Potassium trifluorozincate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

211 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

5.27 mg/m³

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:

91 µg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

6

Dose descriptor:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

483 µg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

3

Dose descriptor starting point:

NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

765 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No dermal study available. Conversion into dermal NOAEL assuming 100% oral absorption and 0.98% dermal absorption for potassium trifluorozincate

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Results of repeated-dose toxicity studies

In the 7-day inhalation range-finding study, at a concentration of 10 mg/m3 Nocolok Zn Flux, increased lung weights were observed in females, all animals showed olfactory epithelial degeneration (though less severe than at 25 mg/m3 ), and one female also showed focal alveolitis. Focal alveolitis was also found in the lungs of two animals of the low concentration group, exposed to a target concentration of 2 mg/m3 Nocolok Zn Flux.

 

In the 28-day repeated-dose inhalation toxicity study, the following pulmonary effects were observed at 8 mg/m3 Nocolok Zn Flux (high-concentration): statistically significantly increased lung weight (absolute and relative to body weight) in both sexes, increased numbers of alveolar macrophages in all animals, and focal alveolitis, similar to the alveolitis observed in the 7-day study, in two male animals. No treatment-related changes were observed at the 0.5 mg/m3 and 2 mg/m3 concentration level. 2 mg/m3 (actual concentration: 2.16 mg/m3) and 8 mg/m3 (actual concentration: 8.41 mg/m3) were considered to be the NOAEC for local and systemic effects, respectively.

Sub-chronic inhalation exposure to potassium trifluorozincate (OECD 413, GLP) resulted in treatment-related changes in the nose and lungs, consisting of reversible, slight degenerative effects on the olfactory mucosa (nose) and multifocal accumulation of alveolar macrophages accompanied by increased weight of the lungs. Since the changes in the nose were also observed – although at a lower incidence – at the low concentration level of 1.09 mg/m3, this concentration was considered to be the LOAEC in rats after sub-chronic (90‑day) exposure by inhalation to Nocolok Zn Flux.

 

In the combined oral repeated-dose toxicity study with reproduction/developmental toxicity screening test, two females in the high-dose group (75 mg/kg bw/day) and one male in the mid-dose group (25 mg/kg bw/day) died. Body weights and feed consumption were statistically significantly decreased in males of the high-dose group. Total protein and albumin plasma concentrations were decreased in high-dose rats of both sexes and in mid-dose males. Glucose in plasma was decreased in high-dose females and the relative weights of the kidneys and adrenals were increased in high-dose males. The stomach of several mid- and high-dose rats macroscopically showed red or pale discoloration and/or mucosal swelling. Microscopic examination showed a range of pathological changes in the stomach in all test groups. Inflammation, hyperaemia and epithelial vacuolization was still present in several low-dose animals.Based on mortality and decreased plasma levels of total protein and albumin in the mid- and high-dose group, the NOAEL for systemic effects was placed at 7.5 mg/kg bw/day, the lowest dose tested. Because of pathological changes in the stomach in all test groups, the NOAEL for local effects was below 7.5 mg/kg bw/day.

 

DNEL derivation

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. The substance is classified for acute oral and inhalation toxicity. No short-term DNELs are deemed necessary because the long-term DNELs are considered to ensure sufficient protection after peak exposure. However, due to the observed local effects in the lung after repeated inhalation exposure, a short-term inhalation DNEL for local effects has been derived.

The substance is not classified as irritating to the skin, but causes irritation to the eyes. A 10% (w/v) dilution of the substance in acetone/olive oil (v/v 4:1), which was the maximum, technically attainable concentration, was not sensitizing to the skin. Therefore, no local dermal DNELs need to be derived.

Since only a sub-chronic inhalation and a sub-acute oral toxicity study are available, route-to-route extrapolation is needed to derive the DNEL for systemic effects by the dermal route.

As described in the toxicokinetic statement, 100% absorption is assumed for the oral and inhalation route and 0.98% absorption is assumed for the dermal route in workers. As there is no consumer use for KZnF3, no DNELs for the general population were calculated.

 

Worker DNELs

(i) Long-term DNEL - systemic effects, inhalation

 

Long-term – inhalation, systemic effects (based on sub-chronic inhalation toxicity study with rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 10.48 mg/m3	No adverse systemic effects were observed at the highest concentration tested in the sub-chronic inhalation study.
Step 2) Modification of starting point	0.75     0.67	Correction for duration of exposure (6 hour to 8 hour exposure)   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.
Modified dose-desciptor	10.48 * 0.75 * 0.67 = 5.27 mg/m3
Step 3) Assessment factors
Interspecies	2.5	For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
Intraspecies	5	Default assessment factor for workers.
Exposure duration	2	Extrapolation to chronic exposure based on a sub-chronic toxicity study.
Dose response	1
Quality of database	1
DNEL	Value
	5.27 / (2.5 x 5 x 2 x 1 x 1) = 5.27 / 25 = 211 µg/m3

 

(ii)       Long-term DNEL - local effects, inhalation

a)        Long-term DNEL, local effects, inhalation based on 90-day inhalation study with KZnF3

Long-term – inhalation, local effects (based on sub-acute inhalation toxicity study with rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 1.09 mg/m3	Inhalation exposure to potassium trifluorozincate (OECD 413, GLP) resulted in treatment-related changes in the nose and lungs, consisting of reversible, slight degenerative effects on the olfactory mucosa (nose)and multifocal accumulation of alveolar macrophages accompanied by increased weight of the lungs. Since the changes in the nose were also observed – although at a lower incidence – at the low concentration level of 1.09 mg/m3, this concentration was considered to be the LOAEC in rats after sub-chronic (90‑day) exposure by inhalation to Nocolok Zn Flux. Although in the context of the study, the lowest dose level of 1.09 mg/m3 does not represent an NOAEC, but a LOAEC, the findings in the nose were of transient nature and it is known that ratsare more sensitive to the effects of nasal olfactory irritants compared to humans. In a study of Frederick et al (1998) a scientific basis for interspecies extrapolation of nasal olfactory irritants from rodents to humans is provided.By using a series of short-termin vivostudies,in vitrostudies with nasal explants, and computer modeling, regional nasal tissue dose estimates were made and comparisons of tissue doses between species were conducted. The results of thesecalculationsindicate that the olfactory epithelium of the human nasal cavity is exposed to two- to threefold lower tissue concentrations of a representative inhaled organic acid vapor, acrylic acid, than the olfactory epithelium of the rodent nasal cavity when the exposure conditions are the same. The increased susceptibility toeffects on the olfactory mucosaof rats relative to humans may be attributed to the large rodent olfactory surface area (greater than 50% of the nasal cavity) and its highly susceptible location (particularly, a projection of olfactory epithelium extending anteriorly in the dorsal meatus region). In contrast, human olfactory epithelium occupies a much smaller surface area (less than 5% of the nasal cavity), and it is in a much less accessible dorsal posterior location (Frederick et al, 1998). Pemberton et al. (2012) used model calculations of Methyl methacrylate metabolites to estimate a rat-human dosimetric adjustment factor (DAF) of 3 for olfactory effects, consistent with observed lower sensitivity in humans compared to rats. The authors pointed out that the 3.0 estimate for the DAF is in itself conservative, as it does not take into account that the breathing pattern in humans is oronasal compared to obligatory nasal in rats. In conclusion, humans are considered less sensitive for olfactory effects compared to rats and therefore it is considered appropriate to use the concentration of 1.09 mg/m3 as a NOAEC for subchronic expsure of humans by inhalation.
Step 2) Modification of starting point	0.75     0.67	Correction for duration of exposure (6 hour to 8 hour exposure).   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10m3).
Modified dose-desciptor	1.09 * 0.75 * 0.67 = 0.55 mg/m3
Step 3) Assessment factors
Interspecies	1	No factor for allometric scaling is needed in case of inhalation exposure. For respiratory (local) toxicity effects after inhalation of particles of most metal-containing substances in the respirable range, 1-5 µm, rats seem to be more susceptible to toxicity effects than primates or humans (Oberdörster, 1995; Mauderly, 1997; ILSI, 2000; Nikula et al., 2001; Greim and Ziegler-Skylakakis, 2007). As rats are the most sensitive animal species to the inhalation effects of inorganic particulates, further toxicodynamic adjustments are not needed.
Intraspecies	3	This assessment factor is introduced since it is expected that a greater variability in response from the most to least sensitive human would be seen, relative to an experimental animal population. The distributions of human data for various toxicokinetic and toxicodynamic parameters were examined in datasets from healthy adults of both sexes, as well as in limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension (Hattis et al. 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus 1998). Analysis and comparison of these datasets by an ECETOC Task Force resulted in a numerical value that represents the total intra-species variability for toxicokinetic and toxicodynamic parameters. For systemic effects, a value of 5 is recommended for the general population, so as to take this variability into account. For the more homogeneous worker population, where normal hygiene practices and risk management are in place, an assessment factor of 3 is recommended. Details of the calculations can be found in Section 5.4 of the ECETOC 2003 Report 86. The value of 3 for workers is supported by the Hattis and Silver (1994) analyses of the variability in toxicodynamic responses for local effects (skin effects, eye irritation and a number of respiratory effects such as pulmonary function and pulmonary discomfort). Therefore, an overall intraspecies factor of ≤ 3 seems appropriate for workers when local respiratory effects by inorganic metal compounds that do not undergo metabolism are considered (Hattis et al., 1987; Hattis and Silver, 1994; Renwick and Lazarus, 1998 ECETOC (2010).
Exposure duration	2	Extrapolation from sub-chronic to chronic exposure.
Dose response	1
Quality of database	1
DNEL	Value
	0.55 / (1 x 3 x 2 x 1 x 1) = 0.55 / 6 = 91 µg/m3

 

b)      Long-term DNEL, local effects, inhalation based on available OELs for zinc and fluoride

Regarding selection of the value to be used for the risk characterisation it is noted that according to the REACH regulation ‘DNELs’ already derived for the substance under consideration in an EU-RAR should be considered. In Annex I of REACH, section 0.5, it is explicitly mentioned that:

“…. Where available and appropriate, an assessment carried out under Community legislation (e. g. risk assessments completed under Regulation (EEC) No 793/93) shall be taken into account in the development of, and reflected in, the chemical safety report. Deviations from such assessments shall be justified”.

For potassium trifluorozincate no official Occupational Exposure Limits (OELs) are available. Under physiological conditions, KZnF3 will dissociateto form its consituent ions, potassium, zinc and fluoride. The local and systemic effects of exposure to the substance will be driven by fluoride and zinc ions.

 

The SCOEL have recommended (1998) IOEL values of 1.5 mg/m3 (8-hour TWA) for inorganic fluorides (as F-) and 2.5 mg/m3 (15-minute STEL) specifically for HF. They concluded that the 8-hour TWA was sufficient to protect against systemic effects (fluorosis) and that the STEL value for HF was adequate to limit peaks of exposure which could result in irritation.

In several countries there are occupational limit values for zinc oxide fumes and for dust (see Table below). Dust exposure is relevant for occupational exposure scenarios when commercial grades of zinc oxide are handled.

 

Table: Occupational limit values for zinc oxide  

Country / organisation	8-hour TWA (mg/m^3)	15-min STEL (mg/m^3)	References
USA	5 (fumes^1) 10 (dust^2)	10 (fumes) ceiling	ACGIH (1991) (guidance values)
USA	5 (fumes) 15 (dust; total) 5 (dust; respirable)		OSHA (1989) (legal limit values)
The Netherlands	5 (fumes)		SZW (1997)
Germany^3)	5 (fumes) 6 (dust)		DFG (1997)
UK	5 (fumes) 10 (dust)	10	HSE (1998)
Sweden	5 (fumes)		National Board of Occupational Safety and Health, Sweden (1993)
Denmark	4 (fumes) 10 (dust)		Arbejdstilsynet (1992)

1) Operational definition for this risk assessment: zinc fumes are formed from volatilised zinc/zinc oxide by condensation. Ultrafine fume (diameter < 0.1 µm) is known to be generated only in operations involving cutting or welding of galvanised structures, where the zinc coating will be subjected to a flame temperature of close to 1,000ºC.

2) Operational definition for this risk assessment: zinc dust is defined as particles of zinc with an average diameter of > 0.1 microns.

3) Fumes measured as respirable aerosols

 

The occupational limit values as described above are predominantly based on the occurrence of metal fume fever and irritation. However according to the EU-RAR of zinc oxide, more recent studies on metal fume fever, indicate effects at concentrations at the level of the current OELs, which should be taken into account for the establishment of OELs. The OEL for zinc oxide is on the agenda of the SCOEL committee and the preparation of the recommendation is ongoing. Recently, the current OELs were reviewed by the German MAK Comission (2014) resulting in a MAK value for zinc of 0.1 mg/m3 for the respirable fraction of zinc compounds.

The systemic IOELfor fluoride is 1.5 mg/m3 and is therefore considered less critical than the occupational exposure limit of 0.1 mg/m3 for zinc that

has been derived. Correcting the TWA value of 0.1 mg/m3 for the zinc content of potassium trifluorozincate results in a DNEL of 0.25 mg/m3 (molecular weight fraction for zinc is 40.7%).

c)      Summary and conclusions: long-term DNEL, local effects, inhalation

For prolonged inhalation exposure of workers to KZnF3, no data on possible health effects are available.Under physiological conditions, potassium trifluorozincate will dissociateto form its consituent ions, potassium, zinc and fluoride. The local and systemic effects of exposure to the substance will therefore bedriven by fluoride and zinc ions.

The SCOEL have recommended (1998) IOEL values of 1.5 mg/m3 (8-hour TWA) for inorganic fluorides (as F-) and 2.5 mg/m3 (15-minute STEL) specifically for HF. They concluded that the 8-hour TWA was sufficient to protect against systemic effects (fluorosis) and that the STEL value for HF was adequate to limit peaks of exposure which could result in irritation.

For zinc oxide data on possible health effects during production and processing of zinc are available from the zinc industry. The critical effects for fine and ultrafine zinc oxide particles are the occurrence of zinc fever and an increase in inflammation markers. Taking into account these effects, an exposure limit for zinc of 0.1 mg/m3 for the respirable fraction of zinc compounds was obtained (MAK Commission 2014). Correcting the TWA value of 0.1 mg/m3 for the zinc content of KZnF3 would result in a DNEL of 0.25 mg/m3.

In a well-conducted 90-day inhalation study (TNO, 2013) rats were exposed nose-only to particulate aerosols of KZnF3 in the concentration of 0, 1.09, 3.05, and 10.5 mg/m3. Local effects were observed in the nose and lungs,consisting ofreversible, slight degenerative effects on the olfactory mucosa (nose)and multifocal accumulation of alveolar macrophages accompanied by increased weight of the lungs. No systemic effects were observed. The low dose (1.09 mg/m3) was considered as a NOAEC. For the risk assessment this NOAEC of 1.09 mg/m3 is used as starting point concerning effects of KZnF3 after repeated inhalation exposure.It is known that ratsare more sensitive to the inhalation effects of particulates and therefore the NOAEC from the animal data gives a very precautious value for the evaluation of this endpoint. On that background it was considered appropriate to use reduced factors for inter- and intraspecies extrapolation. The critical exposure level calculates then to 0.091 mg/m3.

As a precautionary principle, the lower value for KZnF3 should be selected as DNEL for local effects. Accordingly, a concentration of 91 µg/m3 is derived as long-term DNELs for local effects in workers exposed by inhalation to potassium trifluorozincate.

(iii)      Acute DNEL - local effects, inhalation

Short-term – inhalation, local effects (based on sub-acute inhalation toxicity study with rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 2.16 mg/m3	Based on treatment-related changes in the lungs of animals of the 8 mg/m3 concentration group of the 28-day repeated dose inhalation study. The NOAEC in this 28-day study was 2.16 mg/m3. In the 7-day dose range-finding study, slight focal alveolitis was observed at 2 mg/m3. The absence of pulmonary changes at this concentration at the end of the 28-day study indicates full reversibility of the focal alveolitis despite continued exposure to the test substance. Therefore, it is considered justified to use the NOAEC of the 28-day study as dose-descriptor for derivation of the short-term DNEL for local effects.
Step 2) Modification of starting point	0.67	Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.
Modified dose-desciptor	2.16 * 0.67 = 1.45 mg/m3
Step 3) Assessment factors
Interspecies	1	No factor for allometric scaling is needed in case of inhalation exposure. For respiratory (local) toxicity effects after inhalation of particles of most metal-containing substances in the respirable range, 1-5 µm, rats seem to be more susceptible to toxicity effects than primates or humans (Oberdörster, 1995; Mauderly, 1997; ILSI, 2000; Nikula et al., 2001; Greim and Ziegler-Skylakakis, 2007). As rats are the most sensitive animal species to the inhalation effects of inorganic particulates, further toxicodynamic adjustments are not needed.
Intraspecies	3	An overall intraspecies factor of ≤ 3 seems appropriate for workers when local respiratory effects by inorganic metal compounds that do not undergo metabolism are considered (Hattis et al., 1987; Hattis and Silver, 1994; Renwick and Lazarus, 1998; ECETOC 2010).
Exposure duration	1	No correction for exposure duration is needed since an acute DNEL is derived and, therefore, correction for a longer exposure period is not warranted.
Dose response	1
Quality of database	1
DNEL	Value
	1.45 / (1 x 3 x 1 x 1 x 1) =1.45 / 3 = 483 µg/m3

(iv)      Long-term DNEL - systemic effects, dermal

Long-term – dermal, systemic effects (based on sub-acute oral toxicity study with rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 7.5 mg/kg bw/day	Based on mortality and decreased plasma levels of total protein and albumin.
Step 2) Modification of starting point	100/0.98	Conversion into dermal NOAEL (in mg/kg bw/day) assuming 100% oral absorption and 0.98% dermal absorption for pure KZnF3.
Modified dose-desciptor	7.5*(100/0.98) = 765 mg/kg bw
Step 3) Assessment factors
Interspecies	4 x 2.5	Default assessment factors for allometric scaling and remaining interspecies differences.
Intraspecies	5	Default assessment factor for workers
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study.
Dose response	1
Quality of database	1
DNEL	Value
	765 / (4 x 2.5 x 5 x 6 x 1 x 1) = 765/300 = 2.6 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 µg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

7.5 mg/kg bw/day

Acute/short term exposure

DNEL related information

Additional information - General Population

As there is no consumer use for KZnF3, no inhalation and dermal DNELs for the general population were calculated. However, the deposition of KZnF3 onto soil or vegetation may contribute to the total zinc and fluoride intake of the general public, therefore, a long-term oral DNEL for the general population was calculated. No route-to-route extrapolation had to be performed since the DNEL has been derived from a NOAEL observed in a sub-acute oral toxicity study.

Long-term – oral, systemic effects (based on sub-acute oral toxicity study with rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 7.5 mg/kg bw/day	Based on mortality and decreased plasma levels of total protein and albumin.
Step 2) Modification of starting point	-
Step 3) Assessment factors
Interspecies	4 x 2.5	Default assessment factors for allometric scaling and remaining interspecies differences.
Intraspecies	10	Default assessment factor for general population
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study.
Dose response	1
Quality of database	1
DNEL	Value
	7.5 / (4 x 2.5 x 10 x 6 x 1 x 1) = 7.5/600 =12.5 µg/kg bw/day