Reaction mass of calcium hydrogen phosphonate and dialuminium tricalcium hexaoxide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: accepted QSAR method

Objective of study:

distribution

Principles of method if other than guideline:

The Multiple-Path Particle Dosimetry Model (MPPD, v2.11; CIIT, 2013, available via Internet http://www.ara.com/products/mppd.htm) was used to predict this fractional deposition behaviour in the human respiratory tract.

GLP compliance:

no

Type:

other: fractional deposition in respiratory tract of total dustiness (119.32 mg/g (11.93 % of total substance mass))

Results:

naso-pharyngeal (head) region: 89.1 %; tracheobronchial region: 1.4 %; pulmonary (alveolar) region: 4.3 %

Details on absorption:

not determined

Details on distribution in tissues:

not determined

Details on excretion:

not determined

Metabolites identified:

no

Details on metabolites:

not determined

Particle size distribution of measured total dustiness (119.32 mg/g) was determined in study DMT 2013 (see Technical Dossier Section 4.5, endpoint study record: key_Particle size distribution (Granulometry) DMT GS 3 – 00 005 13rev1) and the calculated MMAD and GSD values were used as input parameters for the prediction of the inhalable amount (94.8% of total dustiness) and its fractional deposition behaviour in the respiratory tract applying the Multiple Path Particle model (MPPD)(ver.2.11).

Only very few amounts of the total dustiness fraction (4.3 %) will reach the pulmonary (alveolar) region. The vast majority of inhaled dust will be withheld in the naso-pharyngeal (head) region (89.1 %) and minor amounts in the tracheobronchial region (1.4 %). Deposits in the alveolar region would not get directly absorbed as the substance is an poorly soluble dust. The alveolar dust deposits would mainly be engulfed by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed. Dusts depositing in the tracheo-bronchial region would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed (c.f. ECHA TGD R7a, R.7.12.2.1).

Thus, direct inhalative systemic bioavailability is highly unlikeley due to the deposition behaviour, crystalline structure and limited solubility.

Conclusions:

Direct inhalative systemic bioavailability is unlikely due to the deposition behaviour, crystalline structure and limited solubility

Executive summary:

Prediction of respiratory deposition patterns using the MPPD model

MMAD (9.9 µm) and GDS (3.6) were used as distribution parameter for the MPPD model enabling an estimation of deposited dust fractions in the human respiratory tract: Using the derived particle size distribution parameters, it is possible to quantify the deposited fractions of the airborne dust in the human respiratory tract. The Multiple-Path Particle Dosimetry Model (MPPD, v2.11; CIIT, 2013) was used to predict this fractional deposition behaviour for workers.

Particle size distribution of measured total dustiness (119.32 mg/g) was determined in study DMT 2013 (see Technical Dossier Section 4.5, endpoint study record: key_Particle size distribution (Granulometry) DMT GS 3 – 00 005 13rev1) and the calculated MMAD and GSD values were used as input parameters for the prediction of the inhalable amount (94.8% of total dustiness) and its fractional deposition behaviour in the respiratory tract.

Only very few amounts of the total dustiness fraction (4.3%) will reach the pulmonary (alveolar) region. The vast majority of inhaled dust will be withheld in the naso-pharyngeal (head) region (89.1%) and minor amounts in the tracheobronchial region (1.4%). Deposits in the alveolar region would not get directly absorbed as the substance is an poorly soluble dust. The alveolar dust deposits would mainly be engulfed by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed. Dusts depositing in the tracheo-bronchial region would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed (c.f. ECHA TGD R7a, R.7.12.2.1).

Thus, direct inhalative systemic bioavailability is unlikely due to the deposition behaviour, crystalline structure and limited solubility.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Substance "reaction mass of calcium hydrogen phosphonate and dialuminium tricalcium hexaoxide" can be considered as dermally non-absorbable as it is an inorganic, sparingly soluble ionic solid of lamellar structure. Particle size distribution of measured total dustiness (119.32 mg/g) was determined and the calculated MMAD and GSD values were used as input parameters for the prediction of the fractional deposition behaviour in the respiratory tract applying the Multiple Path Particle Dosimetry model (MPPD)(ver.2.11). Only very few amounts of the total dustiness fraction (4.3 %) will reach the pulmonary (alveolar) region. The vast majority of inhaled durst will be withheld in the naso-pharyngeal (head) region (89.1 %) and minor amounts in the tracheobronchial region (1.4 %). Deposits in the alveolar region would not get directly absorbed as the substance is a poorly soluble dust. The alveolar dust deposits would mainly be engulfed by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Poorly water-soluble dusts depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed. Dusts depositing in the tracheo-bronchial region would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed (c.f. ECHA TGD R7a, R.7.12.2.1).

Thus, direct inhalative systemic bioavailability is unlikely due to the deposition behaviour, crystalline structure and limited solubility. However, inhaled and subsequently swallowed amounts may decompose under the strong acidic conditions of the stomach and the released ions may become bioavailable. The assumption, that the substance acts, if at all, via its dissolved ions and therefore data on the ions can be used for hazard assessment, is in line with ECHA REACH TGD R6. However, providing compliance to the DNEL, even under worst case considerations no toxicity deriving from the released ions is expected:

- As DNEL long-term exposure systemic inhalation worker, the German general dust limits for respirable dust (1.25 mg/m³) is used in compliance with ECHA REACH TGD R.8.

- Considering an exposure to 1.25 mg/m³ during the whole working week, the summed up exposure by use of standard default values (c.f. ECHA REACH TGD R.8: length of working day: 8h, working days/week: 5, inhalation volume: 10 m³ in 8 h, body weight: 70 kg) is 62.5 mg/worker/week or 0.89 mg/kg bw/week (12.5 mg/worker/day or 0.18 mg/kg bw/day).

- Highly conservative worst case assumption that inhaled dust, regardless whether depositted in the naso-pharyngeal (head) region (89.1 %), the tracheobronchial region (1.4 %) or the pulmonary (alveolar) region (4.3 %), is not cleared of the body by expectoration or sneezing, but completely cleared from the respiratory tract by the mucociliary mechanism and completely swallowed. Theoretically possible systemic absorption of small amounts via phagocytosis with subsequent transportation to the blood via the lymphatic system or engulfing by alveolar macrophages and subsequent transfer into the pulmonary interstitium and lymphoid tissues not considered for reason of simplification.

- Highly conservative worst case assumption that after swallowing, the material undergoes complete acidic dissolution in the stomach with 100 % release of the respective ions calcium, phosphonate and aluminium.

- Highly conservative worst case assumption that resorption rate of released ions is 100 %.

Calcium and phosphonates respectively phosphates are normal constituents of the body. As they are effectively processed and regulated in the body by natural physiological mechanisms, they are not expected to have any relevant toxic effect. For adults, an upper intake level "UL of 2500 mg of calcium per day for calcium intake from all sources" has been derived by the European Food Safety Authority (EFSA), who also stated, "that normal healthy individuals can tolerate phosphorus (phosphate) intakes up to at least 3000 mg/day without adverse systemic effects" (c.f. TOLERABLE UPPER INTAKE LEVELS FOR VITAMINS AND MINERALS, Scientific Committee on Food, Scientific Panel on Dietetic Products, Nutrition and Allergies, European Food Safety Authority (February 2006), http://www.efsa.europa.eu/fr/ndatopics/docs/ndatolerableuil.pdf). Thus, systemic intake of calcium and phosphonate deriving from exposure to substance "reaction mass of calcium hydrogen phosphonate and dialuminium tricalcium hexaoxide" is even under highly conservative worst case considerations negligible and not expected to have any toxic effect.

Aluminium intake has been associated with some toxic effects to the nervous system and reproduction. A tolerated weekly intake (TWI) of 1 mg/kg bw/week has been derived by the European Food Safety Authority (EFSA) (c. f. Safety of aluminium from dietary intake, Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Food Contact Materials (AFC), The EFSA Journal (2008) 754, 1-34 http://www.efsa.europa.eu/de/efsajournal/doc/754.pdf and Scientific Option Re-evaluation of aluminium sulphates (E 520 -523) and sodium aluminium phosphate (E541) as food additives, The EFSA Journal (2018) 16(7):5372 https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2018.5372). The Joint FAO/WHO Expert Committee on Food Additives (JECFA) increased the TWI from 1 mg/kg bw/week to 2 mg/kg bw/week (WHO (2012) Joint FAO/WHO Expert Committee on Food Additives. Safety evaluation of certain food additives and contaminants. WHO Food Additives Series 65; http://whqlibdoc.who.int/publications/2012/9789241660655_eng.pdf). Considering that the total aluminium amount of inhaled substance "reaction mass of calcium hydrogen phosphonate and dialuminium tricalcium hexaoxide" (average aluminium content of the substance is 7.95 % by weight (7.70 – 8.20 %)) is bioavailable, the worker will be systemically exposed to approximately 0.07 mg/kg bw/week. However, beside the unlikelihood of 100 % clearance of inhaled dust via swallowing, according to EFSA (c.f. Statement of EFSA on the evaluation of a study related to the bioavailability of aluminium in food, The EFSA Journal (2011, 9(5) 2157; http://www.efsa.europa.eu/de/efsajournal/doc/2157.pdf), “oral bioavailability of aluminium from twelve different aluminium-containing compounds, including the food additives aluminium sulphate, … and sodium aluminium silicate, ranges merely from 0.02 to 0.21 %.” Considering this information, the real bioavailability of aluminium from inhaled and subsequent swallowed substance "reaction mass of calcium hydrogen phosphonate and dialuminium tricalcium hexaoxide", will be most likely significantly less than 1 %, which reduces the systemic exposure even under highly conservative worst case assumptions to less than 0.0007 mg/kg bw/week, a dose not expected to result in any toxic effect. There is also no reason to expect a bioaccumulation potential as “Following ingestion, absorbed aluminium from the blood is eliminated primarily by the kidneys, presumably as the citrate, and excreted in the urine (Krewski et al., 2007; ATSDR, 2008). Unabsorbed aluminium is excreted in the faeces. Excretion via the bile constitutes a secondary, but minor route” (c.f. EFSA (2011).

Thus, it can be inferred from toxikokinetic considerations, that even under highly conservative worst case assumptions neither substance "reaction mass of calcium hydrogen phosphonate and dialuminium tricalcium hexaoxide" as such nor its dissolved ionic constituents are systemically bioavailable in an amount likely to induce any adverse effects. Missing systemic toxicity has been proved in a 28-day oral toxicity study performed according to OECD Guideline No. 407 and EEC Directive 84/449/EEC, Part B.7. Up to and including the highest dose tested of 1000 mg/kg bw/day, no mortality occurred and there were no changes in clinical appearance, body weights, food consumption, ophthalmoscopic examination, clinical laboratory investigations, macroscopic examinations, organ weights and microscopic examination that were considered to be an adverse effect of treatment. Therefore, further systemic toxicity studies either in respect of general toxicity or specific target toxicity (e.g. subchronic studies or studies on reproductive toxicity) are not justifiable and respective data requirements are waived in accordance with Annex XI.