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Description of key information

Subchronic (90-day) study oral (gavage), rat (Sprague-Dawley) m/f (OECD guideline 408, GLP): NOAELneurotoxicity: 1000 mg/kg bw/day (both sexes); read-across substance Phosphoric acid, C9-15 branched and linear alkyl esters, potassium salts

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available study is a high quality guideline study with original RL1. In accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Reliable data on neurotoxicity of PAE are available from a 90-day gavage study in rats on the read-across substance Phosphoric acid, C9-15 branched and linear alkyl esters, potassium salts.

The read-across approach is appropriate due to similar composition of source and registered substance. From the available data is can be concluded that the repeated dose toxicity of substances with different alkyl moieties (C12, C14, C9-15 linear and branched) is comparable.

Phosphoric acid alkyl esters are hydrolysed unspecifically by phosphatases, e.g. acid phosphatase or alkaline phosphatase. Both enzymes are found in most organisms from bacteria to human. Alkaline phosphatases are present in all tissues, but are particularly concentrated in liver, kidney, bile duct, bone and placenta. In human and most other mammals three isoenzymes of Alkaline phosphatase exist: intestinal ALP, placental ALP, tissue non-specific ALP (present in bone, liver, kidney, skin).

Seven different forms of Acid phosphatase are known in humans and other mammals. These are also present in different tissues and organs (predominantly erythrocytes, liver, placenta, prostate, lung, pancreas).

Linear and branched primary aliphatic alcohols are oxidised to the corresponding carboxylic acid, with the corresponding aldehyde as a transient intermediate. The carboxylic acids are further degraded via acyl-CoA intermediates in by the mitochondrial beta-oxidation process. Branched aliphatic chains can be degraded via alpha- or omega-oxidation (see common text book on biochemistry).

“The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential (Bevan, 2001).

Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides) (Kabir, 1993; 1995 a,b).

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed.” (OECD SIDS, 2006)

The PAEs with branched fatty alcohols can be considered as a worst case scenario because the metabolism of the resulting branched fatty acids occurs less efficient compared to linear fatty acids.

 

In a subchronic toxicity study according to OECD guideline 408 Phosphoric acid, C9-15 branched and linear alkyl esters, potassium salts (34.35% a. i.) was administered to 5 Sprague-Dawley rats/sex/dose by oral gavage at dose levels of 0 (control), 8, 40, 200 and 1000 mg/kg bw/day). The animals were dosed for 91 days. Additional 5 males and 5 females were added to the control group and 1000 mg/kg group as a recovery group to examine the reversibility of the effects. Those animals were observed for another 14 days.  

No adverse reaction was observed in hematology, blood biochemistry or organ weight measurement. Concerning neurological toxicology and behavior toxicology, no toxic effect was seen in detailed clinical observation, sensory response test, grip strength test, or histopathological examination of neurological organs and tissues. No change was noted in ophthalmological examination.  

The changes observed during the dosing period or at the end of the dosing period such as salivation, abnormal respiratory sound, low body weight, low urine pH, thickening of the forestomach mucosa, dilatation of cecum, hyperplasia and erosion of squamous cells of the forestomach and hypertrophy of the cortical glomerular zone of the adrenal gland were not observed during the recovery period or at the end of the recovery period except for the change in the adrenal gland. The change in the adrenal gland also became milder and these changes were confirmed to be reversible.

The above results show that toxic effect after repeated oral administration of Phosphoric acid, C9-15 branched and linear alkyl esters, potassium salts appears mainly in the adrenal gland and forestomach.

 

The NOAEL for neurobehavioural effects is 1000 mg/kg bw/d in both sexes.

The BMDL10 for overall effects (adrenal gland, for details see repeated dose toxicity part of this study) is 240.30mg/kg bw/d (corresponding BMD =374.61 mg/kg bw/d).

There is no data gap in neurotoxicity. There is no reason to believe that results of the study would not be relevant for neurotoxicity in humans and, therefore, for risk assessment.

Justification for selection of effect on neurotoxicity via oral route endpoint:

OECD guideline study, no deviations, GLP; 90 d study

Justification for classification or non-classification

In conclusion, the results of the available data on neurotoxicity indicate that Phosphoric acid, C16-18-alkyl esters, potassium salts does not need to be classified according to Directive 67/548/EEC as well as CLP, EU GHS (Regulation 1272/2008/EC) and therefore labelling is not necessary.