Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.27 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
750
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As a point of departure for the inhalation long term DNEL, the LOAEL of 100 mg/kg bw/day from the oral prenatal developmental toxicity study in rabbits was chosen. In the absence of any experimental absorption data for both the starting route (oral) and the end route (inhalation), the worst case assumption was made, assuming a limited absorption for the oral route, leading to a low (conservative) internal NOAEL. It is proposed, in the absence of route-specific information on the starting route, to include a default factor of 2 (50% absorption is assumed for oral absorption, and 100% for inhalation) in accordance with ECHA guidance document R.8 (ECHA, 2012). Furthermore, a higher end of assessment factor of 10 is applied for dose-response relationship, since the LOAEL is used as the dose descriptor and given the sensitivity of the effects (major foetal malformations in the tested species).

AF for dose response relationship:
10
Justification:
The starting point is a LOAEL with major foetal malformations
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
NA for inhalation
AF for other interspecies differences:
1
Justification:
Addressed by modification of starting point
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
1
Justification:
Data available on the test substance appropriate for the tonnage band
AF for remaining uncertainties:
2.5
Justification:
Default value
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:
0.08 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 800
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As a point of departure for the dermal long term DNEL, the LOAEL of 100 mg/kg bw/day from the oral prenatal developmental toxicity study in rabbits was chosen. A maximal absorption was already occurred by the oral route and no additional correction factor was introduced.

Based on the inherent properties of the registered substance, the absence of dermal absorption is likely (see section 7.1). However, in the absence of measured data on dermal absorption, ECHA guidance document R.7c (ECHA, 2017) suggests the assignment of either 10% (MW > 500 and log Pow < -1 or > 4) or 100% default dermal absorption rates (ECHA, 2017). For the purpose of risk assessment for the registered substance, a conservative dermal absorption factor of 100% is applied. However, the currently available scientific evidence on dermal absorption of some metals indicates that lower figures than the lowest proposed default value of 10% could be expected (HERAG, 2017). A default dermal absorption factor of 0.1% is proposed for metal cations from dry (dust) exposure and 1.0% from exposure to liquid/wet media based on the HERAG fact sheet (HERAG, 2017).

AF for dose response relationship:
10
Justification:
The starting point is a LOAEL with major foetal malformations
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic
AF for interspecies differences (allometric scaling):
2.4
Justification:
Rabbit to human
AF for other interspecies differences:
1
Justification:
Addressed by modification of starting point
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
1
Justification:
Data available on the test substance appropriate for the tonnage band
AF for remaining uncertainties:
2.5
Justification:
Default value
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:
no hazard identified

Additional information - workers

Rationale for a key study selection for DNELs for slags, ferromanganese-manufg.

The main in vivo mammalian toxicity studies for the registered substances, were all guideline compliant studies conducted in accordance with GLP, and are summarised in the below table. In the key 90-day oral (gavage) repeated dose toxicity study (Cooper, 2016; IUCLID section 7.5.1), administration of the read-across substance silico-manganese slag (SiMn slag) to Sprague-Dawley rats at doses up to 1000 mg/kg/day did not cause any systemic toxicity. The NOAEL for systemic toxicity was considered to be 1000 mg/kg bw/day.

There are two prenatal developmental toxicity studies for the registered substance slags, ferromanganese-manufg. (FeMn Slag). In the rat study (Thacker, 2016;IUCLID section 7.8.2), administration of the test material was well tolerated, with no critical effects in dams up to the limit dose. There was no adverse effect on embryo-foetal survival, development or growth. Therefore, the NOAEL for maternal and developmental toxicity was considered to be 1000 mg/kg bw/day in this study. Whereas in rabbits (Stannard, 2020; IUCLID section 7.8.2), despite no clear effects of treatment in the maternal animals up to the highest dose given, as reflected in the NOAEL for maternal toxicity at 800 mg/kg/day, there was a slightly increased incidence of post implantation loss at 800 mg/kg/day. Therefore, the dose level of 300 mg/kg bw/day was concluded to be the NOAEL for embryo-foetal survival. Confounding vehicle effects were apparent in the maternal animals at all dose levels, including controls. There was an increased overall incidence of major visceral foetal abnormalities in all treated groups, with minor skeletal ossification delays also apparent at 300 or 800 mg/kg bw/day. Therefore, a NOAEL for embryo-foetal development was not established. The aetiology of these foetal malformations was unclear.

Comparisons of the prenatal developmental toxicity studies indicates a potential inter-species difference in the sensitivity of foetal development towards oral administration of FeMn slag. However, the bioanalysis for FeMn Slag in rats showed that all plasma samples analysed for proof of absorption were found to have concentrations less than the lower limit of quantification for the elements manganese, silicon, aluminium and barium (Cooper, 2019; IUCLID section 7.1.1). There is substantial evidence to support the registered substance is poorly absorbed via the oral route (see IUCLID section 7.1). This is supported by a lack of systemic effects in in vivo studies in rats. Therefore, the mechanism(s) responsible for the overt foetal toxicity seen in the prenatal study in rabbits remains unknown.

The effects on foetal development were only observed in rabbits with confounding vehicle effects (see more discussion in section 7.8), with morphological changes being disparate and without a clear dose-response. Furthermeore, there were no maternal or developmental effects of prenatal exposure to the registered substance in rats.  This is considered to lower the concern for human relevance but based on the findings in the rabbit study, CLP classification as Category 2 (H361) for developmental toxicity has been assigned for FeMn slag, reflecting the uncertainty in the evidence from the rabbit prenatal developmental toxicity study. Consequently, the LOAEL from the prenatal developmental toxicity study in rabbits (i.e. 100 mg.kg bw/day) is used for DNEL derivations for the human health risk assessment. This precautionary measure will be reviewed once any new evidence becomes available.

Summary of in vivo mammalian toxicity studies

Test substance

Study (Reference; Klimisch)

OECD TG

Duration of exposure

Route of
administration

Species, strain

No. of animals / group

Dose levels [mg/kg bw/day] (vehicle)

Critical effects

NOAEL
[mg/kg bw/day]

SiMn slag

90-day repeated dose toxicity study in rats (Cooper, 2016; 2#1)

408 (GLP)

90 day

Gavage

Sprague-Dawley rats

10/sex/dose

10, 100, 1000 (corn oil)

No critical systemic effects. Localised histopathological changes in the glandular and non-glandular stomach at 100 and/or 1000 mg/kg bw/day, considered to be attributed to the physical properties of the test material.

Systemic: 1000

FeMn Slag

Prenatal developmental toxicity study in rats (Thacker, 2016; 1)

414 (GLP)

14 days (GD 6 - 19)

Gavage

Sprague-Dawley rats

20 F/dose

100, 330, 1000 (corn oil)

No critical effects

Maternal: 1000
Developmental: 1000

FeMn Slag

Prenatal developmental toxicity study in rabbits (Stannard, 2020; 2)

414 (GLP)

23 days (GD 6 - 28)

Gavage

New Zealand White rabbits

22 F/dose

100, 300, 800 (corn oil)

↑ (Slight) post-implantation loss at 800 mg/kg bw/day, ↑ incidence of major visceral abnormalities in foetuses at ≥ 100 mg/kg bw/day with minor skeletal ossification delays at ≥ 300 mg/kg bw/day

Maternal: 800
Embryo-survival: 300
Developmental: Not established#2

#1 The Klimisch score for this study is due to read-across from an analogue substance, not due to the reliability of the study.

#2 In view of the nature and incidence of major foetal abnormalities detected in all treated groups, which exceeded the concurrent control and historical control data ranges, a NOAEL for embryo-foetal development was not established.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 500
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As a point of departure for the inhalation long term DNEL, the LOAEL of 100 mg/kg bw/day from the oral prenatal developmental toxicity study in rabbits was chosen. In the absence of any experimental absorption data for both the starting route (oral) and the end route (inhalation), the worst case assumption was made, assuming a limited absorption for the oral route, leading to a low (conservative) internal NOAEL. It is proposed, in the absence of route-specific information on the starting route, to include a default factor of 2 (50% absorption is assumed for oral absorption, and 100% for inhalation) in accordance with ECHA guidance document R.8 (ECHA, 2012). Furthermore, a higher end of assessment factor of 10 is applied for dose-response relationship, since the LOAEL is used as the dose descriptor and given the sensitivity of the effects (major foetal malformations in the tested species).

 

AF for dose response relationship:
10
Justification:
The starting point is a LOAEL with major foetal malformations
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
NA for inhalation
AF for other interspecies differences:
1
Justification:
Addressed by modification of starting point
AF for intraspecies differences:
10
Justification:
Default value for general population
AF for the quality of the whole database:
1
Justification:
Data available on the test substance appropriate for the tonnage band
AF for remaining uncertainties:
2.5
Justification:
Default value
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:
0.03 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3 600
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As a point of departure for the dermal long term DNEL, the LOAEL of 100 mg/kg bw/day from the oral prenatal developmental toxicity study in rabbits was chosen. A maximal absorption was already occurred by the oral route and no additional correction factor was introduced.

AF for dose response relationship:
10
Justification:
The starting point is a LOAEL with major foetal malformations
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic
AF for interspecies differences (allometric scaling):
2.4
Justification:
Rabbit to human
AF for other interspecies differences:
1
Justification:
Addressed by modification of starting point
AF for intraspecies differences:
10
Justification:
Default value for general population
AF for the quality of the whole database:
1
Justification:
Data available on the test substance appropriate for the tonnage band
AF for remaining uncertainties:
2.5
Justification:
Default value
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

No acute toxicity hazard (leading to C&L) has been identified for the registered substance following the oral and dermal exposure. Therefore, according to ECHA R8 Guidance, no DNEL (acute) should be set.

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:
0.03 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3 600
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As a point of departure for the dermal long term DNEL, the LOAEL of 100 mg/kg bw/day from the oral prenatal developmental toxicity study in rabbits was chosen. A maximal absorption was already occurred by the oral route and no additional correction factor was introduced.

AF for dose response relationship:
10
Justification:
The starting point is a LOAEL with major foetal malformations
AF for differences in duration of exposure:
6
Justification:
Subacute to chronic
AF for interspecies differences (allometric scaling):
2.4
Justification:
Rabbit to human
AF for other interspecies differences:
1
Justification:
Addressed by modification of starting point
AF for intraspecies differences:
10
Justification:
Default value for general population
AF for the quality of the whole database:
1
Justification:
Data available on the test substance appropriate for the tonnage band
AF for remaining uncertainties:
2.5
Justification:
Default value
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

As for workers.