Polyethylene glycol laxatives are made of 100% polyethylene glycol 3350 (PEG 3350), a polymer derived from petroleum. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+5159.
PEG is not found in the human body, is not found in any food required by humans, and cannot be considered a natural substance by any scientific or consumer definition. Polyethylene glycol is a synthetic substance made from a chain of ethylene oxide (EO) molecules through a manufacturing process and may break down into ethylene glycol (EG) and/or diethylene glycol (DEG) in the body. EG and DEG are key ingredients in antifreeze, and are toxic to humans. Potential for PEG 3350 to break down into EG and/or DEG is being studied by the U.S. Food and Drug Administration (FDA) as a result of our 2012 FDA petition regarding PEG 3350 safety in children.https://www.regulations.gov/searchResults?rpp=25&po=0&s=fda-2012-p-0566&fp=true&ns=true
The PEG 3350 safety concerns acknowledged by the FDA include symptoms similar to those of ethylene glycol toxicity. Empire State Consumer Project’s FDA Citizen Petition grant includes an agreement by the FDA to study the potential for PEG 3350 to degrade into ethylene glycol (EG) and diethylene glycol (DEG), and to study the long term effects of PEG 3350 products on pediatric patients. Ethylene glycol and diethylene glycol are synthetic chemicals used to make antifreeze. Both are toxic to the central nervous system, liver, and kidneys when ingested. In recent history, DEG contaminated cough and acetaminophen syrups killed hundreds of adults and children. In 2007, the FDA issued a warning for consumers not to buy toothpaste from China, as some brands were made with DEG.
In addition to the ethylene glycol and diethylene glycol children may be exposed to through the degradation of PEG 3350, the FDA has tested 8 lots of polyethylene glycol 3350 and found ethylene glycol and diethylene glycol contaminants in the product itself… “To better understand the level of polyethylene glycol impurities in PEG, the FDA Chemistry and Manufacturing group evaluated PEG 3350. This analysis of eight lots of PEG 3350 confirmed the presence of small amounts of ethylene glycol and diethylene glycol in all lots tested. Based upon the recommended daily adult dose of 17g daily dose PEG 3350, the maximum daily exposure of ethylene glycol would be 0.005 mg/kg/day for a 60 kg patient, or 0.015 mg/kg/day for a 20 kg pediatric patient (approx 5 years of age). Other low molecular weight (LMW) PEGs were not included in this analysis. However, it is not known if any of these LMW species are absorbed and if so to what extent. Understanding the human absorption profile of LMW species is the first step needed in trying to understand the possible contribution of PEG 3350 use to the development of adverse events in children using this product chronically.”
https://grants.nih.gov/grants/guide/rfa-files/RFA-FD-14-088.html
The adult doses of PEG 3350 tested were found to contain 0.3 mg of ethylene glycol of daily exposure for a 44 lb. child. This exposure is in addition to any EG and DEG exposure that may be found to occur from PEG 3350 degradation of the laxative products. The health effects of long term exposure of children to PEG 3350 are not known, although risks from short term exposure to EG and DEG are well documented in humans.
Empire State Consumer Project petitioned the FDA to issue a Drug Safety Communication regarding the finding of ethylene glycol and diethylene glycol in all lots of PEG 3350 it tested, so that parents of study participants and all parents can be made aware of the potential for PEG 3350 to contain ethylene glycol and diethylene glycol. This petition for a Drug Safety Communication was denied. Although another FDA test did not show the presence of EG and DEG, we have asked the FDA to perform ongoing testing of PEG 3350 products to show whether EG and DEG are contaminants, as one test is not a comprehensive study, nor an assurance of safety. Our request was denied.
The US Environmental Protection Agency (EPA) recommends that children not be exposed to more than 20 mg/L or 20 parts per million (ppm) of ethylene glycol in drinking water per one day or 6 mg/L or 6 ppm per day over 10 days. (The daily drinking water consumption for the 22 lb child is assumed to be 1 L/day.) PEG 3350 laxatives are allowed to contain up to 620 ppm ethylene glycol per 17 g dose.
https://docs.google.com/document/d/1YMOFPD4TFFlEMEuF6UDVPFSVHiIXHA_7WBx_VWiE79c/edit?usp=sharing
https://www.atsdr.cdc.gov/csem/csem.asp?csem=12&po=7
https://www.epa.gov/sites/production/files/2018-03/documents/dwtable2018.pdf
https://www.spectrumchemical.com/OA_HTML/SCI_DOCS/PO125_SD.pdf
Ethylene oxide causes reproductive harm; 1,4-dioxane causes reproductive harm in animals. Ethylene oxide can harm the brain and nervous system. Studies show that breathing air containing elevate ethylene oxide levels over many years increases the risks of some types of cancers of the white blood cells (including Non-Hodgkin’s Lymphoma, myeloma, and lymphocytic leukemia), and breast cancer in females. Recently, ethylene oxide has been in the news as the EPA shut down the Sterigenics facility in Willowbrook, Illinois for the toxic levels of ethylene oxide emitted by the company causing an “imminent and substantial endangerment to the community.”
The U.S. Environmental Protection Agency (EPA) has established a 1 day health advisory of 4.0 mg/L (4 ppm) and a 10 day health advisory of .4 mg/L (.4 ppm) for 1,4-dioxane for a 22 lb. (10 kg) child and a lifetime health advisory of .2 mg/L (.2 ppm) in drinking water. The daily drinking water consumption for the 22 lb child is assumed to be 1 L/day. PEG 3350 laxatives are allowed to contain up to 10 ppm 1,4-dioxane per 17 g dose.
https://www.atsdr.cdc.gov/phs/phs.asp?id=953&tid=199
https://www.epa.gov/sites/production/files/2014-03/documents/ffrro_factsheet_contaminant_14-dioxane_january2014_final.pdf
https://www.epa.gov/sites/production/files/2018-03/documents/dwtable2018.pdf
https://www.epa.gov/hazardous-air-pollutants-ethylene-oxide/fact-sheet-epa-taking-steps-address-emissions-ethylene-oxide
https://www.spectrumchemical.com/OA_HTML/SCI_DOCS/PO125_SD.pdf
The California Office of Environmental Health Hazard Assessment (OEHHA) has established Proposition 65 (Prop 65) thresholds for requiring the Prop 65 toxicity warning on products on products sold in California - No Significant Risk Levels (NSRLs) and Maximum Allowable Dose Levels (MADLs). These are adult levels, not levels allowed for children.
Chemical No Significant Risk Level Maximum Allowable Dose Level
Ethylene Glycol 8700 ug/day or 8.7 mg/day
(ingested)
Ethylene Oxide 2 ug/day or .002 mg/day 20 ug/day or .02 mg/day
1,4-Dioxane 30 ug/day or .03 mg/day
https://oehha.ca.gov/proposition-65/general-info/current-proposition-65-no-significant-risk-levels-nsrls-maximum
PEG 3350 is known to contain degradation products acetaldehyde, formaldehyde, and formic acid.
https://patentimages.storage.googleapis.com/f4/a3/e9/9dda8bcafbd410/US20140080918A1.pdf
From page 7 of the FDA document below ... "Rationale: PEG 3350, polyethylene glycol 3350, is one of the active ingredients of Plenvu, and could potentially be metabolized to multiple metabolites in vivo, if absorbed. There has been a notion that PEG3350 would not be absorbable upon oral administration because of its high molecular weight, and thus, the systemic exposure to PEG3350 and its metabolites have not been historically well characterized despite its wide spread use (e.g., colon preparation agencies). Importantly, some metabolites of PEG, such as ethylene glycol, and diethylene glycol, have been linked to potential toxicities in published literatures. Per published literature, PEG metabolites of interest are diethylene glycol, ethylene glycol, glycolic acid, diglycolic acid, glyoxylic acid, glycoaldehyde, oxalic acid, and 2-hydroxyethoxyacetic acid (HEAA). In this NDA, PEG 3350 concentrations found to be measurable in plasma when evaluated for a prototype formulation. However, PEG3350 concentration in plasma was not measured for the tobe-marketed formulation. Additionally, the systemic exposures of PEG metabolites after Plenvu administration were not studied and are unknown at this point. During the pre-NDA meeting dated 02/02/2016, the FDA had requested the sponsor to measure the PK of PEG3350 related metabolites. The sponsor clarified that blood samples from the clinical trial were no longer available for additional analyses for metabolites of PEG, and proposed to conduct a postmarketing study. The FDA agreed that the PK evaluation of PEG3350-related metabolites in human could be conducted as a post-marketing study. As such in this study, the systemic exposure of PEG3350 and its metabolites will be characterized for the to-be-marketed Plenvu. This study results should be used to inform the PK assessment for PEG and PEG metabolites in pediatric patients. "
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209381Orig1s000ClinPharmR.pdf
From the FDA regarding impurities in products being protected as trade secrets:
From: Earley, @fda.hhs.gov>
Sent: Friday, May 14, 2021 9:42 AM
"... Unfortunately, we are unable to provide the unredacted document for the reasons set forth below.
When a firm submits trade secret information or confidential commercial information to FDA, the agency is required to follow applicable federal disclosure laws and regulations that generally prohibit public disclosure of such information. Those federal laws include section 301(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. § 331(j)) (regarding trade secret information) and the Trade Secrets Act, 18 U.S.C. § 1905 (regarding both trade secret information and confidential commercial information). FDA’s main disclosure regulations may be found at 21 C.F.R. part 20, and you may wish to review, in particular, section 20.61 (21 C.F.R § 20.61).
FDA made the redactions in the email to withhold the names of impurities in the finished drug product and the specification for the impurities. The names of the impurities in a finished drug product, and the specifications for those impurities, can reveal a particular manufacturing step or component of the finished drug product. In general, FDA considers the names of impurities, and the specifications for those impurities, to be trade secret information. FDA generally is prohibited from releasing trade secret information under section 301(j) of the FD&C Act, section 1905 of the Trade Secrets Act, and section 20.61 of FDA’s regulations. Information that meets the definition of a trade secret is exempt from disclosure under the Freedom of Information Act (5 U.S.C § 552(b)(4)). ..."
PEG is not found in the human body, is not found in any food required by humans, and cannot be considered a natural substance by any scientific or consumer definition. Polyethylene glycol is a synthetic substance made from a chain of ethylene oxide (EO) molecules through a manufacturing process and may break down into ethylene glycol (EG) and/or diethylene glycol (DEG) in the body. EG and DEG are key ingredients in antifreeze, and are toxic to humans. Potential for PEG 3350 to break down into EG and/or DEG is being studied by the U.S. Food and Drug Administration (FDA) as a result of our 2012 FDA petition regarding PEG 3350 safety in children.https://www.regulations.gov/searchResults?rpp=25&po=0&s=fda-2012-p-0566&fp=true&ns=true
The PEG 3350 safety concerns acknowledged by the FDA include symptoms similar to those of ethylene glycol toxicity. Empire State Consumer Project’s FDA Citizen Petition grant includes an agreement by the FDA to study the potential for PEG 3350 to degrade into ethylene glycol (EG) and diethylene glycol (DEG), and to study the long term effects of PEG 3350 products on pediatric patients. Ethylene glycol and diethylene glycol are synthetic chemicals used to make antifreeze. Both are toxic to the central nervous system, liver, and kidneys when ingested. In recent history, DEG contaminated cough and acetaminophen syrups killed hundreds of adults and children. In 2007, the FDA issued a warning for consumers not to buy toothpaste from China, as some brands were made with DEG.
In addition to the ethylene glycol and diethylene glycol children may be exposed to through the degradation of PEG 3350, the FDA has tested 8 lots of polyethylene glycol 3350 and found ethylene glycol and diethylene glycol contaminants in the product itself… “To better understand the level of polyethylene glycol impurities in PEG, the FDA Chemistry and Manufacturing group evaluated PEG 3350. This analysis of eight lots of PEG 3350 confirmed the presence of small amounts of ethylene glycol and diethylene glycol in all lots tested. Based upon the recommended daily adult dose of 17g daily dose PEG 3350, the maximum daily exposure of ethylene glycol would be 0.005 mg/kg/day for a 60 kg patient, or 0.015 mg/kg/day for a 20 kg pediatric patient (approx 5 years of age). Other low molecular weight (LMW) PEGs were not included in this analysis. However, it is not known if any of these LMW species are absorbed and if so to what extent. Understanding the human absorption profile of LMW species is the first step needed in trying to understand the possible contribution of PEG 3350 use to the development of adverse events in children using this product chronically.”
https://grants.nih.gov/grants/guide/rfa-files/RFA-FD-14-088.html
The adult doses of PEG 3350 tested were found to contain 0.3 mg of ethylene glycol of daily exposure for a 44 lb. child. This exposure is in addition to any EG and DEG exposure that may be found to occur from PEG 3350 degradation of the laxative products. The health effects of long term exposure of children to PEG 3350 are not known, although risks from short term exposure to EG and DEG are well documented in humans.
Empire State Consumer Project petitioned the FDA to issue a Drug Safety Communication regarding the finding of ethylene glycol and diethylene glycol in all lots of PEG 3350 it tested, so that parents of study participants and all parents can be made aware of the potential for PEG 3350 to contain ethylene glycol and diethylene glycol. This petition for a Drug Safety Communication was denied. Although another FDA test did not show the presence of EG and DEG, we have asked the FDA to perform ongoing testing of PEG 3350 products to show whether EG and DEG are contaminants, as one test is not a comprehensive study, nor an assurance of safety. Our request was denied.
The US Environmental Protection Agency (EPA) recommends that children not be exposed to more than 20 mg/L or 20 parts per million (ppm) of ethylene glycol in drinking water per one day or 6 mg/L or 6 ppm per day over 10 days. (The daily drinking water consumption for the 22 lb child is assumed to be 1 L/day.) PEG 3350 laxatives are allowed to contain up to 620 ppm ethylene glycol per 17 g dose.
https://docs.google.com/document/d/1YMOFPD4TFFlEMEuF6UDVPFSVHiIXHA_7WBx_VWiE79c/edit?usp=sharing
https://www.atsdr.cdc.gov/csem/csem.asp?csem=12&po=7
https://www.epa.gov/sites/production/files/2018-03/documents/dwtable2018.pdf
https://www.spectrumchemical.com/OA_HTML/SCI_DOCS/PO125_SD.pdf
Ethylene oxide causes reproductive harm; 1,4-dioxane causes reproductive harm in animals. Ethylene oxide can harm the brain and nervous system. Studies show that breathing air containing elevate ethylene oxide levels over many years increases the risks of some types of cancers of the white blood cells (including Non-Hodgkin’s Lymphoma, myeloma, and lymphocytic leukemia), and breast cancer in females. Recently, ethylene oxide has been in the news as the EPA shut down the Sterigenics facility in Willowbrook, Illinois for the toxic levels of ethylene oxide emitted by the company causing an “imminent and substantial endangerment to the community.”
The U.S. Environmental Protection Agency (EPA) has established a 1 day health advisory of 4.0 mg/L (4 ppm) and a 10 day health advisory of .4 mg/L (.4 ppm) for 1,4-dioxane for a 22 lb. (10 kg) child and a lifetime health advisory of .2 mg/L (.2 ppm) in drinking water. The daily drinking water consumption for the 22 lb child is assumed to be 1 L/day. PEG 3350 laxatives are allowed to contain up to 10 ppm 1,4-dioxane per 17 g dose.
https://www.atsdr.cdc.gov/phs/phs.asp?id=953&tid=199
https://www.epa.gov/sites/production/files/2014-03/documents/ffrro_factsheet_contaminant_14-dioxane_january2014_final.pdf
https://www.epa.gov/sites/production/files/2018-03/documents/dwtable2018.pdf
https://www.epa.gov/hazardous-air-pollutants-ethylene-oxide/fact-sheet-epa-taking-steps-address-emissions-ethylene-oxide
https://www.spectrumchemical.com/OA_HTML/SCI_DOCS/PO125_SD.pdf
The California Office of Environmental Health Hazard Assessment (OEHHA) has established Proposition 65 (Prop 65) thresholds for requiring the Prop 65 toxicity warning on products on products sold in California - No Significant Risk Levels (NSRLs) and Maximum Allowable Dose Levels (MADLs). These are adult levels, not levels allowed for children.
Chemical No Significant Risk Level Maximum Allowable Dose Level
Ethylene Glycol 8700 ug/day or 8.7 mg/day
(ingested)
Ethylene Oxide 2 ug/day or .002 mg/day 20 ug/day or .02 mg/day
1,4-Dioxane 30 ug/day or .03 mg/day
https://oehha.ca.gov/proposition-65/general-info/current-proposition-65-no-significant-risk-levels-nsrls-maximum
PEG 3350 is known to contain degradation products acetaldehyde, formaldehyde, and formic acid.
https://patentimages.storage.googleapis.com/f4/a3/e9/9dda8bcafbd410/US20140080918A1.pdf
From page 7 of the FDA document below ... "Rationale: PEG 3350, polyethylene glycol 3350, is one of the active ingredients of Plenvu, and could potentially be metabolized to multiple metabolites in vivo, if absorbed. There has been a notion that PEG3350 would not be absorbable upon oral administration because of its high molecular weight, and thus, the systemic exposure to PEG3350 and its metabolites have not been historically well characterized despite its wide spread use (e.g., colon preparation agencies). Importantly, some metabolites of PEG, such as ethylene glycol, and diethylene glycol, have been linked to potential toxicities in published literatures. Per published literature, PEG metabolites of interest are diethylene glycol, ethylene glycol, glycolic acid, diglycolic acid, glyoxylic acid, glycoaldehyde, oxalic acid, and 2-hydroxyethoxyacetic acid (HEAA). In this NDA, PEG 3350 concentrations found to be measurable in plasma when evaluated for a prototype formulation. However, PEG3350 concentration in plasma was not measured for the tobe-marketed formulation. Additionally, the systemic exposures of PEG metabolites after Plenvu administration were not studied and are unknown at this point. During the pre-NDA meeting dated 02/02/2016, the FDA had requested the sponsor to measure the PK of PEG3350 related metabolites. The sponsor clarified that blood samples from the clinical trial were no longer available for additional analyses for metabolites of PEG, and proposed to conduct a postmarketing study. The FDA agreed that the PK evaluation of PEG3350-related metabolites in human could be conducted as a post-marketing study. As such in this study, the systemic exposure of PEG3350 and its metabolites will be characterized for the to-be-marketed Plenvu. This study results should be used to inform the PK assessment for PEG and PEG metabolites in pediatric patients. "
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209381Orig1s000ClinPharmR.pdf
From the FDA regarding impurities in products being protected as trade secrets:
From: Earley, @fda.hhs.gov>
Sent: Friday, May 14, 2021 9:42 AM
"... Unfortunately, we are unable to provide the unredacted document for the reasons set forth below.
When a firm submits trade secret information or confidential commercial information to FDA, the agency is required to follow applicable federal disclosure laws and regulations that generally prohibit public disclosure of such information. Those federal laws include section 301(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. § 331(j)) (regarding trade secret information) and the Trade Secrets Act, 18 U.S.C. § 1905 (regarding both trade secret information and confidential commercial information). FDA’s main disclosure regulations may be found at 21 C.F.R. part 20, and you may wish to review, in particular, section 20.61 (21 C.F.R § 20.61).
FDA made the redactions in the email to withhold the names of impurities in the finished drug product and the specification for the impurities. The names of the impurities in a finished drug product, and the specifications for those impurities, can reveal a particular manufacturing step or component of the finished drug product. In general, FDA considers the names of impurities, and the specifications for those impurities, to be trade secret information. FDA generally is prohibited from releasing trade secret information under section 301(j) of the FD&C Act, section 1905 of the Trade Secrets Act, and section 20.61 of FDA’s regulations. Information that meets the definition of a trade secret is exempt from disclosure under the Freedom of Information Act (5 U.S.C § 552(b)(4)). ..."