Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 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:
Absorption oral compared to dermal assumed to be identical
AF for dose response relationship:
1
Justification:
Default factor if the starting point is a NOAEL.
AF for differences in duration of exposure:
6
Justification:
For extrapolation of exposure duration subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Differences rat vs. human
AF for other interspecies differences:
1
Justification:
A factor 2.5 is suggested by ECHA Guidance, Chapter R.8, 2012 for remaining interspecies differences, but justified deviations are possible. Interspecies differences are already covered by the principle of allometric scaling; see ECETOC TECHNICAL REPORT No. 110, 2010. With the lack of adverse effects and no indication of systemic availability in both the subacute toxicity study and the developmental study there is no evidence of a mode of action that would lead to interspecies differences higher than based on allometric scaling. Regarding toxicity of hydrolysis products (cf. chapter hydrolysis): hydrolytic degradation is independent from e.g. enzymatic processes for which species differences could be expected, therefore also the theoretical hydrolytic degradation does not point to a higher interspecies variability.
AF for intraspecies differences:
5
Justification:
Default factor for intraspecies differences for workers
AF for the quality of the whole database:
1
Justification:
The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

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:
medium hazard (no threshold derived)

Additional information - workers

For Zinc hexacyanocobaltate(III), tertiary butyl alcohol/polypropylene glycol complex the most relevant routes of exposure in an occupational setting are dermal and inhalation.

Zinc hexacyanocobaltate(III), tertiary butyl alcohol/polypropylene glycol complex proved to have a low toxicity after acute oral and inhalation exposure (LD50 > 2000 mg/kg bw, OECD 401; LC50 > 5790 mg/m³, OECD 403 ). No test substance related adverse effects were observed after repeated oral administration (EU Method B.7) and after developmental toxicity testing (OECD TG 414), thus for both studies the NOAEL was 1000 mg/kg. No sensitisation potential was observed in a Guinea Pig Maximation test (OECD 406). Overall, based on the available tests no systemic availability can be concluded after oral, dermal and inhalation exposure.

After acute inhalation unspecific signs that might be indicative for a local irritant effect (shallow respiration, slight increase in lung weights, impairment of general condition) were observed at the limit concentration of 5790 mg/m³. An irritant potential of the substance is confirmed in an in vivo eye irritation/corrosion experiment (OECD 405), that justifies classification as eye damage Cat. 1. On the other hand, no findings at all (Draize scores all zero) were reported from a skin irritation test (OECD 404). Taken together, a respiratory irritation potential for higher concentrations cannot be excluded and a DNEL for local effects after inhalative exposure has to be derived for workers.

For risk assessment a DNELlong-term, systemic for workers for dermal exposure is delineated from the NOAEL of the oral repeated dose study according to ECHA Guidance, Chapter R.8, 2012: 

Oral NOAEL (rat) from a subacute toxicity study:                                1000 mg/kg bw/day

Absorption oral compared to dermal assumed to be identical:              1

For interspecies differences rat vs. human (allometric scaling):            4

1For remaining interspecies differences:                                                1

For intraspecies differences in workers:                                                 5

For extrapolation of exposure duration subacute to chronic:                6

For reliability of dose-response:                                                            1

For quality of whole database:                                                               1

Overall factor:                                                                                      120

Worker DNELlong-term, systemic for oral/dermal exposure:      8.3 ~ 8mg/kg bw/day

                              

 

1A factor 2.5 is suggested by ECHA Guidance, Chapter R.8, 2012 for remaining interspecies differences, but justified deviations are possible. Interspecies differences are already covered by the principle of allometric scaling; see ECETOC TECHNICAL REPORT No. 110, 2010. With the lack of adverse effects and no indication of systemic availability in both the subacute toxicity study and the developmental study there is no evidence of a mode of action that would lead to interspecies differences higher than based on allometric scaling. Regarding toxicity of hydrolysis products (cf. chapter hydrolysis): hydrolytic degradation is independent from e.g. enzymatic processes for which species differences could be expected, therefore also the theoretical hydrolytic degradation does not point to a higher interspecies variability.

 

No DNELlong-term, systemic is delineated for inhalation exposure for workers, because an acute inhalation study with the substance indicates as leading health effect after inhalation exposure solely an unspecific local effect and no systemic effect can be concluded after oral, dermal and inhalation exposure. Regarding local effects after inhalation exposure it needs to be taken into consideration that without a repeated dose inhalation study, it is currently not possible to determine irritation thresholds and DNELs for local effects after inhalation exposure. Therefore, a different approach of determination of DNELlong-term,local for inhalation was chosen.

For Zinc hexacyanocobaltate(III), tertiary butyl alcohol/polypropylene glycol complex, the possible generation of the substance’s hydrolysis products zinc chloride, zinc hexacyanocobaltate and the organic components tertiary butyl alcohol and polypropylene glycol (cf. chapter hydrolysis) has to be taken into account. In fact, the effects after acute (4 hours) inhalation exposure to a concentration of 5790 mg/m³ resemble basically those of Zinc and its inorganic compounds, documented by the German scientific expert committee “MAK Comission” in 2010 (currently only available in german in “The MAK Collection for Occupational Health and Safety”, DFG, Germany), which takes also into account EU Risk assessment reports of the various Zinc species, 2004 (European Commission, Joint Research Center, Institute for Health and Consumer Protection, European Chemicals Bureau, Ispra, Italy). For instance, the LC50 of Zinc (metallic) and Zinc oxide are in the same order of magnitude as the LC50 of Zinc hexacyanocobaltate(III), tertiary butyl alcohol/polypropylene glycol complex, but also lower and higher LC50 were reported, depending mainly on the water solubility of the zinc species. The MoA (Mode of Action) reveals to be for zinc and its inorganic compounds a local irritant effect with a subsequent inflammatory process to the lung. Based on the available data this Mode of Action could be also true for Zinc hexacyanocobaltate(III), tertiary butyl alcohol/polypropylene glycol complex. Clinical signs included effects on ventilation and on general condition immediately after exposure, but were for both substances reversible during a 14-days postexposure observation.

 

Zinc and its inorganic compounds*

Zinc hexacyanocobaltate(III), tertiary butyl alcohol/polypropylene glycol complex

Zn: LC50 (4 h, rat, dust aerosol, OECD 403) > 5410 mg/m³
(> 5410 mg Zn/m³) (MMAD 6.2 µm, GSD 1.7)

Cited from EU RAR, 2004
“Clinical signs after exposure consisted of visually decreased breathing rate (first 2 days) and sluggishness in all animals (only shortly after exposure) and blepharospasm in two male and two female rats (first day). No mortalities occurred during the 14-day observation period. Abnormalities at necropsy consisted of lung changes (white spots on three or all five lung lobes) in two males and four females (Arts, 1996).”

Furthermore, in MAK documentation, 2010, inflammatory changes in the lung (respective parameters in BAL fluid increased), were reported 24 hours after a single 3-hours exposure to zinc oxide at 2.5 and 5 mg/m³ (2 and 4 mg Zn/m³).

ZnO: LC50 (4 h, rat) > 5700 mg/m³ (> 4579 mg Zn/m³)
ZnCl2: LC50 (10 min., rat) < 1975 mg/m³ (<940 mg Zn/m³)
Zn(C18H35O2)2 (distearat): LC50 (1 h, rat) > 200000 mg/m³ (> 20680 mg/m³)

LC50 (4 h, rat, dust aerosol, OECD 403)
> 5790 mg/m³ (approx. > 1346 mg Zn/m³; calculation based on mean molecular weight of the substance) (MMAD 2.23 µm, GSD 2.74)

see chapter Acute Toxicity: “Treatment-related clinical signs included lethargy, cold to touch, semi closed eyes and shallow respiration for up to 4 hours after exposure, additionally hunched posture up to day 2. After exposure on Day 1 and 2, treated animals lost slightly more body weight than the controls, but this effect was resolved by the end of the study. The only finding at necropsy was a slight increase in mean lung weights.”
 

*Values from “Zinc and its inorganic compounds”, The MAK Collection for Occupational Health and Safety”, 2010, DFG, Germany

For Zinc hexacyanocobaltate(III), tertiary butyl alcohol/polypropylene glycol complex, an organometallic substance of variable composition with a mean molecular weight of 1125 g/mol, it is not assumed that the zinc content is totally released after entering the pulmonary tract, but without further information on the processes after inhalation the DNELlong-term, local for workers is based on the worst case assumption that zinc would be fully bioavailable after inhalation. Based on that worst case assumption the occupational exposure limit (referring to an 8-hour exposure period) derived from the German MAK Commission of zinc and its anorganic compounds (CAS no. 7440-66-6) was set as DNELlong-term, local for workers forZinc hexacyanocobaltate(III), tertiary butyl alcohol/polypropylene glycol complex. This value is 0.1 mg Zn/m³ for the respirable fraction and 2 mg Zn/m³ for the inhalable fraction. This exceedingly conservative approach was employed to reach a high level of protection without the need of generating further information, in view of animal welfare. This approach is in line with ECHA Guidance, chapter R.8, 2012, which states that a national occupational exposure limit could be used as surrogate for a DNEL.

MAK establishes a ceiling limit value of 4 mg Zn/m3 for the inhalable fraction and 0.4 mg Zn/m3 for the respirable fraction for zinc and its inorganic compounds. These ceiling limits were used as surrogate DNELacute/short term, local.

Additionally, substances with R41/Eye Dam. 1 have to be allocated to the moderate hazard category (ECHA Guidance, Part E, 2012).

General Population - Hazard via inhalation route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 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):
240
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Absorption oral compared to dermal assumed to be identical
AF for dose response relationship:
1
Justification:
Default factor if the starting point is a NOAEL.
AF for differences in duration of exposure:
6
Justification:
For extrapolation of exposure duration subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Differences rat vs. human
AF for other interspecies differences:
1
Justification:
A factor 2.5 is suggested by ECHA Guidance, Chapter R.8, 2012 for remaining interspecies differences, but justified deviations are possible. Interspecies differences are already covered by the principle of allometric scaling; see ECETOC TECHNICAL REPORT No. 110, 2010. With the lack of adverse effects and no indication of systemic availability in both the subacute toxicity study and the developmental study there is no evidence of a mode of action that would lead to interspecies differences higher than based on allometric scaling. Regarding toxicity of hydrolysis products (cf. chapter hydrolysis): hydrolytic degradation is independent from e.g. enzymatic processes for which species differences could be expected, therefore also the theoretical hydrolytic degradation does not point to a higher interspecies variability.
AF for intraspecies differences:
10
Justification:
Default factor for intraspecies differences for the general population.
AF for the quality of the whole database:
1
Justification:
The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

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:
4 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):
240
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default factor if the starting point is a NOAEL.
AF for differences in duration of exposure:
6
Justification:
For extrapolation of exposure duration subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Differences rat vs. human
AF for other interspecies differences:
1
Justification:
A factor 2.5 is suggested by ECHA Guidance, Chapter R.8, 2012 for remaining interspecies differences, but justified deviations are possible. Interspecies differences are already covered by the principle of allometric scaling; see ECETOC TECHNICAL REPORT No. 110, 2010. With the lack of adverse effects and no indication of systemic availability in both the subacute toxicity study and the developmental study there is no evidence of a mode of action that would lead to interspecies differences higher than based on allometric scaling. Regarding toxicity of hydrolysis products (cf. chapter hydrolysis): hydrolytic degradation is independent from e.g. enzymatic processes for which species differences could be expected, therefore also the theoretical hydrolytic degradation does not point to a higher interspecies variability.
AF for intraspecies differences:
10
Justification:
Default factor for intraspecies differences for the general population.
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population