relevant studies.

Modification of the starting point:

Considering all available data on the target substance it becomes clear that these substances exert their 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 only for workers. No DNELs are needed for general population since there are no consumer uses for the target substance.

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:

Based on the molecular weight of 201.24 g/mol, negative logPow (< -2.78) value and high water solubility (240.5 g/L, EPIWIN) the target substance is expected to be well absorbed via gastrointestinal tract. The substance will be readily dissolved into the gastrointestinal fluids and may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. However, the available toxicity data point to a low toxicity potential by oral route. No mortality was observed in animals administered test substance at 5000 mg/kg bw. At necropsy, mottled lungs were detected in three animals, the fact indicating systemic absorption. No toxicologically significant effects were observed in animals treated up to 1000 mg/kg bw during 8 weeks in the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422, Dunster, 2013). Based on this data, absorption by oral route is considered to be significant (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IULID file).The oral absorption is therefore set to 100 % (worst-case) for the purposes of hazard assessment (DNEL derivation). 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 target substance. The negative logPow value (< -2.78) is out of the range of the optimal logPow values favourable for dermal absorption (-1 to 4). Furthermore, the substance has very high water solubility (204.5 g/L, EPIWIN). Therefore, the substance may be to hydrophilic to cross lipid rich environment of the stratum corneum. The molecular weight of 201.24 g/mol (< 500 g/mol) points to a moderate absorption through the skin.The substance is not irritating to skin and therefore no enhancement of dermal absorption is expected due to irritating properties. The systemic toxicity via the skin is low. This has been shown by the results of the acute dermal toxicity study, in which no mortality occurred after dermal application of 2000 mg/kg bw in rats. Based on these data, 50 % dermal absorption is considered appropriate. Dermal absorption in rats, rabbits and in humans is assumed to be the same since no information for dermal absorption of the target substance in humans is available.

Inhalation absorption

Absorption by inhalation is considered to be negligible due to the low vapour pressure (4.24E-5 Pa at 25 °C, EPIWIN) of the target substance. However, a certain amount of the substance can be available for inhalation due to its appearance form as powder and its high water solubility (204.5 g/L, EPIWIN). The average particle size is 32.101 µm (< 100 µm), indicating the potential to be inspired. According to the Endpoint specific guidance R.7.C., particles with aerodynamic diameters below 50 µm may reach thoracic region of lungs. Moreover, water soluble dusts could readily diffuse/dissolve into the mucus lining the respiratory tract and thereafter be absorbed through aqueous pores due to its high solubility in water. Based on this data, 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/sRVrat) x (ABSoral-rat/ABSinh-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, ECHA REACH Guidance R.8):

Corrected dermal NOAEL = oral NOAEL x (ABSoral-rat/ABSderm-rat) x (ABSderm-rat/ABSderm-human) = oral NOAEL x (ABSoral-rat/ABSderm-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 Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422) 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 3 was applied for duration of exposure. The exposure duration in the present screening study was up to 8 weeks.According to the ECETOC technical report No.86 “Derivation of Assessment Factors for Human Health Risk Assessment”, “…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 month 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-month’ exposure. This default factor should be the same for extrapolation from one month to chronic exposure. Consequently, a default factor of 2 would be assumed to be appropriate when extrapolating from studies of three to six months.” Further, “…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 NOAEL in 28-day studies close to those for chronic studies”. The target substance is relatively harmless; it is of low acute toxicity, not irritating, not sensitising and did not produce toxicologically relevant systemic effects in the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422). The exposure duration of 8 weeks corresponds to approximately 2 months. Considering the principle of “linearity of bioaccumulation and damaging effects” outlined in the guidance, an appropriate assessment factor for exposure duration of 56 days would be 3 (6 months/2 months (= 56 days)). 

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 Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422) (the dose spacing was chosen properly).

Calculation of DNELs:

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

The oral rat NOAEL of 1000 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinhal-human) x (6.7 m³/10 m³) = 1000 mg/kg bw x (1/0.38 m³/kg/day) x (100 %/100 %) x (6.7/10) = 1763.2 mg/m³

DNEL = 1763.2 mg/m³/(2.5 x 5 x 3 x 1 x 1) = 47.02 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 3 – study duration (screening study of 56 days), 1 – dose response, 1 – quality of data base. The total AF amounts to 37.5.

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

For the oral rat NOAEL of 500 mg/kg bw the following conversion was necessary:

Dermal NOAEL =oral NOAEL x (ABSoral-rat/ABSderm-human) = 1000 x (100 %/50 %) = 2000 mg/kg bw

DNEL = 2000 mg/kg bw/(4 x 2.5 x 5 x 3 x 1 x 1) = 13.33 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 3 – study duration (screening study of 56 days), 1 – dose response, 1 – quality of data base. The total AF amounts to 150.

Selected DNELs

DNEL systemic inhalation = 47.02 mg/m³

DNEL systemic dermal (long-term) = 13.33 mg/kg bw

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.59 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):
75
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
869.57 mg/m³
Explanation for the modification of the dose descriptor starting point:

Due to the low vapour pressure of the test substance an exposure hazard via inhalation is not very likely for humans and hence, repeated dose toxicity testing via the inhalation route was not done. The oral route was chosen as it is better suited to assess overall systemic effects. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case, is justified.

A systemic NOAEL of 1000 mg/kg bw /day from the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422) (Dunster, 2013) was converted into the corrected inhalatory NOAEC by using the default respiratory volume for rats (8 h), assuming 100% absorption by oral route and 100% absorption by inhalation route, as set out in detail in subchapter „Toxicokinetics“.

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:
3
Justification:
the default assessment factor was adjusted taking into account study duration of 56 days (see Discussion)
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 for general population
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are 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:
DNEL (Derived No Effect Level)
Value:
6.67 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):
300
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A systemic NOAEL of 1000 mg/kg bw /day from the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422)  (Dunster, 2013) was converted into the corrected dermal NOAEL taking into account the rates for absorpion (oral 100 %, dermal 50 %).Thereby the corrected dermal NOAEL is: oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 2000 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:
3
Justification:
the default assessment factor was adjusted taking into account study duration of 56 days (see Discussion)
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats 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:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are 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:
DNEL (Derived No Effect Level)
Value:
3.33 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):
300
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
other: no modification required
Explanation for the modification of the dose descriptor starting point:

NOAEL was derived from oral study, no modification required.

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:
3
Justification:
the default assessment factor was adjusted taking into account study duration of 56 days (see Discussion)
AF for interspecies differences (allometric scaling):
4
Justification:
default factor for allometric scaling (rat to human) as given in ECHA guidance R.8
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 for general population
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are 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

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 target chemical 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 (instead 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 (oral)

The oral NOAEL of 50 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAEL rat = oral NOAEL human = 1000 mg/kg bw.

DNEL = 1000 mg/kg bw/(1 x 3 x 4 x 2.5 x 10 x 1 x 1) = 3.33 mg/kg bw.

Assessment factors are:1 – dose response (clear dose response), 3 – study duration (screening study of 56 days), 4 – interspecies, allometric scaling, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

 

Long-term exposure - systemic effects (dermal)

The oral NOAEL of 1000 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 1000 mg/kg bw x (100%/50%) = 2000 mg/kg bw.

DNEL = 2000 mg/kg bw/(1 x 3 x 4 x 2.5 x 10 x 1 x 1) = 6.67 mg/kg bw.

Assessment factors are: 1 – dose response (clear dose response), 3 – study (screening study of 56 days), 4 – interspecies, allometric scaling, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

 

Long-term exposure - systemic effects (inhalation)

The oral NOAEL of 1000 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 m³/kg bw is standard respiratory volume of rats during 24 h, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 1000 mg/kg bw x (1/1.15 m³/kg/day) x (100%/100%) = 869.57 mg/m³

DNEL = 869.57 mg/m³/(1 x 3 x 1 x 2.5 x 10 x 1 x 1) = 11.59 mg/m³.

Assessment factors are:1 – dose response (clear dose response), 3 – study duration (screening study of 56 days), 1 – interspecies, no allometric scaling required for oral to inhalation exposure, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).