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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
44 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
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:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
312.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
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:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Worker-DNEL acute systemic effects:

A DNEL for acute toxicity is not established because no acute toxicity hazard (leading to classification and labelling) has been identified.

A default DNEL for acute toxicity could be set for a reference period of 15 minutes at 3 times the value (default 3) of the long-term DNEL. This approach is particularly valid because similar mechanisms of actions are probably involved in the responses to single and repeated exposure (TGD R8).

Local irritation of the respiratory tract

Inhalation studies are not available. A reliable dose descriptor for local irritation of the respiratory tract could not be derived from the available oral and dermal studies. Due to low concentration of substance in preparations used for spray applications local toxicity (respiratory tract irritation) is not expected.

Local effects dermal

A reliable dose descriptor for local irritation could not be derived from the available acute dermal toxicity/irritation studies. A DNEL acute - local effects is not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to GHS Regulation EC No 1272/2008.

Worker-DNEL long-term for dermal route (systemic)

The RA concluded that long-term repeated exposure to TEA-Esterquat might have the potential to cause mild systemic effects on the urinary bladder such as enhanced desquamation and regressive epithelial changes. These are the only critical systemic substance induced effects identified and the relevance of the findings are somewhat hampered by the concurrent bacterial infection of the test animals. The effects have not been detected in the 28-day study up to the highest tested dose of 1000 mg/kg bw/d. A dose descriptor has been identified from a 90-day oral study on rats with a NOEL of 300 mg/kg bw/d.

Correction of starting point (route-to-route extrapolation oral to dermal):

No studies have been undertaken by the dermal route to characterize the dose-response relationship for systemic effects therefore it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. Experimental data show an oral absorption of about 40 % for MTEA-I, the iodide form of the metabolite of a TEA-based Esterquat and somewhat higher absorption rates of 41% for males and 63% for female rats for DEEDMAC (HERA RAR 2009). As a realistic worst case a 50% oral absorption is assumed for TEA based Esterquats. A cut-off of 50% GI absorption is also recommended in the TGD R7c to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature (TGD on information requirements R7c). In the worst case (under occlusive conditions) only up to 2% absorption occurred for similar substances after dermal application (data taken from HERA RAR 2009). The corrected dermal NOAEL´s are therefore:

300 x 50/2 = 7500 mg/kg/day (90-day study); 1000 x 50/2 = 25 000 mg/kg/day (28-day study)

Assessment factors and DNEL calculation for worker DNELlong-term dermal systemic effects:

The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans. There are no data for TEA-Esterquat to quantify other differences between animals and humans that could affect extrapolation. There is no evidence for a different variability in susceptibility to the effects of long-term exposure to TEA-Esterquat in the human population. An informed factor of 3 for workers will therefore be used to take account of intraspecies variability. For differences in duration of exposure a factor of 2 was applied to correct for sub-chronic to chronic and a factor of 6 for sub-acute to chronic. Effects on urinary bladder such as enhanced desquamation and regressive epithelial changes are the only critical systemic substance induced effects identified. The probable substance related effects in the urinary bladder seen in the 90-day study have not been confirmed by the 28-day study therefore an additional AF for dose response and endpoint specific severity was not considered necessary. The key studies were conducted to modern regulatory standards and were adequately reported. The bacterial infection of the animals did not influence the outcome of the study. Furthermore in the 28-day study no systemic effects have been detected up to the limit dose. The probable substance related effects in the urinary bladder seen in the 90-day study have not been confirmed by the 28-day study. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

This gives an overall assessment factor of 24 for derivation from the sub-cronic study and an overal AF of 72 for derivation from the sub-acute study resulting in a DNEL of 312.5 mg/kg bw/d (from the suc-chronic study) e.g. 347 mg/kg bw/d (from the sub-acute study).

The DNEL of 312.5 mg/kg bw/d derived from the 90-d study is used for the risk assessment.

Worker-DNEL long-term for inhalation route (systemic)

No studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects therefore it will be necessary to obtain a long-term inhalatory DNEL by route-to-route extrapolation. Human data is not available.

Correction of starting point (route-to-route extrapolation oral to inhalation):

The NOAEL for systemic toxicity identified from an oral 90-day- study in the rat was 300 mg/kg bw/d. As has been already discussed, a 50 % oral absorption is assumed for TEA based Esterquats for the purpose of route-to-route extrapolation. As a worst-case assumption a 100 % absorption after inhalatory exposure is assumed in absence of any experimental data as recommended in TGD R8.

For the derivation of a NOAEC for the worker the following corrections have to be applied to the oral NOAEL (rat). The oral NOAEL (rat) is multiplied with 1/0.38 m3/kg bw/8h (default respiratory volume in rat, Table R.8.2 of CSR guidance) to give the corresponding rat inhalation 8h-NOAEC (no-observed adverse effect concentration). To adjust the NOAEC for bioavailability this value is multiplied with 0.5 (x50/100). To obtain the starting point for workers, a factor of 0.67 is applied to the NOAEC to account for the differences in inhalation rates between animals at rest and humans involved in light activity.

For workers the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC = oral NOEL x 1/sRVrat x ABSoral-rat / ABSinh-human x sRVhuman / wRV

= 300 x 1/0.38 x 50/100 x 6.7/10

The corrected inhalatory NOAECworker (8h) is therefore:

= 264 mg/m3 (8h-TWA)

Assessment factors and DNEL calculation for worker DNELlong-term inhalation systemic effects:

It is not necessary to apply an allometric scaling factor because the starting point has been corrected for differences in respiratory volume and this takes account of differences in metabolic rates. There is no evidence for a different in susceptibility to the effects of long-term exposure to TEA-Esterquat in the human population. An informed factor of 3 for workers will therefore be used to take account of intraspecies variability. It is expected that the severity of effects could increase with duration. Since the dose descriptor is derived from a 90-day study, it is necessary to apply a factor of 2 to take account of extrapolation of subchronic data from the 90-day study to chronic exposure. The effects seen in the 90-day study are only minor toxicological effects. The possibly substance related effects in the urinary bladder seen in the 90-day study have not been confirmed by the 28-day study. In the 28 day study there were no effects up to the limit dose, It is therefore not necessary to apply a factor to take account of this. The key studies were conducted according to modern regulatory standards and were adequately reported. The bacterial infection of the animals did not crucially influence the outcome of the study. Furthermore in the 28-day study no systemic effects have been detected up to the limit dose. The probable substance related effects in the urinary bladder seen in the 90-day study have thus not been confirmed by the 28-day study. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

This results in an overall assessment factor of 6.

The endpoint specific DNEL from the 90-day study is therefore calculated as follows:

264/6 = 44 mg/m3 (8h-TWA)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13 mg/m³
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
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:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
187.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
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:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
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

Additional information - General Population

DNEL acute systemic effects:

A DNEL for acute toxicity is not established because no acute toxicity hazard (leading to classification and labelling) has been identified.

A default DNEL for acute toxicity could be set for a reference period of 15 minutes at 3 times the value (default 3) of the long-term DNEL. This approach is particularly valid because similar mechanisms of actions are probably involved in the responses to single and repeated exposure (TGD R8).

Local irritation of the respiratory tract

Inhalation studies are not available. A reliable dose descriptor for local irritation of the respiratory tract could not be derived from the available oral and dermal studies. Due to low concentration of substance in preparations used for spray applications local toxicity (respiratory tract irritation) is not expected.

Local effects dermal

A reliable dose descriptor for local irritation could not be derived from the available acute dermal toxicity/irritation studies. A DNEL acute - local effects is not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to GHS Regulation EC No 1272/2008.

General population-DNEL long-term for dermal route (systemic)

The long term DNEL dermal for general population was derived from the oral 90-day oral study with rats by applying route-to-route extrapolation (derivation see worker part: Correction of starting point (route-to-route extrapolation oral to dermal):

The corrected dermal NOAEL is therefore: 300 x 50/2 = 7500 mg/kg/day

The following assessment factors were applied (discussion in detail see worker part): 4 for interspecies variability, 5 for intraspecies variability general population and 2 for time extrapolation. This results in an overall assessment factor of 40. The endpoint specific DNEL from the 90-day study is therefore calculated as follows:

7500/40 = 187.5 mg/kg bw/d

General population-DNEL long-term for inhalation route (systemic)

Concerning route-to-route extrapolation see discussion above (worker).

For the derivation of a NOAEC for the general population the following corrections have to be applied to the oral NOAEL (rat). The oral NOAEL (rat) of 300 mg/kg bw/d is multiplied with 1/1.15 m³/kg bw/d (default respiratory volume in rat, Table R.8.2 of CSR guidance) to give the corresponding rat inhalation NOAEC (no-observed adverse effect concentration). To adjust the NOAEC for bioavailability this value is multiplied with 0.5 (x50/100).

For general population in case of 24h exposure/d the corrected inhalatory NOEC is calculated according to the following equation:

corrected inhalatory NOAEC = oral NOEL x 1/sRVrat x ABSoral-rat / ABSinh-human

= 300 x 1/1.15 x 50/100

The corrected inhalatory NOAECgeneral population (24h) is therefore:

= 130 mg/m3

It is not necessary to apply an allometric scaling factor because the starting point has been corrected for differences in respiratory volume and this takes account of differences in metabolic rates.

The following assessment factors were applied: 5 for intraspecies variability general population and 2 for time extrapolation. This results in an overall assessment factor of 10.

Endpoint specific DNEL (from 90-day study) 130/10 = 13 mg/m3 /d

General population-DNEL long-term for oral route (systemic)

The long term DNEL for general population was derived from the oral 90-day oral study with rats (NOEL 300 mg/kg bw/d).

The following assessment factors were applied: 4 for interspecies variability, 5 for intraspecies variability general population and 2 for time extrapolation. This results in an overall assessment factor of 40.

Endpoint specific DNEL (from 90-day study) 300/40 = 7.5 mg/kg bw/d

Overall Discussion – Worker and general population:

Reproductive Toxicity: Fertility

No effects on organ weights of ovary and testis and histopathology of gonads from 28-day and 90-day repeated dose studies were detected with doses of up to 1000 mg/kg bw/d. There is no information available in humans. The key study used for the derivation of a DNELfertility is the 90 day repeated dose toxicity study with a NOAEL of 1000 mg/kg bw/d for effects on fertility.

The long term DNEL fertility dermal for worker and general population was derived by applying route-to-route extrapolation (derivation see worker part: Correction of starting point (route-to-route extrapolation oral to dermal):

The corrected dermal NOAEL´s is therefore:

1000 x 50/2 = 25000 mg/kg/day

The following assessment factors were applied: 4 for interspecies variability, 5 (3) for intraspecies variability general population (worker) and 2 for time extrapolation sub-chronic to chronic. Due to the higher degree uncertainty of available data, which is driven by the fact that only a repeated dose toxicity study was available for assessing effects on fertility, an additional assessment factor of 2 was applied. This results in an overall assessment factor of 80 (48).

DNEL worker fertility dermal                      25 000/48 = 520 mg/kg bw/day

DNEL general population fertility dermal       25 000/80 = 312.5 mg/kg bw/day

For derivation of the DNEL fertility inhalation, the corrected inhalatory NOEC is calculated according to the following equations:

Worker:

corrected inhalatory NOAEC = oral NOEL x 1/sRVrat x ABSoral-rat / ABSinh-human x sRVhuman / wRV

= 1000 x 1/0.38 x 50/100 x 6.7/10

The corrected inhalatory NOAECworker (8h) is therefore:

= 882 mg/m3 (8h-TWA)

General Population:

corrected inhalatory NOAEC = oral NOEL x 1/sRVrat x ABSoral-rat / ABSinh-human

= 1000 x 1/1.15 x 50/100

The corrected inhalatory NOAECgeneral population (24h) is therefore:

= 435 mg/m3

The following assessment factors were applied: 5 (3) for intraspecies variability general population (worker) and 2 for time extrapolation sub-chronic to chronic. Due to the higher degree uncertainty of available data which is driven by the fact that only a repeated dose toxicity study was available for assessing effects on fertility, an additional assessment factor of 2 was applied. This results in an overall assessment factor of 20 (12).

DNEL worker fertility inhalation                     882/12 = 73.5 mg/m3

DNEL general population fertility inhalation   435/20 = 21.75 mg/m3

The long term DNEL fertility for general population was derived from the oral 90-day oral study with rats (NOEL fertiltiy 1000 mg/kg bw/d). The following assessment factors were applied: 4 for interspecies variability, 5 for intraspecies variability general population and 2 for time extrapolation. Due to the higher degree uncertainty of available data which is driven by the fact that only a repeated dose toxicity study was available for assessing effects on fertility, an additional assessment factor of 2 was applied. This results in an overall assessment factor of 80.

DNEL general population fertility oral 1000/80 = 12.5 mg/kg bw/day

The DNELs derived from this study by applying an additional safety factor of 2 to account for higher uncertainty are higher than the DNELs for repeated dose toxicity. Therefore the DNELs for repeated dose toxicity (oral, dermal and inhalative) are also protective for fertility.

Reproductive Toxicity: Developmental toxicity

The potential embryotoxicity/teratogenicity of TEA-Esterquats has been evaluated in a reliable OECD 414 guideline compliant prenatal developmental toxicity study with the similar substance MDEA-Esterquat. In the HERA RAR Esterquats (2009) the potential embryotoxicity/teratogenicity of esterquats has been evaluated in a second reliable OECD 414 guideline compliant prenatal developmental toxicity study. In conclusion, in both studies no effects on maternal reproduction, embryolethality, or developmental effects were observed following maternal exposure to MDEA-Esterquat or HEQ at doses up to 1000 mg/kg bw/day. A read-across is deemed appropriate in terms of animal welfare (please refer to detailed justification in chapter 5.9.2).

A DNEL derived from these studies will in any case be higher than the DNEL derived for repeated dose toxicity even if an additional assessment factor of 2 is applied for the uncertainty of using read across data. Therefore the DNELs for repeated dose toxicity (oral, dermal and inhalation) are also protective for developmental toxicity.

Carcinogenicity

The mutagenic and clastogenic potential of TEA-Esterquat has been evaluated in the full range of in-vitro and in a single in-vivo genotoxicity studies. There was no evidence for genotoxic properties of any of the investigated TEA esterquats. Although carcinogenicity studies are not available for esterquats, the absence of genotoxicity or inflammatory responses in repeated dose toxicity studies do no raise any specific concerns with regard to carcinogenicity.