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Description of key information

Oral, rat: NOAEL ≥ 4176.5 mg/kg bw/day  (Ondreicka et al., 1966a)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from reference substances with similar structure and intrinsic properties of dissociation products of the target substance. Read-across is justified based on dissociation products (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity

No studies are available on repeated dose toxicity of Fatty acids, C16-18 (even numbered), aluminum salt. However, there are reliable data on analogue substances which are considered suitable for read-across. According to the general rules defined in Regulation (EC) No. 1907/2006, Annex XI, Item 1.5 for the grouping of substances and read-across approach, similarities between substances may be based on “common functional groups” and “common precursors and/or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals”. Bonds between metal salts and carboxylic acids are known to readily dissociate into the corresponding metal and carboxylic acid in the ambient environment (at neutral pH) and in the digestive tract (at low pH) where complete dissociation occurs, as determined for aluminium di- and tristearate in the US HPV Chemical Challenge Program (2007). Thus, nearly complete dissociation of aluminum fatty acid salts into aluminium, stearic (C18) and/or palmitic (C16) acid is expected to occur in the digestive tract after oral ingestion thereby indicating that toxicity of Fatty acids, C16-18 (even numbered), aluminum salt can be evaluated based on reliable data for the dissociation products and structural analogues of those. The first dissociation product, C16 and 18 fatty acids are stepwise degraded within the mitochondrium matrix by β (–) Oxidation in which C2 units are released (CIR, 1987). Therefore, read-across to saturated fatty acids of different chain length is feasible because of the likelihood of common breakdown products. The second dissociation product,aluminium exists in 4 different forms in the living organisms, including free ions, low-molecular-weight complexes, physically bound macromolecular complexes, and covalently bound macromolecular complexes (Ganrot 1986). As the pathways leading to toxic outcomes are mainly dominated by the chemistry and biochemistry of the aluminium ion (Al3+) (Krewski et al., 2007; ATSDR, 2008), different aluminium compounds may serve as surrogates for read-across to the free metal component ofFatty acids, C16-18 (even numbered), aluminum salt.

As noted in Regulation (EC) No. 1907/2006, Article 13 (1) "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” Information shall therefore be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related or surrogate substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”. For details on the read-across approach please refer to the analogue justification in section 13 of the technical dossier.

As no data are available on repeated dose toxicity ofFatty acids, C16-18 (even numbered), aluminum salts, read-across to reliable data on the analogue and surrogate substances lauric acid (CAS 143-07-7, C12) and aluminium chloride (CAS 7446-70-0) was performed.

A subchronic repeated dose toxicity study with lauric acid was performed in 5 male Osborne-Mendel rats, which were fed a diet containing 10% lauric acid for 18 weeks (Fitzhugh et al., 1960). No mortality occurred during the study. Moreover, no clinical signs of toxicity were observed. Body weight gain appeared unaffected in test animals. Gross organ pathology did not reveal any significant differences and individual organ weights were comparable between control and test animals. Thus, 10% lauric acid is considered to be the NOAEL corresponding to ca. 5000 mg/kg bw/day, based on an average daily food consumption of 5 g/100 g bw (WHO, 1987). 

Non-hazardous properties of saturated fatty acids were also proven in a repeated dose toxicity study with docosanoic acid (CAS 112-85-6) in a combined repeated dose and reproductive/developmental toxicity screening test performed according to OECD guideline 422 (Nagao et al., 2002). The study included groups of 13 male and female Sprague-Dawley rats which received 100, 300 and 1000 mg/kg bw/day docosanoic acid daily by gavage. Males were treated for 42 days including two weeks prior to mating, the mating period and two weeks post mating. Females were exposed over a time period of approx. 50 days covering the period of 14 days prior to mating until Day 3 of lactation. No mortality or abnormalities were observed in test animals. Slight alterations on body weight gain and food consumption were observed in low-dose males. A statistically significant decrease in food consumption was observed in females of the same dose group during lactation. Haematology revealed a statistically significant decrease of 3% in mean corpuscular haemoglobin concentration in males of the mid- and high-dose groups after the treatment period. Glucose, total protein, calcium and alkaline phosphatase (ALP) levels were significantly decreased in mid-dose males. At gross pathology, a significant liver weight increase in low-dose males and a significant decrease in kidney weights of females of the same dose group were observed. Moreover, isolated changes in size and colouring of organs were observed in few animals in every dose group. As the above mentioned alterations were not correlated to 1. a dose-response or 2. histopathological alterations verifiying adverse effects and 3. no similarity was found in both sexes, the effects were regarded as incidental and not treatment-related. Therefore, the NOAEL for repeated oral dose toxicity of docosanoic acid was determined to be ≥ 1000 mg/kg bw/day (Nagao et al., 2002).

 

Repeated dose toxicity of aluminium chloride was evaluated by Ondreicka et al. in a subacute toxicity study (Ondreicka et al., 1966a). 10 male Dobra Voda mice were exposed to 355 mg Al/kg bw for 40 days via the diet. Control animals were included in the study which received plain diet containing 160 – 180 mg /kg aluminium. Despite a statistically significant decrease in food consumption, no differences were noted between test and control animals including body weight gain, growth curves, water consumption, haematology and urinalysis. Analysis of aluminium content in faeces and urine determined a significantly higher aluminium intake and faecal excretion in test animals whereas urinary excretion and retention of aluminium seemed to be unaffected. However, the biological significance of the decreased food consumption remains questionable as no further adverse effects were observed in test animals. Therefore, a NOAEL ≥ 355 mg Al/kg bw/day is defined based on this study. Considering a content of up to 8.5% aluminium, a corresponding NOAEL of 4176.5 mg/kg bw/day is defined for Fatty acids, C16-18 (even numbered), aluminum salt.

The findings of the subacute study are supplemented by a two-generation study performed by Hirata-Koizumi: Sprague Dawley rats were exposed to up to 3000 ppm aluminium sulfate via drinking water according to OECD guideline 416 (Hirata-Koizumi et al., 2011). Based on decreased body weight gain and food consumption, a NOAEL of 8.06 mg Al/kg bw/day (600 ppm) and a LOAEL of 31.2 mg Al/kg bw/day (3000 ppm) was derived for parental systemic toxicity which corresponds to a NOAEL of 94.82 or a LOAEL of 367.1 mg Fatty acids, C16-18 (even numbered), aluminum salt/kg bw/day calculated as worst case assumption with a content of up to 8.5% aluminium.

Moreover, Ondreicka evaluated toxicity of aluminium chlorid in a three generation study, in which mice were exposed to 19.3 mg Al/kg bw/day via drinking water over 180 – 390 days. As no adverse effects were observed in any generation, no NOAEL was determined thereby proving low toxicity of aluminium after chronic exposure (Ondreicka, 1966b).

In addition, 8 male Wistar rats were exposed daily to 2835 mg Al/kg bw/day sulfate via the diet over 8 days. Based on the reduced body weight and food consumption, a LOAEL of 141.8 mg Al/kg diet was established in the conducted study (Ondreicka, 1966c) which corresponds to a LOAEL of 1668.2 mg/kg bw/dayFatty acids, C16-18 (even numbered), aluminum salt considering a content of 8.5% aluminium.

In conclusion, repeated dose toxicity ofFatty acids, C16-18 (even numbered), aluminum saltis sufficiently covered by available data of structural analogues of dissociation products. A LOAEL ≥ 5000 mg/kg bw was derived after subchronic exposure for fatty acids, the first dissociation product. Exposure to aluminum resulted in NOAELs ≥ 300 mg/kg bw/day or≥ 355 mg/kg bw/day after exposure for 37 or 40 days, respectively. Thus, available data demonstrate low toxicity ofFatty acids, C16-18 (even numbered), aluminum salt after repeated dose exposures. 

 

References not included in IUCLID:

ATSDR (Agency for Toxic Substances and Disease Registry) (2008).Toxicological Profile for Aluminum.Atlanta: Department of Health and Human Services, Public Health Service.

CIR (1987). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, stearic acid. J. of the Am. Coll. of Toxicol.6 (3): 321-401

Ganrot, P.O. (1986). Metabolism and possible health effects of aluminum. Environ Health Perspect 65:363-441.   

Krewski et al. (2007). Human Heaklth Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide. J Toxicol Environ Heakth B Crit Rev 10(1):1-269

U.S. High Production Volume (HPV) Chemical Challenge Program (2007)


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No study was selected as hazard assessment was conducted by a weight of evidence of read-across from structural surrogates of dissociation products. The selected key studies are the most adequate and reliable studies based on exposure period and similarities in structure and intrinsic properties between the source and dissociation products of the target substance. The most sensitive effet level was chosen for the key information.

Justification for classification or non-classification

The available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.