Ferrate(1-), bis[4-[2-[5-chloro-2-(hydroxy-.kappa.O)phenyl]diazenyl-.kappa.N1]-3-(hydroxy-.kappa.O)-N-phenyl-2-naphthalenecarboxamidato(2-)]-, ammonium (1:1)

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance  Ammonium bis[4-[(5-chloro-2-hydroxy-phenyl)azo]-3-hydroxy-N- phenyl-2 naphthalenecarboxamidato(2-)]ferrate (1-) (DL-N33) is a mono-constituent organometallic with a purity of 95-98% with a typical concentration of 96.6%. There are 23 minor organic impurities; none are present at >1% with a total typical concentration of 3.4%.

A full ADME toxicokinetic study in the rat with DL-N33 is not available. In vivo studies in rats covering the oral route are available (acute oral toxicity, 28-day repeated dose toxicity, screening for reproductive/developmental toxicity). In vivo studies covering the dermal route are available (guinea pig maximisation test, skin irritation study in rabbits). An acute inhalation toxicity study in rats is available. Further details on endpoints are available in the IUCLID 6 registration dossier. The toxicokinetic analysis is based on the physicochemical and in vivo toxicological data.

The absorption rates of 50% (oral), 10% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

1. Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of DL-N33 in the body.

Absorption - oral

The molecular weight of DL-N33 is 905 g/mol and is outside the range for favourable oral absorption (<500 g/mol). DL-N33 is highly insoluble in water (0.007 mg/L at 21°C) and moderately lipophilic (log Kow >4.9) These characteristics will not facilitate transport via passive diffusion and absorption of DL-N33 is more likely via the lymphatic system through micellular solubilisation.

Absorption – dermal

The water insolubility, log Kow and molecular weight of DL-N33 indicate dermal exposure will be very low.

Absorption – inhalation

DL-N33 has very low volatility (1.3x10-12 Pa at 25 °C) but is also considered a dusty solid. The particle size distribution report indicates that 19.2% of particles are <10.2 μm and 3.83% are <5.4 μm). This indicates that a fraction of the particles are available in the inhalable fractions of air (<100 μm). Particles with aerodynamic diameters of above 1-5 μm have the greatest probability of settling in the nasopharyngeal region whereas particles with aerodynamic diameters below 1-5 μm are most likely to settle in the tracheo-bronchial or pulmonary regions. As there are fractions in both these categories, the substance is likely to be distributed throughout the respiratory tract upon inhalation. Greater than 50% of particles will be able to penetrate the alveolar region of the respiratory tract (<15 µm). As an insoluble dust, DL-N33 could be coughed or sneezed out of the body or swallowed (refer to oral absorption). Based on the water insolubility and lipophilicity, it is likely that any absorption will be very low and occur via micellular solubilisation and the lymphatic system.

Distribution/Metabolism/Excretion

Based on the molecular weight and water insolubility, DL-N33 will not be distributed widely. DL-N33 is expected to be excreted mainly unchanged in the faeces.

2. Information from other studies in the dossier

Absorption - oral

In the acute oral toxicity study in Crl:CD(SD)BR rats (OECD 401), no signs of toxicity were observed other than pilo-erection throughout day 1 and day 2. There were no other clinical signs and recovery was complete by Day 3. The LD50 (male/female) was >5000 mg/kg bw.

In the sub-acute toxicity study (Annex V; Method B7), DL-N33 was administered by oral gavage to Charles River Crl:CD(SD)BR rats (5/sex/group) in 1% aqueous methylcellulose at 0, 62.5, 250 or 1000 mg/kg bw/day for 28 days, 7 days per week. No treatment-related deaths or clinical signs of toxicity. Mean haemoglobin concentration decreased (p <0.05) in top dose females relative to controls and was marginally lower than the lower end of the historical value range. No other treatment-related effects were observed. No gross or microscopic treatment-related effects were observed. The NOEL (male/female) was 250 mg/kg bw/day and the NOAEL (male/female) was 1000 mg/kg bw/day.

In the reproduction/developmental toxicity screening test (OECD 421/GLP), DL-N33 was administered to 4 groups of Wistar Han:RccHanTM:WIST rats (10 animals/sex/group) by gavage in arachis oil at dose levels of 0, 30, 300 and 1000 mg/kg bw/day, 7 days per week, for up to eight weeks (including a two week maturation phase, pairing, gestation and early lactation for females). There were no unscheduled deaths. There were no treatment-related effects on any parameters in the study. The NOEL (male/female) was 1000 mg/kg bw/day.

These studies together with the physicochemical data indicate that absorption via the oral route is likely to be low. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

Absorption – dermal

In a skin irritation study in rabbits (OECD 404), there were no skin reactions at any timepoint. In the guinea pig maximisation test (OECD 406), there was evidence of sensitisation in control animals at both challenge doses (2/19 positive at 25% and 4/19 positive at 50%) so the positive results in the test groups are doubtful (4/20 at 25% and 5/20 at 50%). Overall, DL-N33 is not sensitising and not a skin irritant so dermal absorption is considered to be very low. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Kow is <-1 or >4, otherwise 100% dermal absorption is used. The molecular weight of DL-N33 is 905 g/mol and the log Kow is >4.9 so 10% dermal absorption is accepted for chemical safety assessment purposes.

Absorption – inhalation

In an acute inhalation toxicity study (GLP), groups of Sprague-Dawley rats (5/sex) were given DL-N33 (whole body) at a dose of 3.37mg/L air (limit test; maximum attainable concentration) for 4 hours. There were no mortalities in males or females. Signs of exposure were confined to staining of the skin, fur and tail by the substance. There was a small reduction in food and water consumption in male exposed rats on day 1. The lungs of all treated animals were coloured greyish due to the substance. Lung to bodyweight ratios were unaffected. No treatment-related changes were found in tissues examined microscopically (lungs, liver, kidneys). The LC50 (male/female) was >3.37mg/L air.

These studies together with the physicochemical data indicate that absorption via the inhalation route is likely to be low. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, based on the most conservative approach.

Distribution/Metabolism/Excretion

Based on the lack of adverse effects noted in the 28-day repeated dose toxicity study and reproduction/developmental toxicity screening test, together with the molecular weight, water insolubility and lipophilicity, DL-N33 is not distributed widely and is likely to be excreted mainly unchanged in the faeces.