Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.82 mg/m³
Most sensitive endpoint:
effect on fertility
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:
325 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
286.5 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

= [325 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 286.5 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:
1.08 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
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:
325 mg/kg bw/day
DNEL value:
325 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)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Relevant endpoint for DNEL derivation: toxicity to reproduction - NOAEL = 325 mg/kg bw/d

The study was performed according the requirements of OECD TG 422 guideline under GLP conditions. Following a previously conducted 14-day sighting study, the systemic toxic potential of the test item in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints was conducted by oral gavage administration for at least five weeks with additional subgroups used to assess reversibility, persistence or delayed effects for 14 days post treatment. Three toxicology treatment groups with a control was conducted, each comprising five or ten male and five female rats which received oral gavage test item at doses of 0 (Control), 100, 325 or 1000 mg/kg bw/day test item formulated in corn oil vehicle. Ten males were treated in the 100 and 325 mg/kg bw/day doses for pairing purposes with the reproductive phase females. Recovery phase groups included five males and females treated at 0 (Control) and 1000 mg/kg bw/day. Reproductive phase females, ten per group (10) were treated at doses of 0 (Control), 100, 325 or 1000 mg/kg bw/day. Toxicity phase males were treated for two weeks before pairing up to necropsy after six weeks. Toxicity phase females were treated for six weeks. Recovery phase males were treated for two weeks before pairing up to necropsy after six weeks followed by a 2-week recovery period. Recovery phase females were treated for six weeks followed by a 2-week recovery period. Reproductive phase females were treated for two weeks before pairing, throughout pairing, gestation and until Day 12 of lactation. The offspring received no direct administration of the test item; any exposure was in utero or via the milk. Selected F1 offspring were sampled and killed on Day 4 or Day 13 of age for analysis of blood thyroid hormone levels. The remaining F1 offspring were killed on Day 13 of age. A similarly constituted Control group was assigned to each phase, and received, the vehicle: corn oil at the same dose volume as treated groups.

 

There were no treatment-related premature mortalities among adult animals during the course of the study. There was no adverse effect on clinical condition, sensory reactivity and grip strength, motor activity, food consumption, haematology, blood chemistry, urinalysis, estrous cycles, pre-coital interval, mating performance, fertility and gestation length on the adult animals. Body weight gain from Day 1 to Day 43 for animals given the test item was lower than controls, although there was no dose relationship. There were no effects on body weight gain during gestation or lactation. During lactation, forelimb grip strength and high beam motor activity was statistically significantly lower for females given 1000 mg/kg bw/day and but this was within the historic control data range or the response was atypical. Macroscopic examination performed after 5 weeks of treatment revealed pale areas in the liver of two toxicity phase males given 1000 mg/kg bw/day. No test item related changes were seen at microscopic examination of the full list of tissues/organs examined; the hepatocyte vacuolation seen in animals given 1000 mg/kg bw/day and the controls was considered coincidental given the finding correlated with the macroscopically pale liver in only one male. After five weeks of treatment, seminal vesicle weights were higher in males given 1000 mg/kg/day. There were no test item related macropathological or micropathological findings, therefore the finding was not considered to be treatment related. There were no test item related effects on T3 (triiodothyronine) or T4 (thyroxine) levels. There was no effect of parental treatment on offspring clinical signs, sex ratio, offspring survival, ano-genital distance, body weight or T3 (triiodothyronine) or T4 (thyroxine) levels. The presence of nipples on Day 13 of age in male offspring from all treated groups was considered not adverse and not test item related as the incidence fell within the historical control ranges and there was no dosage relationship. At scheduled termination of the offspring two male pups, from separate litters, within the 1000 mg/kg/day group, were found to have soft pale masses, one on the left lower jaw and one on the left inner cheek, confirmed histologically as squamous cell papilloma. A relationship to treatment is uncertain. It was considered within the study, that there was potential evidence to suggest that the test item may well be incidental. There were no other significant macroscopic findings or histopathological finding observed.

 

Conclusion:

Oral gavage administration of test item to CD rats at concentrations up to and including 1000 mg/kg bw/day was generally well tolerated. There was no adverse effect of treatment on clinical condition, sensory reactivity, motor activity, body weight, food consumption, hematology, blood chemistry, urinalysis, estrous cycles, pre-coital interval, mating performance, fertility, gestation length, organ weights, macropathology or histopathology of the adult animals. Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was considered to be 1000 mg/kg bw/day. There was no effect of parental treatment on offspring clinical signs, sex ratio, offspring survival, ano-genital distance or body weight. A higher occurrence of nipples were observed in male pups from dams given the test item, but the incidence was within the historical control data range. At scheduled termination of the offspring two male pups, from separate litters, within the 1000 mg/kg/day group, were found to have soft pale masses, one on the left lower jaw and one on the left inner cheek, confirmed histologically as squamous cell papilloma. A relationship to treatment is uncertain. It was considered within the study, that there was potential evidence to suggest that the test item may well be incidental. For reproductive / developmental toxicity for males and females a precautionary NOAEL is set at 325 mg/kg bw/day, although for all other parameters the NOAEL was 1000 mg/kg/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.942 mg/m³
Most sensitive endpoint:
effect on fertility
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:
325 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
141.3 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 [325 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [1/2].

Thus, the corrected dose descriptor for inhalation is 141.3 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:
0.542 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
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:
325 mg/kg bw/day
DNEL value:
325 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)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.542 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
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:
325 mg/kg bw/day
DNEL value:
325 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

Relevant endpoint for DNEL derivation: toxicity to reproduction - NOAEL = 325 mg/kg bw/d

The study was performed according the requirements of OECD TG 422 guideline under GLP conditions. Following a previously conducted 14-day sighting study, the systemic toxic potential of the test item in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints was conducted by oral gavage administration for at least five weeks with additional subgroups used to assess reversibility, persistence or delayed effects for 14 days post treatment. Three toxicology treatment groups with a control was conducted, each comprising five or ten male and five female rats which received oral gavage test item at doses of 0 (Control), 100, 325 or 1000 mg/kg bw/day test item formulated in corn oil vehicle. Ten males were treated in the 100 and 325 mg/kg bw/day doses for pairing purposes with the reproductive phase females. Recovery phase groups included five males and females treated at 0 (Control) and 1000 mg/kg bw/day. Reproductive phase females, ten per group (10) were treated at doses of 0 (Control), 100, 325 or 1000 mg/kg bw/day. Toxicity phase males were treated for two weeks before pairing up to necropsy after six weeks. Toxicity phase females were treated for six weeks. Recovery phase males were treated for two weeks before pairing up to necropsy after six weeks followed by a 2-week recovery period. Recovery phase females were treated for six weeks followed by a 2-week recovery period. Reproductive phase females were treated for two weeks before pairing, throughout pairing, gestation and until Day 12 of lactation. The offspring received no direct administration of the test item; any exposure was in utero or via the milk. Selected F1 offspring were sampled and killed on Day 4 or Day 13 of age for analysis of blood thyroid hormone levels. The remaining F1 offspring were killed on Day 13 of age. A similarly constituted Control group was assigned to each phase, and received, the vehicle: corn oil at the same dose volume as treated groups.

 

There were no treatment-related premature mortalities among adult animals during the course of the study. There was no adverse effect on clinical condition, sensory reactivity and grip strength, motor activity, food consumption, haematology, blood chemistry, urinalysis, estrous cycles, pre-coital interval, mating performance, fertility and gestation length on the adult animals. Body weight gain from Day 1 to Day 43 for animals given the test item was lower than controls, although there was no dose relationship. There were no effects on body weight gain during gestation or lactation. During lactation, forelimb grip strength and high beam motor activity was statistically significantly lower for females given 1000 mg/kg bw/day and but this was within the historic control data range or the response was atypical. Macroscopic examination performed after 5 weeks of treatment revealed pale areas in the liver of two toxicity phase males given 1000 mg/kg bw/day. No test item related changes were seen at microscopic examination of the full list of tissues/organs examined; the hepatocyte vacuolation seen in animals given 1000 mg/kg bw/day and the controls was considered coincidental given the finding correlated with the macroscopically pale liver in only one male. After five weeks of treatment, seminal vesicle weights were higher in males given 1000 mg/kg/day. There were no test item related macropathological or micropathological findings, therefore the finding was not considered to be treatment related. There were no test item related effects on T3 (triiodothyronine) or T4 (thyroxine) levels. There was no effect of parental treatment on offspring clinical signs, sex ratio, offspring survival, ano-genital distance, body weight or T3 (triiodothyronine) or T4 (thyroxine) levels. The presence of nipples on Day 13 of age in male offspring from all treated groups was considered not adverse and not test item related as the incidence fell within the historical control ranges and there was no dosage relationship. At scheduled termination of the offspring two male pups, from separate litters, within the 1000 mg/kg/day group, were found to have soft pale masses, one on the left lower jaw and one on the left inner cheek, confirmed histologically as squamous cell papilloma. A relationship to treatment is uncertain. It was considered within the study, that there was potential evidence to suggest that the test item may well be incidental. There were no other significant macroscopic findings or histopathological finding observed.

 

Conclusion:

Oral gavage administration of test item to CD rats at concentrations up to and including 1000 mg/kg bw/day was generally well tolerated. There was no adverse effect of treatment on clinical condition, sensory reactivity, motor activity, body weight, food consumption, hematology, blood chemistry, urinalysis, estrous cycles, pre-coital interval, mating performance, fertility, gestation length, organ weights, macropathology or histopathology of the adult animals. Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was considered to be 1000 mg/kg bw/day. There was no effect of parental treatment on offspring clinical signs, sex ratio, offspring survival, ano-genital distance or body weight. A higher occurrence of nipples were observed in male pups from dams given the test item, but the incidence was within the historical control data range. At scheduled termination of the offspring two male pups, from separate litters, within the 1000 mg/kg/day group, were found to have soft pale masses, one on the left lower jaw and one on the left inner cheek, confirmed histologically as squamous cell papilloma. A relationship to treatment is uncertain. It was considered within the study, that there was potential evidence to suggest that the test item may well be incidental. For reproductive / developmental toxicity for males and females a precautionary NOAEL is set at 325 mg/kg bw/day, although for all other parameters the NOAEL was 1000 mg/kg/day.