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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.8 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.34 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
215.4 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
15
Dose descriptor starting point:
other: NOAEL

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 (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

For 1-(tert-dodecylthio)propan-2-ol, DNELs are needed for:

1) acute exposure by dermal route (local effects, workers and consumers),

2) long-term exposure by oral route (systemic effects; only for consumers),

3) long-term exposure by dermal route (systemic effects; workers and consumers),

4) long-term exposure by inhalation routes (systemic effects; workers and consumers).

 

Since the substance is not acutely toxic by dermal route of exposure, no DNEL for acute systemic effects needs to be derived. A LD50 greater than 2000 mg/kg bw (OECD 434) is considered to be a NOAEL because no mortalities and no systemic signs of toxicity were observed in treated animals (Morris, 1991). Signs of slight dermal irritation were noted. Any risk should be assessed qualitatively.

 

Acute dermal DNEL for local effects is calculated because the test material is a weak skin sensitizer in a LLNA study in rats (OECD 429) (Sanders, 2012). The DNEL is derived from the corrected NOAEL which was obtained by conversion of EC3 value of 14.2 wt %. Such a DNEL can be used to judge the remaining /residual likelihood of risks. However, the general approach for assessing and controlling of risk of dermal sensitization is qualitative (see Appendix III "Derivation of DNEL for skin sensitization").

 

Acute DNELs for inhalation (systemic and local) are not necessary since there is no acute toxic hazard by inhalation.

 

Long-term systemic DNELs (dermal and inhalation) are derived from the results of one-generation study in rats (OECD 415) (Thorsrud, 2002). Reproductive toxicity was considered to be the most sensitive endpoint. These DNELs ensure sufficient that reproductive toxicity effects in humans will not occur. The dose level of 167 mg/kg bw was determined to be NOAEL for parental toxicity and for developmental effects (see Discussion in section 5.9.3 of CSR or refer to section 7.8. of IUCLID file).

 

No long-term local DNEL (inhalation) is because there is no dose-response and route-specific information on this endpoint. The substance is not irritating/or sensitizing to respiratory system and does not pose a hazard for humans by inhalation route of exposure (low vapour pressure of 0.63 Pa). Long-term systemic DNEL covers sufficiently local effects.

 

No long-term dermal DNEL for local effects is derived because the substance is not irritating to skin and the systemic dermal DNEL is sufficient to cover local effects.

A qualitative approach in hazard assessment for eye and skin irritation/corrosion is used because no dose descriptors are available on these endpoints.

For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No Observed Effect Level could not be established from the relevant studies. Hence, the hazard characterization is based on a qualitative approach.

 

Mode of action:

From all available data for the different human health endpoints it is clear that 1-(tert dodecylthio) propan-2- exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the related substances, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.

Bioavailability (absorption)

Observations noted in treated animals in the oral acute, sub-acute and in the one-generation study point to the fact that the substance became systemic available. The absorption by oral route is considered 100% and assumed to be the same in rats and in humans due to the absence of route specific information on rate of absorption. Dermal absorption of the test susbtance is considered to be 50% (see Discussion in section 7.1.2. "Dermal absorption" of the IUCLIF file and Appendix I in the CSR) and assumed also to be equal in rats and in humans. A negligible absorption by inhalation is assumed for the target chemical but in the absence of information it is set to 100%.

Route-to-route extrapolation:

Oral-to dermal extrapolation is performed to derive long-term DNEL for systemic effects. Since oral absorption was set to 100% and dermal to 50%, a factor of 2 was used to adjust systemic available oral dose to the systemic available dose resulting after dermal exposure (see Annex I "Oral-to-dermal extrapolation" in the CSR). Oral-to-inhalation extrapolation is performed to assess long-term inhalation effects in humans. Due to the low vapour presure (0.63 Pa at 20°C), a low bioavalability by inhalation route is considered for the target chemical. Therefore, absorption rates by inhalation cannot be higher than the absorption rates by oral route and assumed to be the same and equal to 100% (realistic "worst-case") (see Annex II "Oral-to-inhalation extrapolation").

Exposure conditions:

Exposure time differed in workers and in animals in the one-generation study. Rats were exposed to the test substance per oral daily (5 days/week), while workers are exposed 8h daily (5days/week). However, the dose descriptor (the NOAEL of 167 mg/kg bw) was not adjusted to 8h exposure because exposure time is not really relevant for the systemic dose.

Respiratory volumes:

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the sub-chronic dietary 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.

 

Conversion of EC3 value to NOAEL

The substance induced a dermal sensitization response with a calculated EC3 of 14.2 wt% and meets the criteria as a weak dermal sensitizer (ECETOC Technical Report 87, “Contact Sensitisation: Classification According to Potency”; Griem et al., 2003). It is recognized that EC3 values is close enough to the human NOAEL from human sensitization tests designed to confirm lack of induction and therefore it can be used as a surrogate for the NOAEL (ECHA Guidance R. 8, Appendix R.8 -10).

A threshold for skin sensitization can be defined as EC3 concentration (%), which is converted into dose per skin area (in µg/cm²):

EC3[%] x ρ x 250 [µg/cm²/%] = EC3[µg/cm²] = NOAEL

where ρ is density of the liquid, 250 factor is calculated by converting 25 µL (applied to the mouse ear in a standard LLNA protocol) into µg/cm².

 

LLNA descriptor:

EC3 [%] x ρ x 250 [µg/cm²/%] = 14.2 x 0.91 x 250 = 3230.5 [µg/cm²]

 

Conversion of the oral NOAEL into dermal NOAEL (long-term exposure - systemic effects)

Corrected dermal NOAEL = oral rat NOAEL x (ABS oral-rat/ABS dermal-human) = 167 mg/kg bw x (100%/50%) = 334 mg/kg bw. There is no information available on oral absorption in rat and in human therefore it is assumed to be the same and equal 100% (worst case). Low dermal absorption potential (50%) is considered for the target substance. (see Annex I "Oral-to-dermal extrapolation").

 

Conversion of the oral NOAEL into inhalation NOAEC (long-term exposure - systemic effects)

Corrected NOAEC = oral rat NOAEL x (1/0.38m³) x (ABS oral-rat/ABS inh-human) x (6.7/10)m³ = 167 mg/kg bw x (1/0.38m³) x (100%/100%) x (6.7/10)m³ = 294.4 mg/m³. A low bioavalability by the inhalation route is considered for the taget substance.

 

 

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the correct 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 is applied in case of usage of oral NOAEL to derive dermal DNEL;

Interspecies differences factor of 1 is applied in case of derivation of acute dermal DNEL for local effects using EC3 value from sensitization study because skin sensitization is local immunological effect (see Appendix III "Derivation of DNEL for skin sensitization");

No allometric scaling factor is applied in case of oral-to-inhalation extrapolation;

Remaining interspecies differences:

 Additional assessment factors of 2.5 is applied for remaining interspecies differences in toxicodynamics between rat and human. In case of DNEL for dermal sensitization, no factor for remaining differences have been applied since toxicokinetic and toxycodynamic by sensitization response are the same across mammalian species (Api, 2006; Basketter, 2000, listed in Appendix III).

 

Intraspecies differences:

 Assessment factor of 5 is applied for workers for all endpoints and for all exposure routes.

 

Extrapolation of duration:

Assessment factor of 2 was applied for duration of exposure (one –generation study). Males were exposed 119 days to test material; females were exposed 14 days before mating, throughout the gestation (21 days) and lactation (21 days) resulting in 56 days (exposure duration is between sub-acute and sub-chronic). "Compounds, such as most industrial chemicals, that have relatively short-hilf 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" is mentioned in the ECETOC Technical Report No.86 "Derivation of Assessment Factors for Human Health Risk Assessment". Based on the toxicity pattern of test substance, the NOAEL of 167 mg/kg bw obtained in the one-generation study is expected to be close to one of subchronic duration and therefore the assessment factor of 2 is considered appropriate.

Issues related to dose response:

Assessment factor of 3 was used in case of using EC3 value for the derivation of DNEL for dermal sensitization. Two independent studies were conducted on this substance, and the test material is shown to be weak sensitizer (Sanders, 2012).

 

Quality of whole data base:

The assessment factor for uncertainties to the quality of the data base is regarded to be 1.

Calculation of DNELs:

Acute exposure – local effects (dermal)

 

DNELdermal sensitization= 3230.5 µg/cm²÷(1 x 1 x 5 x 3 x 1) = 215.4 µg/cm² where AFs are: 1 -interspecies, 1 - remaining interspecies differences, 5 - intraspecies, 3 – dose response, 1 - quality of data base.

 

Long-term exposure - systemic effects (dermal)

 

DNELdermal systemic= 334 mg/kg bw ÷ (4 x 2.5 x 5 x 2 x 1) = 3.34 mg/kg bw. AFs are: 4 - interspecies, 5 - intraspecies, 2.5 - remaining interspecies differences in toxicodynamics between rat and human, 2 - duration of exposure (one-generation study), 1- quality of data base.

Long-term exposure - systemic effects (inhalation)

 

DNELinhalation systemic= 294.4 mg/m³ ÷ (2.5 x 5 x 2 x 1) = 11.8 mg/m³. AFs are: 2.5 - remaining interspecies differences, 5 - intraspecies, 2 - duration of exposure (one-generation study), 1 - quality of data base.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.67 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
107.7 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
30
Dose descriptor starting point:
other: NOAEL

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.84 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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 by oral route)

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.

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

The conversion of the repeated oral rat NOAEL into inhalation NOAEC was performed as follows:

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