Literature was systematically reviewed regarding CO₂ exposure and facemask use. Observational and experimental data are helpful for a risk-benefit assessment for masks as a popular non-pharmaceutical intervention against SARS-CoV2 in the populace. Masks impede breathing by increasing the resistance and dead space volume leading to a re-breathing of CO₂ with every breath taken. Fresh air has around 0.04% CO₂, while wearing masks more than 5 minutes bears a possible chronic exposure to carbon dioxide of 1.41% to 3.2% of the inhaled air. Although the buildup is usually within the short-term exposure limits, long-term consequences must be considered due to experimental data. US Navy toxicity experts set the exposure limits for submarines carrying female crews to 0.8% CO₂ based on animal studies indicating an increased risk for stillbirths. Additionally, in mammals chronically exposed to 0.3% CO₂ experimental data demonstrates teratogenicity with irreversible damage of neurons and reduced spatial learning caused by brainstem neuron apoptosis and a reduced blood level of the insulin-like growth factor 1. With significant impact on three readout parameters (morphological, functional, marker) this chronic 0.3% CO₂ exposure has to be defined as being toxic. Additional data exists on the exposure of chronic 0.3% CO₂ in adolescent mammals causing neuron destruction, which includes less activity, increased anxiety and impaired learning and memory. There is a possible negative impact risk by imposing extended mask mandates especially for vulnerable subgroups. Circumstantial evidence exists that extended mask use may be related to current observations of stillbirths and to reduced verbal motor and overall cognitive performance in children born during the pandemic. Extended masking in pregnant women, children and adolescents has not been thoroughly tested and studied. As a result of the animal experimental data available, a risk-benefit analysis is urgent and a need exists to rethink mask mandates, which provide appropriate warnings.