Comment Period - Intent to List: Atrazine, Propazine, Simazine and their Chlorometabolites DACT, DEA and DIA

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to list the chemicals identified in the table below as known to the State to cause reproductive toxicity under the Safe Drinking Water and Toxic Enforcement Act of 1986.¹ This action is being proposed under the authoritative bodies listing mechanism.²

Background on listing via the authoritative bodies mechanism: A chemical must be listed under Proposition 65³ and its implementing regulations when two conditions are met:

1. An authoritative body formally identifies the chemical as causing reproductive toxicity (Section 25306(d)⁴).
2. The evidence considered by the authoritative body meets the sufficiency criteria contained in the regulations (Section 25306(g)).

However, the chemical is not listed if scientifically valid data which were not considered by the authoritative body clearly establish that the sufficiency of evidence criteria were not met (Section 25306(h)).

The U.S. Environmental Protection Agency (U.S. EPA) is one of several institutions designated as authoritative for the identification of chemicals as causing reproductive toxicity (Section 25306(l)).

OEHHA is the lead agency for Proposition 65 implementation. After an authoritative body has made a determination about a chemical, OEHHA evaluates whether listing under Proposition 65 is required using the criteria contained in the regulations.

OEHHA’s determination: Atrazine, propazine, simazine and their chlorometabolites 2,3-diamino-6-chloro-s-triazine (DACT), des-ethyl atrazine (DEA), and des-isopropyl atrazine (DIA) meet the criteria for listing as known to the State to cause reproductive toxicity under Proposition 65, based on findings of the U.S. EPA (2002a, 2002b, 2005, 2006a, 2006b, 2006c, 2006d), as outlined below.

Formal identification and sufficiency of evidence: OEHHA is relying on the U.S. EPA’s conclusion that the triazine pesticides atrazine, propazine, simazine and their chlorometabolites DACT, DEA, and DIA cause developmental and reproductive effects through a common mechanism of toxic action. This conclusion meets the requirements of Section 26306(d)(1)⁵ and is made in a number of U.S. EPA documents, including:

• Triazine Cumulative Risk Assessment (U.S. EPA, 2006b)
• 2006 Decision Documents for Atrazine (U.S. EPA, 2006a)
• Atrazine. Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision Document (Second revision) (U.S. EPA, 2002a)
• Memorandum on ATRAZINE/DACT - Fourth Report of the Hazard Identification Assessment Review Committee (U.S. EPA, 2002b)
• Reregistration Eligibility Decision Document for Simazine (U.S. EPA, 2006d)
• Propazine: Revised HED [Health Effects Division] Risk Assessment for the Tolerance Reassessment Eligibility Decision Document (TRED) (U.S. EPA, 2005)
• Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Propazine (U.S. EPA, 2006c)

In addition, U.S. EPA established several reference doses (RfDs) on the basis of reproductive and developmental toxicity, relying on endpoints that included luteinizing hormone (LH) surge suppression and estrous cycle alterations and delayed ossification of certain cranial bones in fetuses. This also meets the requirements of Section 26306(d)(1)⁶.

Thus, the findings and regulatory actions in these documents satisfy the formal identification and sufficiency of evidence criteria in the Proposition 65 regulations for listing these chemicals.

In several reports, U.S. EPA concluded that these three triazines and their chlorinated metabolites (DACT, DEA, DIA) cause developmental and reproductive toxicity and that these toxic effects are mediated through a common mechanism of action involving disruption of the hypothalamic-pituitary-gonadal (HPG) axis and suppression of luteinizing hormone (LH) surge. The conclusions in the U.S. EPA reports include the following:

Triazine Cumulative Risk Assessment (U.S. EPA, 2006b):

• “The underlying mechanism of the endocrine-related changes associated with atrazine and similar triazines is understood to involve a disruption of the hypothalamic-pituitary-gonadal (HPG) axis… In particular, the triazine-mediated changes in the HPG relating to neuroendocrine and neuroendocrine-related developmental and reproductive toxicity are considered relevant to humans, and these adverse effects were identified as endpoints for the exposure scenarios selected for consideration in the quantitative cumulative assessment.” (p. 4)
• “Atrazine, Simazine, Propazine, and the metabolites Desethyl-s-atrazine (DEA), Desisopropyl-s-atrazine (DIA), and Diaminochlorotriazine (DACT) may be grouped together based on a common end-point (neuroendocrine and neuroendocrine-related developmental, reproductive and carcinogenic effects) and a known mechanism of toxicity for this endpoint.” (p. 11)
• In concluding what the critical toxicological effects were for the “common mechanism group (CMG)” triazines (atrazine, simizine, propazine, DEA, DIA, DACT), U.S. EPA stated:
  • “Neuroendocrine effects are considered the critical endpoints for assessing the health effects of the CMG Triazines. The CMG triazines have been shown to lead to various endocrine-related changes as a result of an effect on the hypothalamic-pituitary-gonadal axis. The consequences of this action include a diminishment of hypothalamic gonadotrophin releasing hormone (GnRH) and norepinephrine levels. These triazines also increase dopamine level which can result in a diminished pituitary secretion of PRL [prolactin]. Therefore, the CMG triazines operate at the level of the hypothalamus. In both humans and rats, hypothalamic GnRH controls pituitary hormone secretion (e.g., luteinizing hormone and PRL).
  • The hypothalamic-pituitary axis is involved in the development of the reproductive system, and its maintenance and functioning in adulthood. Additionally, reproductive hormones modulate the function of numerous other metabolic processes (i.e., bone formation, and immune, central nervous system, and cardiovascular functions). Therefore, altered hypothalamic-pituitary function can potentially broadly affect an individual’s functional status and lead to a variety of health consequences.” (p. 22)
• The selected endpoints for cumulative risk assessment for the CMG triazines for dietary (drinking water) 90-day exposure scenarios was based on LH surge suppression and estrous cycle alterations. (p. 23)

Interim Reregistration Eligibility Decision for Atrazine (U.S. EPA, 2006a):

• “EPA has determined that the triazine pesticides (with a common mechanism group of atrazine, propazine, simazine and their chlorometabolites) have common mechanism of suppression of LH surge and consequent developmental and reproductive effects.” (p. 17)
• Developmental toxicity (“Delayed ossification of certain cranial bones in fetuses”) was the basis of the acute dietary reference dose (RfD) for atrazine and its chlorinated metabolites (p. 19).
• Attenuation of pre-ovulatory LH surge was the basis for the chronic RfD (p. 19).

Reregistration Eligibility Decision Document for Simazine (U.S. EPA, 2006d):

• “After subchronic and chronic exposure to simazine, a variety of species were shown to exhibit neuroendocrine effects resulting in both reproductive and developmental consequences that are considered relevant to humans.” (p. 14)
• Increased incidence of fetal “unossified teeth, head, centra vertebrae, sternabrae, and also on rudimentary ribs” was the basis for simazine’s acute RfD for females ages 13-49. (p. 16)
• Estrous cycle alterations and LH surge suppression was the basis for RfDs for chronic dietary, incidental oral intermediate-term, and dermal and inhalation intermediate and long-term exposures. (pp. 16-17)

Report of the FQPA TRED for Propazine (U.S. EPA 2006c):

• “In a sub-chronic developmental study, incomplete or absent bone formation or ossification was observed in fetal rats following exposure of pregnant rats to propazine. These developmental effects are presumed to occur after a single exposure and are therefore appropriate for consideration in the acute exposure scenario for dietary risk from food. These adverse effects were the basis for identification of a developmental endpoint for acute dietary exposure to propazine in females ages 13 to 49.” (p. 3)
• “Propazine’s two chlorinated degradates, DEA and DACT, are considered to have toxicity equal to the parent compound in respect to their common neuroendocrine mechanism of toxicity.” (p. 4)

Propazine: Revised HED Risk Assessment for the TRED (U.S. EPA, 2005):

• Propazine and atrazine’s mechanism of toxicity “involves a central nervous system (CNS) toxicity, specifically, neurotransmitter and neuropeptide alterations at the level of the hypothalamus, which cause cascading changes to hormone levels, e.g., suppression of the luteinizing hormone surge prior to ovulation resulting in prolonged estrus in adult female rats (demonstrated with atrazine and propazine), and developmental delays, i.e., delayed vaginal opening and preputial separation in developing rats (studied in atrazine and propazine). These neuroendocrine effects are considered the primary toxicological effects of regulatory concern.” (p. 17)
• “Propazine is considered to be of equal potency to atrazine, simazine and the chlorinated degradates with respect to their common mechanism of toxicity, based on the available data on simazine and propazine, which indicate comparable endocrine effects to atrazine. It was concluded that atrazine data can be used as bridging data for propazine because propazine, simazine and atrazine share a common mechanism of toxicity based on neuroendocrine effects, the database for propazine’s potential neuroendocrine effects is less robust than the atrazine database, particularly for the young, and neuroendocrine effects are the effects of primary regulatory concern.

Therefore, for endpoint selection, the team considered atrazine endocrine-related data for selection of endpoints for propazine. Atrazine’s neuroendocrine-related endpoints were selected for all risk assessment scenarios for propazine, except for the acute reference dose which was based on a study conducted with propazine which found developmental effect (incomplete ossification), the nature of which is not clearly linked to an endocrine mechanism.” (pp. 17-18)

OEHHA has reviewed the studies or study descriptions cited by the U.S. EPA (2002a,b, 2005, 2006a,b,c,d) as providing the basis for the Agency’s conclusions regarding the reproductive and developmental toxicity relative to the criteria in Section 25306(g). The criteria for listing atrazine, propazine, simazine and their chlorometabolites DACT, DEA, and DIA through the authoritative bodies mechanism as causing reproductive toxicity (female reproductive and developmental endpoints) have been met.

Request for comments: OEHHA is requesting comments as to whether these chemicals meet the criteria set forth in the Proposition 65 regulations for authoritative bodies listings.

In order to be considered, comments must be received by OEHHA by 5:00 p.m. on Monday, March 24, 2014 Monday, March 10, 2014. We encourage you to submit comments in electronic form, rather than in paper form. Comments transmitted by e-mail should be addressed to P65Public.Comments@oehha.ca.gov with “NOIL - triazines” in the subject line. Comments submitted in paper form may be mailed, faxed, or delivered in person to the addresses below:

Mailing Address: Sam Delson
Office of Environmental Health Hazard Assessment
P.O. Box 4010, MS-19B
Sacramento, California 95812-4010
Fax: (916) 323-2265
Street Address: 1001 I Street
Sacramento, California 95814

Comments received during the public comment period will be posted on the OEHHA web site after the close of the comment period.

If you have any questions, please contact Sam Delson at sam.delson@oehha.ca.gov or at (916) 445-6900.

References

U.S. Environmental Protection Agency (U.S. EPA, 2002a). Atrazine (PC Code: 080803). Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision Document (Second Revision). April 11, 2002.

U.S. Environmental Protection Agency (U.S. EPA, 2002b). Office of Pesticide Programs. Special Docket for Pesticide Reregistration Risk Assessments. Memorandum on ATRAZINE/DACT - Fourth Report of the Hazard Identification Assessment Review Committee. TXR NO. 0050592.

U.S. Environmental Protection Agency (U.S. EPA, 2005). Propazine: Revised HED Risk Assessment for the Tolerance Reassessment Eligibility Decision (TRED) which includes a New Use on Grain Sorghum. PC Code: 080808, DP Barcode: D323271 Memorandum from J. Morales et al. Office of Pesticide Programs and Toxic Substances (OPPTS) Health Effects Division to D. Sherman OPPTS, December 13, 2005.

U.S. Environmental Protection Agency (U.S. EPA, 2006a). Decision Documents for Atrazine. U.S. EPA Office of Prevention, Pesticides and Toxic Substances.

U.S. Environmental Protection Agency (U.S. EPA, 2006b). Triazine Cumulative Risk Assessment (March 28, 2006).

U.S. Environmental Protection Agency (U.S. EPA, 2006c). Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Propazine. U.S. EPA Office of Prevention, Pesticides and Toxic Substances, EPA 738-R-06-009.

U.S. Environmental Protection Agency (U.S. EPA, 2006d). Reregistration Eligibility Decision Document for Simazine. U.S. EPA Office of Prevention, Pesticides and Toxic Substances. EPA 738-R-06-008.

¹ Commonly known as Proposition 65, the Safe Drinking Water and Toxic Enforcement Act of 1986 is codified in Health and Safety Code section 25249.5 et seq.

² See Health and Safety Code section 25249.8(b) and Title 27, Cal. Code of Regs., section 25306.

³ Health and Safety Code section 25249.8(b).

⁴ All referenced sections are from Title 27 of the Cal. Code of Regulations.

⁵ “the chemical … is the subject of a report which is published by the authoritative body and which concludes that the chemical causes … reproductive toxicity”.

⁶ “the chemical … has otherwise been identified as causing … reproductive toxicity by the authoritative body in a document that indicates that such identification is a final action”.

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