Slags, ferromanganese-manufg.

Toxicological Summary

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.