Accepted concentration limits propylene glycol

1. Propylene Glycol (PG)

Propylene Glycol (PG) is a common co-solvent, humectant, and solvent in oral, topical, and injectable (parenteral) products. It is classified by the FDA as Generally Recognized as Safe (GRAS) for use in food.

Safety Profile & Mechanism

Metabolism: Propylene Glycol is primarily metabolized in the liver (around 55%) into pyruvic acid, lactic acid, and acetic acid, which are then either converted to energy or excreted. The remaining amount is excreted unchanged by the kidneys.
Toxicity: PG has a relatively low systemic toxicity. Acute toxicity generally requires very high doses.
Adverse Effects (High Doses): Toxicity, especially with high intravenous or oral doses, is linked to the accumulation of PG or its acidic metabolites. This can lead to:

Hyperosmolality (increased concentration of solutes in the blood).
Lactic Acidosis.
CNS effects (depression, seizures, coma).
Renal dysfunction (acute renal failure).

Concentration/Dose Limits (Daily Exposure)

Safety limits are highly dependent on the patient's age and health status, especially their metabolic and renal maturity.

Patient Population	Proposed Safe Daily Limit (EMA/WHO)	Rationale/Concern
Adults & Children (A $\ge$ 5 years)	Up to 500 mg/kg/day	Generally considered safe and well-tolerated.
Children (1 month to < 5 years)	50 mg/kg/day	Due to limited metabolic capacity and increased risk of accumulation.
Pre-term & Term Neonates	1 mg/kg/day	Due to known immaturity of hepatic (liver) and renal (kidney) clearance.
Food Additive (WHO)	25 mg/kg/day (Maximum Permissible Daily Intake)	Applies to general food consumption.

Crucial Note: For parenteral and oral medicinal products, a warning must be included in the package leaflet if the product contains PG daily doses exceeding 200 mg/kg for children or 400 mg/kg for adults.

2. Parabens (Preservatives)

Parabens (like methylparaben, ethylparaben, propylparaben, and butylparaben) are widely used preservatives in pharmaceuticals, cosmetics, and food due to their strong broad-spectrum antimicrobial efficacy, particularly against fungi.

Safety Profile & Mechanism

Metabolism: Parabens are readily absorbed through the skin and gut and rapidly metabolized (hydrolyzed) in the liver and skin into para-hydroxybenzoic acid (PHBA), which is then excreted in the urine.
Toxicity: They have very low acute toxicity.
Concerns (Endocrine Disruption): The primary concern stems from their ability to weakly mimic estrogen (estrogenic activity). While significantly less potent than natural estrogen, studies have shown that the "long-chain" parabens (Propyl- and Butylparaben) exhibit stronger endocrine-disrupting activity than Methyl- and Ethylparaben.

Concentration Limits (European and Cosmetic Guidelines)

Regulatory bodies often set specific limits for parabens, usually based on the total concentration used:

Paraben Type & Use	Maximum Concentration Limit	Governing Body/Guideline
Single Paraben Ester (e.g., Methylparaben)	Up to 0.4% (expressed as acid)	European Union (EU) Cosmetics Regulation
Mixture of Parabens (Total Concentration)	Up to 0.8% (expressed as acid)	European Union (EU) Cosmetics Regulation
Propyl- and Butylparaben (EU Specific)	Reduced to 0.19% (for any one or any mixture)	European Union (EU) SCCS Opinion

Key Takeaway: While global regulatory bodies generally reaffirm the safety of parabens at currently authorized levels, particularly the widely-used Methyl- and Ethylparaben, there is increased scrutiny and lower limits for the longer-chain parabens (Propyl- and Butylparaben) due to endocrine activity concerns, especially in products intended for young children.