Examining the safety of propylene glycol for reproductive health and fetal development based on NTP-CERHR evaluation and scientific evidence
Imagine a substance so common that you've almost certainly consumed it in your food, applied it on your skin, or ingested it in medicine, yet you've likely never heard its name. Propylene glycol (PG) is one of the world's most ubiquitous—and misunderstood—chemicals. Designated as "Generally Recognized As Safe" (GRAS) by the FDA, this odorless, colorless liquid serves as a humectant, solvent, and preservative in products ranging from ice cream to inhalers 2 4 .
When the National Toxicology Program's Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) decided to investigate these very questions, their findings would challenge both fears and assumptions, offering a nuanced picture of safety that continues to evolve with emerging science.
To understand the concerns, we must first understand the chemical. Propylene glycol (CAS RN 57-55-6) is a small, organic compound known chemically as 1,2-propanediol 5 . Its structure features three carbon atoms with two alcohol groups, making it highly soluble in water and capable of interacting with biological systems in ways that demanded careful scrutiny 4 .
As a solvent for oral, topical, and injectable drugs
As a carrier for flavors and colors
As a moisturizer and texture enhancer
With such widespread exposure, the 2004 NTP-CERHR evaluation represented a critical step in understanding what this meant for human health, particularly during the most sensitive windows of development 3 .
The NTP-CERHR expert panel concluded there is "negligible concern for adverse developmental and reproductive effects in humans" at current exposure levels 3 7 .
This conclusion wasn't reached lightly. The panel examined human epidemiological studies, animal toxicology research, and metabolic data before determining that propylene glycol showed no direct evidence of causing reproductive or developmental harm in humans 3 .
The panel noted that studies in pregnant laboratory animals showed no developmental toxicity in offspring even at oral doses exceeding 1,200 mg/kg of body weight per day, and in some studies up to 10,400 mg/kg per day 3 .
The panel identified a key metabolic difference between species that actually makes humans less vulnerable than laboratory animals to potential toxic effects.
The rate-limiting step in PG metabolism is its conversion to lactaldehyde by alcohol dehydrogenase (ADH), and this enzyme saturates in humans at doses 8-10 times lower than in rats and rabbits. This means humans effectively have a "built-in brake" that limits the production of potentially toxic metabolites 3 .
One pivotal investigation that informed the panel's decision was a continuous breeding study in mice that examined reproductive performance across generations 5 . This study was particularly significant because it tested not just single exposures, but the potential cumulative effects on fertility and offspring.
The findings revealed no adverse effects on fertility in either male or female mice, even at the highest doses tested 3 5 . This absence of reproductive toxicity at remarkably high exposure levels provided strong evidence that PG was unlikely to interfere with fundamental reproductive processes.
| Parameter Measured | Effect at Doses Up to 10,100 mg/kg/day | Significance |
|---|---|---|
| Mating Index | No adverse effects | Suggests PG doesn't interfere with mating behavior |
| Fertility Index | No adverse effects | Indicates PG doesn't impair conception |
| Litter Size | No reduction | Shows PG doesn't affect number of offspring |
| Pup Survival | No adverse effects | Suggests PG doesn't harm offspring viability |
The expert panel also reviewed comprehensive prenatal developmental toxicity studies conducted across multiple species, including mice, rats, hamsters, and rabbits 5 . These studies followed standardized protocols for developmental toxicity testing:
The consistent finding across all species was that PG produced neither developmental nor maternal toxicity at the highest doses tested in each study 5 . The absence of effects across multiple animal models significantly strengthened the conclusion that PG does not pose a significant developmental hazard.
| Species | Highest Dose Tested (mg/kg/day) | Developmental Effects | Maternal Toxicity |
|---|---|---|---|
| CD-1 Mice | 10,400 | None observed | None observed |
| Wistar Rats | 1,600 | None observed | None observed |
| Golden Hamsters | 1,550 | None observed | None observed |
| Dutch-belted Rabbits | 1,230 | None observed | None observed |
One of the most challenging concepts in toxicology is that "the dose makes the poison." The NTP-CERHR evaluation put this into perspective by comparing typical human exposure to levels tested in animals.
Average daily intake of PG from food products in the United States for a 70 kg person 3
Highest dose tested in laboratory animals showing no adverse effects
This substantial margin of safety, combined with the metabolic differences that make humans less susceptible, forms the foundation of the "negligible concern" conclusion.
While the NTP-CERHR evaluation provided substantial reassurance, science continues to evolve. Recent research has explored more nuanced questions about PG safety:
A 2024 study using physiologically based pharmacokinetic (PBPK) modeling highlighted that PG clearance can saturate at high doses, particularly in vulnerable populations like neonates 1 . This saturation occurs when the alcohol dehydrogenase (ADH) enzyme system becomes overwhelmed, potentially leading to accumulation.
The research suggested that in individuals without impaired clearance, a total daily dose of 100-200 mg/kg/day in adults and 25-50 mg/kg/day in neonates is unlikely to result in toxic PG levels or saturation of clearance pathways 1 . This provides more specific guidance for safe exposure levels across different age groups.
The same PBPK modeling study confirmed that neonates have significantly reduced ability to clear PG from their systems, with elimination half-lives estimated at 10-31 hours compared to just 2-5 hours in adults 1 . This explains why regulatory bodies like the European Medicines Agency have set much lower recommended limits for neonates (1 mg/kg/day) compared to older children and adults 1 .
A 2022 zebrafish study investigating PG enantiomers (mirror-image forms of the molecule) found that while basic development was unaffected, high doses of PG could alter locomotor activity and eye development in larval zebrafish 8 . Though zebrafish models don't directly translate to human effects, they suggest potential areas for continued research, particularly regarding subtle neurodevelopmental impacts.
What emerges is a picture not of blanket safety or danger, but of informed, nuanced risk assessment—exactly what regulatory science aims to provide. For the vast majority of the population, the evidence suggests that current exposure levels to propylene glycol pose negligible risk to reproductive health and fetal development.
As we encounter countless chemicals in our daily lives, the extensive evaluation of propylene glycol serves as both a reassurance and a model—demonstrating how rigorous science can help navigate the complex landscape of modern chemical exposures while protecting the most vulnerable among us.