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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.09 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):
25
Dose descriptor starting point:
NOAEL
Value:
62.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
77.14 mg/m³
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 62.5 mg/kg bw/day was determined for the registered substance in a 90-day repeated dose toxicity study in rats (OECD TG 408, GLP). 


This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/0.38 m³/kg/day, the absorption rates (based on ECHA Guidance R.8 the absorption rate of the starting route is by the factor of 2 lower than the one of the end-route in case of route to route extrapolation from oral to inhalation) and the standard respiratory volume in humans/ worker respiratory volume (6.7 m³ (8 h) / 10 m³ (8 h)) and the correction factor between human and experimental exposure conditions of workers (5 working days vs. 7 days continuous exposure) of 1.4.


NOAEC corrected = 62.5 mg/kg bw/day * 1/0.38 m³/kg/day * 0.5 * (6.7 m³/10 m³) * 1.4 = 77.14 mg/m³

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
Default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
Default for workers
AF for the quality of the whole database:
1
Justification:
Sufficient quality of the database
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:
0.875 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):
100
Dose descriptor starting point:
NOAEL
Value:
62.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
87.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 62.5 mg/kg bw/day was determined for the registered substance in a 90-day repeated-dose toxicity study in rats (OECD TG 408, GLP).


Besides a correction factor between human and experimental exposure conditions of workers (5 working days vs. 7 days continuous exposure) of 1.4, no further correction factors need to be applies, as the dermal and oral absorption rates are both considered to be 100 % as a worst-case assumption.


NOAEL corrected = 62.5 mg/kg bw/day * 1.4 = 87.5 mg/kg bw/day

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
5
Justification:
Default for workers
AF for the quality of the whole database:
1
Justification:
Sufficient quality of the database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Route of original study:
Dermal
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:
no hazard identified

Additional information - workers

Justification for selection of Point Of Depature (POD) for DNEL (systemic effects)


Data evaluation


For DNEL derivation, all available data are taken into account and evaluated in order to select an adequate Point Of Departure (POD). Based on relevant NOAELs, sample DNELs (for inhalation route as example) are derived to determine a reliable and protective value.


The oral 90-day repeated dose toxicity study (OECD TG 408, GLP) is the study with the longest test duration and thus, is the likeliest study to detect all possible substance-related systemic effects with repeated application, which is the actual purpose of the testing for repeated-dose toxicity. A NOAEL of 62.5 mg/kg bw/day was derived based on histopathological findings in the salivary glands and changed biochemical parmeters at 250 mg/kg bw/day and further findings at 1000 mg/kg bw/day.



  • NOAEL (systemic) 62.5 mg/kg bw/day - OECD 408

    • NOAEC corrected = 62.5 mg/kg bw/day * 1/0.38 m³/kg/day * 0.5 * (6.7 m³/10 m³) * 1.4 = 77.14 mg/m³

    • Assessment factors: 25 (2 time-extrapolation form sub-chronic to chronic; 2.5 as default, as no substance and route specific information on toxicokinetic and toxicodynamic is available; 5 default for workers).

    • DNEL: 77.14 mg/m³/ 25 = 3.09 mg/m³




In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD TG 422) a NOAEL (systemic) for parental animals was determined to be 250 mg/kg bw/day based on organ weight changes. In the same study a NOAEL for embryo-/fetotoxicity was determined to be 62.5 mg/kg bw/day based on reduced number of pups born alive.



  • NOAEL (embryo-/fetotoxicity) 62.5 mg/kg bw/day - OECD 422

    • NOAEC corrected = 62.5 mg/kg bw/day * 1/0.38 m³/kg/day * 0.5 * (6.7 m³/10 m³) * 1.4 = 77.14 mg/m³

    • Assessment factors: 12.5 (2.5 as default, as no substance and route specific information on toxicokinetic and toxicodynamic is available, 5 default for workers). Note: no time-extrapolation is needed for the effect on reproduction as it is considered to occur within one cycle and thus independent of longer exposure duration.

    • DNEL: 77.14 mg/m³/ 12.5 = 6.17 mg/m³





  • NOAEL (systemic) 250 mg/kg bw/day - OECD 422

    • NOAEC corrected: 250 mg/kg bw/day * 1/0.38 m³/kg/day * 0.5 * (6.7 m³/10 m³) * 1.4 = 308.55 mg/m³

    • Assessment factors: 75 (6 for sub-acute to chronic, 2.5 as default, as no substance and route specific information on toxicokinetic and toxicodynamic is available, 5 default for workers)

    • DNEL: 308.55 mg/m³/ 75 = 4.11 mg/m³




In an OECD 414 rats were treated from 0 to day 19 of gestation. A maternal NOAEL (systemic) of 6.25 mg/kg bw was proposed, as at higher dose levels (62.5 and 625 mg/kg bw/day) a greater food consumption was observed. Because there were neither effects on body weight nor changes of clinical parameters, or behavior, the increased food consumption was not considered as a “critical effect” by the registrants for the DNEL derivation. In the same study, the test item caused faster growth of fetuses in all tested dose groups. However, the registrant of the substance consiered this as a possible response to the increased food intake of the dams.


At the highest dose level, at 625 mg/kg bw increased intrauterine mortality during the early phase of the development was recorded, what might indicate embryotoxic effects, so, a NOAEL of 62.5 mg/kg bw/day could be proposed:



  • NOAEL (embryo-/fetotoxicity) 62.5 mg/kg bw/day - OECD 414

    • NOAEC corrected = 62.5 mg/kg bw/day * 1/0.38 m³/kg/day * 0.5 * (6.7 m³/10 m³) * 1.4 = 77.14 mg/m³

    • Assessment factors: 12.5 (2.5 as default, as no substance and route specific information on toxicokinetic and toxicodynamic is available, 5 default for workers). Note: no time-extrapolation is needed for the effect on reproduction as it is considered to occur within one cycle, and thus independent of a longer exposure duration.

    • DNEL: 77.14 mg/m³/ 12.5 = 6.17 mg/m³




Furthermore, it was stated that there were changes in the number of ossifications points in all treated groups, that might have been related to the test item exposure. However, it was stated that there was no relationship between the dose and the effect, since an increase in the average number of ossification in groups 1 (sternum and metacarpus) and 3 (metacarpus) and a decrease in the average number of ossification points in group 2 (sternum) were observed. The decrease in the number of ossification points is considered as a change associated with the delayed development, which may be caused by toxicity. This, however, does not influence the postnatal development and is later compensated [1, 2]. An increase in the number of ossification points is a result of the intensive growth of fetuses.


Further malformations were observed in one fetus in the low dose group. However, the registrant of the substance concluded that they should not be evaluated as toxicologically relevant, because only one fetus was affected, and no such malformations occurred in animals of the higher dose groups.


Conclusion


Sample DNELs:



  • OECD 408: NOAEL (systemic) 62.5 mg/kg bw/day -> DNEL: 77.14 mg/m³/ 25 = 3.09 mg/m³

  • OECD 422: NOAEL (reproduction) 62.5 mg/kg bw/day -> DNEL: 77.14 mg/m³/ 12.5 = 6.17 mg/m³

  • OECD 422: NOAEL (systemic) 250 mg/kg bw/day -> DNEL: 308 mg/m³/ 75 = 4.11 mg/m³

  • OECD 414: NOAEL (embryo-/fetotoxicity) 62.5 mg/kg bw/day -> DNEL: 77.14 mg/m³/ 12.5 = 6.17 mg/m³


Based on reliable NOAELs form the available data, the NOAEL (systemic) of 62.5 mg/kg bw/day from a 90-day repeated-dose toxicity study was taken to derive the DNELs.


Based on the sample DNELs (see above), the NOAEL from the 90-day repeated dose toxicity study - the study with the longest test duration - was chosen as POD, because it results in most conservative DNEL, hence, it can be assumed that this DNEL is also protective for any other effects. 


 


References:


1. Draft Guidance Document On Reproductive Toxicity Testing And Assessment, OECD
November 10, 2004 (1st version)
2. R.D.Hood: Developmental and Reproductive Toxicology, Second Edition, Taylor &
Francis Group 2006

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.54 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):
50
Dose descriptor starting point:
NOAEL
Value:
62.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
27.17 mg/m³
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 62.5 mg/kg bw/day was determined for the registered substance in a 90-day repeated-dose toxicity study in rats (OECD TG 408, GLP).


This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/1.15 m³/kg/day, the absorption rates (based on ECHA Guidance R.8 the absorption rate of the starting route is by the factor of 2 lower than the one of the end-route in case of route to route extrapolation from oral to inhalation).


NOAEC corrected = 62.5 mg/kg bw/day * 1/1.15 m³/kg/day * 0.5 = 27.17 mg/m³

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
Default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
1
Justification:
Sufficient quality of the database
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:
0.31 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):
200
Dose descriptor starting point:
NOAEL
Value:
62.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
62.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 62.5 mg/kg bw/day was determined for the registered substance in a 90-day repeated-dose toxicity study in rats (OECD TG 408, GLP).


This value does not have to be corrected, as the dermal and oral absorption rates are both considered to be 100 % as a worst-case assumption.

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default for rats
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
1
Justification:
Sufficient quality of the database.
AF for remaining uncertainties:
1
Justification:
Sufficient quality of the database.
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:
0.31 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):
200
Dose descriptor starting point:
NOAEL
Value:
62.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
62.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 62.5 mg/kg bw/day was determined for the registered substance in a 90-day repeated-dose toxicity study in rats (OECD TG 408, GLP).


This value does not have to be corrected, as the oral absorption rates in human and rat are considered to be identical.

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default for rats
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
1
Justification:
Sufficient quality of the database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

For the Justification for selection of Point Of Depature (POD), pelase refer to the information given under "Additional information - workers"