Bis(5-oxo-L-prolinato-N1,O2)zinc

Endpoint summary

Description of key information

Physicochemical properties

The substance is a white to off-white powder with a d50 value determined to be 236.671 µm, and only 4.64% of particles having a diameter <10 μm (MMAD 300.954 µm). It has a molecular weight of 321.6 g/mol. The relative density of the test material was determined to be 1.617 at 20°C. The melting point of the substance could not be measured, since the substance was observed to decompose from 252 °C during the melting point study. The vapour pressure of the substance is 475 Pa at 20 °C and therefore the substance is not considered to be available for inhalation as a vapour.

The partition coefficient logPow of the substance was calculated to be < 1.0. The water solubility was measured to be higher than 94.0 g/L at 20 ± 0.5 °C and therefore the substance is easily soluble in water. The substance is readily biodegradable.

Distribution, Metabolism and Elimination

Once in the body the substance will dissociate into its components i.e. L-pidolic acid (synonyms: pyroglutamic acid, 3.5-oxopyrrolidine-2-carboxylic acid) and zinc.

L-pidolic acid is a cyclized derivative of L-glutamic acid. It is an uncommon amino acid derivative in which the free amino group of glutamic acid cyclizes to form a lactam. L-pidolic acid occurs in numerous plants and is a natural constituent of a number of foods. L-pidolic acid as an endogenous substance plays an important role in the endogenous γ-glutamyl cycle, since it is formed from glutamic acid or γ-glutamyl amino acids. It has been detected in human plasma, urine, bones and other tissues. L-pidolic acid was reported to be present in human blood serum and cerebrospinal fluid at about 0.02 and 0.06 mmol/L, whereas the normal urinary excretion in man is probably 0.5-5 mg/day. Elevated blood levels may be associated with problems of glutamine or glutathione metabolism. 

Zinc is also an endogenous substance, essential for growth and development, testicular maturation, neurological function, wound healing and immunocompetence. Over 300 zinc enzymes have been discovered covering all six classes of enzymes and in different species of all phyla. Zinc has structural, regulatory or catalytic roles in many enzymes. Additionally, it maintains the configuration of a number of non-enzymatic proteins such as pre-secretory granules of insulin, some mammalian gene transcription proteins and thymulin. Well known zinc containing enzymes include superoxide dismutase, alkaline phosphatase and alcohol dehydrogenase. Absorption of zinc takes place in the small intestine and ranges from 15 to 60%. Zinc is transported across the intestinal wall, and once in plasma, it is carried by a number of proteins that include albumin, transferrin and caeruloplasmin and is then taken up by other tissues. Tissue content and activity of zinc-dependent processes are maintained over a wide range of dietary zinc intakes. When zinc intake is increased, the fractional absorption decreases and intestinal excretion increases while urinary losses remain fairly constant. Endogenous faecal zinc losses may increase several fold to maintain zinc homeostasis with high intakes. Most of the absorbed zinc is excreted in the bile and eventually lost in the faeces, without any evidence for bioaccumulation.

Oral absorption

In an acute oral toxicity study, the acute median lethal dose (LD50) of the substance was estimated to be greater than 2000 mg/kg body weight.

According to an EFSA opinion (The EFSA Journal (2007) 495-503, 1-10), repeated-dose toxicity studies with compounds similar to the substance (i.e. calcium L-pidolate and magnesium L-pidolate) are available. Based on these studies, no toxic effects were noted at doses up to 1000 mg/kg bw/day for 90 or 100 consecutive days. EFSA also states that a daily intake of L-pidolic acid of 3 g/day in humans is of no safety concern. Based on a bodyweight of 60 kg for an adult, this is calculated to correspond to 50 mg/kg bw/day of L-pidolic acid or 62 mg/kg bw/day of zinc L-pidolate (the substance). 

However, based on the Scientific Committee of Food of 2006 (Tolerable Upper Intake Levels for Vitamins and Minerals by the Scientific Panel on Dietetic products, nutrition and allergies (NDA) and Scientific Committee on Food (SCF).http://www.efsa.europa.eu/sites/default/files/assets/ndatolerableuil.pdf), a clear NOAEL for zinc is established at 50 mg/day for humans, which corresponds to a human NOAEL of 4 mg/kg bw/day for the substance.

The oral absorption of the substance is considered complete (i.e. 100%) for risk assessment purposes.

Dermal absorption

An acute dermal toxicity study (OECD 402) has been conducted with the substance and the acute median lethal dose (LD50) was estimated to be greater than 2000 mg/kg body weight.

In an in vivo skin irritation study in rabbits, the substance was not a skin irritant or corrosive, but in anin vivoeye irritation study in rabbits it was an eye irritant Cat 1. In anin vivoskin sensitisation study in guinea pigs the substance exhibited no sensitisation potential.

Substances with high water solubility and partition coefficients >0 are expected to be highly absorbed, with optimum absorption occurring for substances with water solubility of 100-10000 µg/mL and log P values of 2-3. In this case, the substance is highly water-soluble but is poorly lipophilic (log P <1.0) and it is therefore predicted to have limited penetration into the stratum corneum. This is supported by the toxicity data which demonstrate no systemic toxicity or skin irritation and sensitisation following dermal exposure to the substance.

Therefore, it can be concluded that dermal absorption will be limited and for the purposes of risk assessment, a dermal absorption value of 25% is considered appropriate, in line with the latest EC guidance document on dermal absorption (Guidance on Dermal Absorption. EFSA Journal 2012;10(4):2665). 

Please note, that this dermal absorption estimate is considered highly protective, given that the substance is a solid and, according to the latest version of the same guidance on dermal absorption (EFSA Journal 2017;15(6):4873), not yet in place, the default dermal absorption value in this case would be 10%.

Inhalation absorption

No inhalation toxicity data are available. The substance is a solid, with large particle size. In addition, based on its vapour pressure of 475 Pa, it is unlikely to produce inhalable vapours. 

Although it is likely that any inhaled substance will be retained in the mucus and transported out of the respiratory tract, in the absence of any quantitative data, absorption by inhalation is assumed to be 100%.

Conclusions

Oral and inhalation absorption of the substance is estimated at 100%, whereas dermal absorption is estimated at 25% for risk assessment purposes. 

There is no potential for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

25

Absorption rate - inhalation (%):

100

Additional information

Although no experimental data on absorption, distribution, metabolism and excretion of the substance in animals are available, the roles, behaviour and fate of the components of the substance in humans, mammals and other phyla is known and, together with the available information on the substance (mainly physicochemical properties), it is allowed to provide a toxicokinetic profile.