Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
97.95 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):
18
Modified dose descriptor starting point:
NOAEC
Value:
1 763.15 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no quantitative data on absorption rates for oral or inhalation route available. From the data generated in the sub-acute oral study it can be concluded that absorption via oral is low, as the substance is nearly unsoluble in water (below the detection limit of 0.00003 g/l). The absorption via inhalation route might be comparable low. Consequently, there is no need to introduce further default value for the extrapolation from oral route to inhalation route. Corrected inhalatory NOAEC= oral NOAEL(1000 mg/kg bw/day) x 1/0.38 x 6.7/10 X 1 Corrected NOAEC (worker) = 1763.15 mg/m³
AF for dose response relationship:
1
Justification:
There are no effects up to the limit dose
AF for differences in duration of exposure:
6
Justification:
subacute to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling rat versus human: the AF of 4 is already included in the route to route extrapolation
AF for other interspecies differences:
1
Justification:
The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day, Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a defaut factor. This view is supported by ERASM project (Barke et al 2010)
AF for intraspecies differences:
3
Justification:
Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks as well as short term inhalation exposure against the highest technical attainable concentration of 2868 mg/m³ for 4 hours was tolerated by rats without mortalitity or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for worker from exposure against Macrolex Rot EG might be unlikely. Consequently the default factor will be lowered taking into account compound specific data
AF for the quality of the whole database:
1
Justification:
There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
97.95 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.89 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):
72
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There is no long term study available using dermal application as exposure route. Therefore the available subacute oral toxicity study in rats has to be considered and the respective NOAEL of 1000 mg/kg bw has to be used as starting point for DNEL calculation. As it can be assumed that dermal absorption would not be higher than the oral absorption ECHA proposed in the Guidance Document R8 not to introduce an additional default factor for the extrapolation from oral to dermal exposure route. NOAEL (oral, rat, subacute) = NOAEL (dermal, rat, subacute) = 1000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
There is no effect up to the limit dose
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling: rat versus human
AF for other interspecies differences:
1
Justification:
The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day. Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 as a default factor is scientifically unjustified. This view is supported by ERASM project (Barke et al 2010).
AF for intraspecies differences:
3
Justification:
Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks was tolerated by rats without mortalitity or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for worker from exposure against Macrolex Rot EG might be low. Consequently the default factor will be lowered taking into account compound specific data
AF for the quality of the whole database:
1
Justification:
There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.89 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
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:
no hazard identified

Additional information - workers

Macrolex Rot EG

CAS-Nr. 20749-68-2

DNEL- Derivation: Worker

I. Introduction

The substance is not classified legally. There is no German or European OEL available which can be used as starting point for the DNEL derivation.

II. Derivation of Worker-DNEL (systemic)

Basis for DNEL Derivation

Macrolex Rot EG was administered by gavage to 5 male and 5 female Wistar rats per dose group indayily doses of 0, 100, 300, 1000 mg/kg bw/day suspended in polyethylene glycol 400 (vehicle) for a period of 28 days. The study was conducted in compliance with OECD TG 407 under GLP conditions.

Survival was not affected by treatment with Macrolex Rot EG and no clinical signs were observed. The observed decreased alkaline phosphatase in females was not considered relevant because neither all other clinical chemistry data nor hematology gave evidence for treatment related effects up to 1000 mg/kg bw. Starting at the mid dose of 300 mg/kg bw,. all animals of both sexes showed changes in feces color (reddish particles), which is a consequence of the strong red color of the test item and thus is not considered as adverse effect. Histopathology revealed minimally to slightly reduced secretion in the seminal vesicles in 3 out of 5 males at 1000 mg/kg bw which was not associated with degeneration of seminal vesicles. Changes in other male genital organs (testes, epididymides, prostate or coagulation glands) could not be found up to and including 1000 mg/kg bw.. Therefore, reduced secretion is regarded as unspecific and possibly stress-related. An adverse effect is not assumed. Female reproductive organs were not affected up to 1000 mg/kg bw/day.

In conclusion, under the conditions described above, the no-adverse-effect-level (NOAEL) for male and female rats after 4 -week daily oral treatment by gavage with Macrolex Rot EG is 1000 mg/kg bw/day.

In an OECD 414 study, one group of 20 females received Macrolex Rot EG at a dose of 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted control group received the vehicle, polyethylene glycol 400 (PEG 400) at the same volume dose as the treated group. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.

Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterine weight recorded and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.

Based on the results of this study, it is concluded that in the absence of any evidence for general systemic toxicity or adverse effects on embryo-fetal survival, growth and development, that the no (NOAEL) observed adverse effect level was 1000 mg/kg/day (highest dose tested).

Therefore, the calculation of a separate DNEL for toxicity to reproduction is not necessary, because the NOAEL of the repeated dose subacute toxicity study and the NOAEL of the OECD TG 414 study is identical.

1.) DNEL long-term, inhalation route –Systemic effects

NOAEL (rat) from a sub-acute oral toxicity study 1000 mg/kg bw/day

Correction of the starting point according to ECHA Guidance Chapter R8

There are no quantitative data on absorption rates for oral or inhalation route available. From the data generated in the sub-acute oral study it can be concluded that absorption via oral is low, as the substance is nearly unsoluble in water (below the detection limit of 0.00003 g/l). The absorption via inhalation route might be comparable low. Consequently, there is no need to introduce further default value for the extrapolation from oral route to inhalation route.

Corrected inhalatory NOAEC= oral NOAEL(1000 mg/kg bw/day) x 1/0.38 x 6.7/10 X 1

Corrected NOAEC (worker) = 1763.15 mg/m³

Overall factor 18

Worker DNEL (long term, systemic for inhalation route) 97.95 mg/m³

2.) DNEL short-term, inhalation route –Systemic effects

There is a reliable study available in which is performed according to OECD TG 403 under GLP conditions. Rats were exposed to the maximum technically attainable concentration of 2868 mg/m³ for 4 hours. No animal died and the exposure was tolerated without any pathodiagnostic effects suggestive of portal of entry or systemic toxicity. Thus, no hazard was identified in this animal experiment. Therefore, it is proposed not to define a special DNEL (short term for inhalation route but to take the DNEL (long term, systemic for inhalation route as surrogate.

Thus, Worker DNEL (long term and short term, systemic for inhalation route) is 97.95 mg/m³

General dust limit:

For insoluble particles, the general threshold value for dust has to be taken into account:

For general dust in Germany the current binding national Occupational Exposure Limit is 10 mg/m³ for inhalable and 3 mg/m³ for respirable dust (TRGS900; http://www.baua.de/cae/servlet/contentblob/666764/publicationFile/55580/TRGS-900.doc).

The use of the official national German value for general dust is in line with the proposal in ECHA Guidance document R8 Version 2.1. dated November 2012. Here it is stated that the general dust limits of 10 mg/m3 for the inhalable airborne fraction and 3 mg/m3 for the respirable airborne fraction used in setting Occupational Exposure Limits in many countries should be considered in combination with nature of the dust. It is stated in the ECHA Guidance document that for non-soluble inert dusts if the derived DNEL for inhalation is above these dust limits, the general dust limits should apply for exposure scenarios with exposure to dust (see chapter 8.7.1, page 48 of ECHA guidance document R.8, Version 2.1 dated November 2012).

For the respirable and inhalable fraction of Macrolex Rot EG the general dust limit has to be considered.

3.) DNEL (long term, systemic , dermal route)

There is no long term study available using dermal application as exposure route. Therefore the available subacute oral toxicity study in rats has to be considered and the respective NOAEL of 1000 mg/kg bw has to be used as starting point for DNEL calculation. As it can be assumed that dermal absorption would not be higher than the oral absorption ECHA proposed in the Guidance Document R8 not to introduce an additional default factor for the extrapolation from oral to dermal exposure route.

NOAEL (oral, rat, subacute) = NOAEL (dermal, rat, subacute) = 1000 mg/kg bw/day

Overall factor 72

Thus, worker DNEL (long term, systemic for dermal route) is 13.89 mg/kg bw/day

4.) DNEL (short term, systemic , dermal route)

There is no acute study available using dermal application to determine acute systemic toxicity after dermal application. Thus, no probable toxic hazard was identified. In addition, in the available study on skin irritation in animals or in the animal study on skin sensitization no systemic toxicity or mortality was observed. Therefore it is proposed to take the Worker long term DNEL for dermal application as surrogate:

Thus, Worker DNEL (long term and short term, systemic for dermal route) is 13.89 mg/kg bw/day

III. Derivation of DNELs (local)

Basis for DNEL derivation

In the available tests on skin irritation and eye irritation Macrolex Rot EG is not irritating to the skin nor to the mucous membranes of rabbits. The modified Local Lymph Node Assay (IMDS) was performed according to OECD Guidelines No. 429 and No. 406. The results show that there is no indication for a skin sensitizing effect after administration Macrolex Rot EG in this test system.

Based on these results no DNELs (local) need to be derived because no hazard was identified

IV. Conclusion (systemic and local)

The systemic DNELs for long term include the short term hazard.

Therefore, the relevant DNELs are

Worker DNEL (systemic, dermal route): 13.89 mg/kg bw/day

Worker DNEL (systemic, inhalation route): 97.95 mg/m³

For the respirable and inhalable fraction of Macrolex Rot EG the general dust limit has to be considered.

With respect to local effects no DNELs are needed because no hazard was identified.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29 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):
30
Modified dose descriptor starting point:
NOAEC
Value:
870 mg/m³
Explanation for the modification of the dose descriptor starting point:
NOAEL (rat) from a sub-acute oral toxicity study 1000 mg/kg bw/day Correction of the starting point according to ECHA Guidance Chapter R8 There are no quantitative data on absorption rates for oral or inhalation route available. From the data generated in the sub-acute oral study it can be concluded that absorption via oral is low. As the substance is nearly unsoluble in water (below the detection limit of 0.00003 g/l). The absorption via inhalation route might be comparable low. Consequently, there is no need to introduce further default value for the extrapolation from oral route to inhalation route. Corrected inhalatory NOAEC= oral NOAEL(1000 mg/kg bw/day) x 1/1.15 x 1 Corrected NOAEC (general population) = 870 mg/m³
AF for dose response relationship:
1
Justification:
There are no effects up to the limit dose
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling rat versus human: the AF of 4 is already included in the route to route extrapolation
AF for other interspecies differences:
1
Justification:
The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day, Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a defaut factor. This view is supported by ERASM project (Barke et al 2010)
AF for intraspecies differences:
5
Justification:
Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks as well as short term inhalation exposure against the highest technical attainable concentration of 2868 mg/m³ for 4 hours was tolerated by rats without mortalitity or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for general population from exposure against Macrolex Rot EG might be unlikely. Consequently the default factor will be lowered taking into account compound specific data.
AF for the quality of the whole database:
1
Justification:
There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
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
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 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):
120
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There is no long term study available using dermal application as exposure route. Therefore the available sub-acute oral toxicity study in rats has to be considered and the respective NOAEL of 1000 mg/kg bw has to be used as starting point for DNEL calculation. As it can be assumed that dermal absorption would not be higher than the oral absorption ECHA proposed in the Guidance Document R8 not to introduce an additional default factor for the extrapolation from oral to dermal exposure
AF for dose response relationship:
1
Justification:
There are no effects up to the limit dose
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat versus human
AF for other interspecies differences:
1
Justification:
The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day, Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a defaut factor. This view is supported by ERASM project (Barke et al 2010)
AF for intraspecies differences:
5
Justification:
Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks was tolerated by rats without mortality or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for general population from exposure against Macrolex Rot EG might be low. Consequently the default factor will be lowered taking into account compound specific data.
AF for the quality of the whole database:
1
Justification:
There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
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:
8.33 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):
120
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Route to rote extrapolation needs not to be performed
AF for dose response relationship:
1
Justification:
There are no effects up to the limit dose
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat versus human
AF for other interspecies differences:
1
Justification:
The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw/day, Consequently it is considered to be a conservative starting point for DNEL calculation and the real NOAEL in rats is probably much higher. In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a defaut factor. This view is supported by ERASM project (Barke et al 2010)
AF for intraspecies differences:
5
Justification:
Based on the considerations by ECETOC Report TR 110 2010. Oral treatment with up to 1000 mg/kg bw/day for a period of 4 weeks was tolerated by rats without mortality or any impairment. In addition, taking into account that the test item is a solid with a molecular weight of 408, melting point of >300 °C, log Pow >7 and water solubility below the detection limit, this indicates that hazard for general population from exposure against Macrolex Rot EG might be low. Consequently the default factor will be lowered taking into account compound specific data.
AF for the quality of the whole database:
1
Justification:
There is information available to cover all relevant toxicological endpoints. The available studies are at most performed according to guideline and GLP. No adverse effects were observed in a guideline sub-acute toxicity study indicating that Macrolex Rot EG has a low toxicological potential and the starting point for the DNEL derivation is conservative.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Macrolex Rot EG

CAS-Nr. 20749-68-2

DNEL- Derivation: General Population

I. Introduction

The substance is not classified legally.

II. Derivation of General Population-DNEL (systemic)

Basis for DNEL Derivation

Macrolex Rot EG was administered by gavage to 5 male and 5 female Wistar rats per dose group indayily doses of 0, 100, 300, 1000 mg/kg bw/day suspended in polyethylene glycol 400 (vehicle) for a period of 28 days. The study was conducted in compliance with OECD TG 407 under GLP conditions.

Survival was not affected by treatment with Macrolex Rot EG and no clinical signs were observed. The observed decreased alkaline phosphatase in females was not considered relevant because neither all other clinical chemistry data nor hematology gave evidence for treatment related effects up to 1000 mg/kg bw. Starting at the mid dose of 300 mg/kg bw, all animals of both sexes showed changes in feces color (reddish particles), which is a consequence of the strong red color of the test item and thus is not considered as adverse effect. Histopathology revealed minimally to slightly reduced secretion in the seminal vesicles in 3 out of 5 males at 1000 mg/kg bw which was not associated with degeneration of seminal vesicles. Changes in other male genital organs (testes, epididymides, prostate or coagulation glands) could not be found up to and including 1000 mg/kg bw.. Therefore, reduced secretion is regarded as unspecific and possibly stress-related. An adverse effect is not assumed. Female reproductive organs were not affected up to 1000 mg/kg bw/day.

In conclusion, under the conditions described above, the no-adverse-effect-level (NOAEL) for male and female rats after 4 -week daily oral treatment by gavage with Macrolex Rot EG is 1000 mg/kg bw/day.

In an OECD 414 study, one group of 20 females received Macrolex Rot EG at a dose of 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted control group received the vehicle, polyethylene glycol 400 (PEG 400) at the same volume dose as the treated group. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.

Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterine weight recorded and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.

Based on the results of this study, it is concluded that in the absence of any evidence for general systemic toxicity or adverse effects on embryo-fetal survival, growth and development, that the no (NOAEL) observed adverse effect level was 1000 mg/kg/day (limit dose; highest dose tested).

Therefore, the calculation of a separate DNEL for toxicity to reproduction is not necessary, because the NOAEL of the repeated dose subacute toxicity study and the NOAEL of the OECD TG 414 study is identical.

1.) DNEL long-term, inhalation route –Systemic effects

NOAEL (rat) from a sub-acute oral toxicity study 1000 mg/kg bw/day

Correction of the starting point according to ECHA Guidance Chapter R8

There are no quantitative data on absorption rates for oral or inhalation route available. From the data generated in the sub-acute oral study it can be concluded that absorption via oral is low. As the substance is nearly unsoluble in water (below the detection limit of 0.00003 g/l). The absorption via inhalation route might be comparable low. Consequently, there is no need to introduce further default value for the extrapolation from oral route to inhalation route.

Corrected inhalatory NOAEC= oral NOAEL(1000 mg/kg bw/day) x 1/1.15 x 1

Corrected NOAEC (general population) = 870 mg/m³

Overall factor 30

General Population DNEL (long term, systemic for inhalation route) is 29 mg/m³

2.) DNEL short-term, inhalation route –Systemic effects

There is a reliable study available in which is performed according to OECD TG 403 under GLP conditions .Rats were exposed to the maximum technically attainable concentration of 2868 mg/m³ for 4 hours. No animal died and the exposure was tolerated without any pathodiagnostic effects suggestive of portal of entry or systemic toxicity. Thus, no hazard was identified in this animal experiment. Therefore, it is proposed not to define a special DNEL (short term for inhalation route) but to take the DNEL (long term, systemic for inhalation route) as surrogate.

Thus, General Population DNEL (long term and short term, systemic for inhalation route) is 29 mg/m³

3.) DNEL (long term, systemic , oral route and dermal route)

There is no long term study available using dermal application as exposure route. Therefore the available sub-acute oral toxicity study in rats has to be considered and the respective NOAEL of 1000 mg/kg bw has to be used as starting point for DNEL calculation. As it can be assumed that dermal absorption would not be higher than the oral absorption ECHA proposed in the Guidance Document R8 not to introduce an additional default factor for the extrapolation from oral to dermal exposure route.

NOAEL (oral, rat, subacute) = NOAEL (dermal, rat, subacute) = 1000 mg/kg bw/day

Overall factor 120

Thus, the General Population DNEL (long term, systemic for oral route and for dermal route) is 8.33 mg/kg bw/day

4.) DNEL (short term, systemic , oral route and dermal route)

There is an oral study in rats available resulting in LD50 value of > 5000 mg/kg bw. No animal died, no animal showed signs of systemic poisoning and at sacrifice no gross pathological finding was detected.

Regarding dermal application there is no acute study available using dermal application to determine acute systemic toxicity after dermal application. In addition, in the available study on skin irritation in animals or in the animal study on skin sensitization no systemic toxicity or mortality was observed. Therefore it can be assumed that acute dermal toxicity is negligible.

Consequently, considering both application routes, it is proposed to take the General Publication long term DNEL for oral exposure and dermal application as surrogate:

Thus, General Population DNEL (long term and short term, systemic, for oral and for dermal route) is 8.33 mg/kg bw/day

III. Derivation of DNELs (local)

Basis for DNEL derivation

In the available tests on skin irritation and on eye irritation Macrolex Rot EG is not irritating to the skin nor to the mucous membranes of the eyes of rabbits.

The modified Local Lymph Node Assay (IMDS) was performed according to OECD Guidelines No. 429 and No. 406. The results show that there is no indication for a skin sensitizing effect after administration Macrolex Rot EG in this test system.

Based on these results no DNELs (local) need to be derived because no hazard was identified

IV. Conclusion (systemic and local)

The systemic DNELs for long term include the short term hazard.

Therefore, the relevant DNELs are

General Population DNEL (systemic, inhalation route): 29 mg/m³

General Population DNEL (systemic, oral route and dermal route): 8.33 mg/kg bw/day

With respect to local effects no DNELs are needed because no hazard was identified.