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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.18 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
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst-case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to-inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8 h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8 h exposure period).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalatory NOAEC = [NOAEL] X (1/SRVrat x ABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

= [100 mg/kg bw/day] X  [1/0.38 m3/kg bw/day] X [1/2] X [6.7 m3/10m3].

Thus, the corrected dose descriptor for inhalation is 88.16 mg/m3 for workers.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Default factor for worker. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database has taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.33 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
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For systemic hazard assessment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is considered the same as the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)).

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
5
Justification:
Default factor for worker. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainities.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

NOAEL (Systemic toxicity) = 100 mg/kg /day; OECD 422; N. Barraclough. (2018)

Long-term systemic hazard assessment for this substance to workers is based on a sub-acute repeated dose toxicity study, combined with reproduction and developmental screening (OECD 422; N. Barraclough., 2018). During the treatment period, mean overall food consumption for male and females administered 100 mg/kg/day was 10% and 12% lower than controls. This resulted into actual body weight loss and lower body weight gain. Instances of raised fur and isolated instances of hunched posture were recorded in males at all doses but considered incidental and not related to test item administration. Alkaline phosphatase activity was significantly raised, significant reduction in total protein and globulin and in-significant increase in A:G ratio were observed at high dose group of 100 mg/kg/day.  This corresponded with increases in liver and kidney weights, higher mean absolute weights and kidney:% total body weight and mean absolute liver weights and liver:% total body weight. Microscopic examination of the kidney revealed increased severity of hyaline droplets was present, which generally correlated with increased kidney weights. Hyaline droplets were characterized by small, generally round eosinophilic droplets in the proximal tubular epithelium. These findings were considered to represent adaptive responses to administration of a xenobiotic and, in the absence of any hepatic pathology, were considered non‑adverse.  A medulloblastoma was present in one male administered 100 mg/kg/day (decedent Animal R0306). This tumor has been observed as a background finding in short term studies, although it is rare. As only one animal was affected, a relationship to the test article was considered unlikely.

Similar effects were evident following 50 mg/kg/day administration. Initial body weight losses, reduced body weight gains, and lower food consumptions were observed for males, with an instance of raised and hair and reduced activity noted during the neurobehavioral assessments. For females, initial reduction in food consumption was evident. In lactation, reduced rearing was evident, compared with control. At scheduled sacrifice, elevated liver weights were evident, compared with concurrent controls. These findings were considered not to represent adverse effects of test article administration.

Weekly functional observation batteries (FOBs) showed a higher incidence of decreased activity for males administered 50 or 100 mg/kg/day, compared with controls. Hind limb foot splay was also shorter for males administered100 mg/kg/day, compared with controls. The mean number of rears was reduced during lactation for females administered 100 mg/kg/day, compared with control. Similar effects were also evident following administration of 50 mg/kg/day, compared with control.  Furthermore, locomotor activity was unaffected by test article administration.

Finally, mean thymus weights (absolute and body weight relative) were lower for females administered the test article at all dose groups, compared with concurrent controls. In the absence of any hematology or microscopic correlations, the lower thymus weights were considered not to have represented adverse effect of test article administration.

No test article-related deaths occurred. The deaths of three animals (two female administered 50 mg/kg/day, and one male administered 100 mg/kg/day) were considered not related to the test article.  No test article-related thyroid hormone or thyroid weight changes were noted for adult males, adult females or offspring at any dose level.

Micronuclei (MN) in the polychromatic erythrocytes (PCE) of the bone marrow were not induced following test article administration at any dose level.

Reproductive performance was unaffected; the test article did not affect estrous cycles, mating, fertility, pregnancy or parturition.

A no observed effect level (NOEL) was considered as 30 mg/kg/day for the males, although a NOEL for females could not be established, due to the lower thymus weights observed in all dose groups.

NOAEL (Reproductive and developmental toxicity) of 100 mg/kg /day considered under  the condition of the study.

NOAEL (Systemic toxicity) = 100 mg/kg /day was therefore used to derive the workers DNELs in accordance with ECHA Guideline

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.289 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):
150
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.48 mg/m³
Explanation for the modification of the dose descriptor starting point:

Concerning absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalator NOAEC = 1/sRVrat x ABSoral-rat/ABSinh-rat x ABSinh-rat/ABSinh-human

= [NOAEL] x [125 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [1/2].

Thus, the corrected dose descriptor for inhalation is 54.35 mg/m3 for the general population.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.167 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):
600
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For systemic hazard assesment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is considered the same as the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)).

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.167 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):
600
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

NOAEL (Systemic toxicity) = 100 mg/kg /day; OECD 422; N. Barraclough. (2018)

Long-term systemic hazard assessment for this substance to workers is based on a sub-acute repeated dose toxicity study, combined with reproduction and developmental screening (OECD 422; N. Barraclough., 2018). During the treatment period, mean overall food consumption for male and females administered 100 mg/kg/day was 10% and 12% lower than controls. This resulted into actual body weight loss and lower body weight gain. Instances of raised fur and isolated instances of hunched posture were recorded in males at all doses but considered incidental and not related to test item administration. Alkaline phosphatase activity was significantly raised, significant reduction in total protein and globulin and in-significant increase in A:G ratio were observed at high dose group of 100 mg/kg/day.  This corresponded with increases in liver and kidney weights, higher mean absolute weights and kidney:% total body weight and mean absolute liver weights and liver:% total body weight. Microscopic examination of the kidney revealed increased severity of hyaline droplets was present, which generally correlated with increased kidney weights. Hyaline droplets were characterized by small, generally round eosinophilic droplets in the proximal tubular epithelium. These findings were considered to represent adaptive responses to administration of a xenobiotic and, in the absence of any hepatic pathology, were considered non‑adverse.  A medulloblastoma was present in one male administered 100 mg/kg/day (decedent Animal R0306). This tumor has been observed as a background finding in short term studies, although it is rare. As only one animal was affected, a relationship to the test article was considered unlikely.

Similar effects were evident following 50 mg/kg/day administration. Initial body weight losses, reduced body weight gains, and lower food consumptions were observed for males, with an instance of raised and hair and reduced activity noted during the neurobehavioral assessments. For females, initial reduction in food consumption was evident. In lactation, reduced rearing was evident, compared with control. At scheduled sacrifice, elevated liver weights were evident, compared with concurrent controls. These findings were considered not to represent adverse effects of test article administration.

Weekly functional observation batteries (FOBs) showed a higher incidence of decreased activity for males administered 50 or 100 mg/kg/day, compared with controls. Hind limb foot splay was also shorter for males administered100 mg/kg/day, compared with controls. The mean number of rears was reduced during lactation for females administered 100 mg/kg/day, compared with control. Similar effects were also evident following administration of 50 mg/kg/day, compared with control.  Furthermore, locomotor activity was unaffected by test article administration.

Finally, mean thymus weights (absolute and body weight relative) were lower for females administered the test article at all dose groups, compared with concurrent controls. In the absence of any hematology or microscopic correlations, the lower thymus weights were considered not to have represented adverse effect of test article administration.

No test article-related deaths occurred. The deaths of three animals (two female administered 50 mg/kg/day, and one male administered 100 mg/kg/day) were considered not related to the test article.  No test article-related thyroid hormone or thyroid weight changes were noted for adult males, adult females or offspring at any dose level.

Micronuclei (MN) in the polychromatic erythrocytes (PCE) of the bone marrow were not induced following test article administration at any dose level.

Reproductive performance was unaffected; the test article did not affect estrous cycles, mating, fertility, pregnancy or parturition.

A no observed effect level (NOEL) was considered as 30 mg/kg/day for the males, although a NOEL for females could not be established, due to the lower thymus weights observed in all dose groups.

NOAEL (Reproductive and developmental toxicity) of 100 mg/kg /day considered under  the condition of the study.

NOAEL (Systemic toxicity) = 100 mg/kg /day was therefore used to derive the workers DNELs in accordance with ECHA Guideline