 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
			WASHINGTON, D.C.  20460


							OFFICE OF CHEMICAL SAFETY 								AND POLLUTION PREVENTION



MEMORANDUM  

DATE:		June 3, 2020

SUBJECT:      IN-11325; Magnesium Sulfate Anhydrous and Hydrated Forms: Human Health 
      Risk and Ecological Effects Assessment of a Food Use Pesticide Inert Ingredient 
 
            CAS Reg. Nos.: 7487-88-9, 14168-73-1, 15320-30-6, 24378-31-2, 15553-21-6, 
                           17830-18-1, 10034-99-8	 
                  PC Code:  850503     
                  Decision:  551826

FROM:	Deirdre Sunderland, MHS, Industrial Hygienist
		Chemistry, Inerts & Toxicology Assessment Branch (CITAB)
		Registration Division (RD)
	

TO:		Kerry B. Leifer, Branch Chief
		CITAB/RD 


 EXECUTIVE SUMMARY

In June 2019, Ecolab, Inc. submitted a petition (IN-11325) to the Environmental Protection Agency (herein referred to as EPA or the Agency) requesting exemptions from the requirement of a tolerance for residues of magnesium sulfate anhydrous (CAS Reg. No. 7487-88-9) and its hydrated forms: magnesium sulfate monohydrate (CAS Reg. No. 14168-73-1); magnesium sulfate trihydrate (CAS Reg. No. 15320-30-6); magnesium sulfate tetrahydrate (CAS Reg. No. 24378- 31-2); magnesium sulfate pentahydrate (CAS Reg. No. 15553-21-6); magnesium sulfate hexahydrate (CAS Reg. No. 17830-18-1); and magnesium sulfate heptahydrate (CAS Reg. No. 10034-99-8), when used as an inert ingredient in antimicrobial pesticide formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils under 40 CFR § 180.940(a) at a maximum end-use concentration of 4400 parts per million (ppm). For ease of reading, this group of chemicals will be referred to as magnesium sulfate throughout the document. 

Magnesium sulfate is ubiquitous in the environment and is currently approved for use as a food use inert ingredient (solid diluent, carrier, safener) in pesticide products under 40 CFR § 180.910 for use pre- and post-harvest. It is also used in various other non-pesticidal food and consumer products, including pharmaceuticals, dietary supplements, fertilizers, cosmetics, and as a food and beverage additive. One form, magnesium sulfate heptahydrate, also known as Epsom salt, has been used for centuries as an over the counter laxative and a soaking agent for aching joints.  

Because of its omnipresence and high use pattern, magnesium sulfate has been the subject of various peer-reviewed assessments (e.g., Cosmetic Ingredient Review (CIR), and Organization for Economic Cooperation and Development (OECD)) which are utilized in this risk assessment to aid in making a safety determination for magnesium sulfate. Available acute studies on magnesium sulfate include an oral toxicity study, a dermal irritation study, and a dermal sensitization study. Repeat dose toxicity testing for magnesium sulfate includes an OECD Test Guideline 422: Combined Repeat Dose Reproduction/Developmental Toxicity Screening Test and a 1-year inhalation cancer study in rats. Magnesium sulfate was also tested for genotoxic and/or mutagenic effects using a bacterial reverse mutation test and an in vitro mammalian chromosome aberration test. 

All studies showed low acute and repeat dose toxicity and no reproductive/developmental toxicity. The primary health effect associated with magnesium sulfate is an osmotic laxative effect at high doses. The laxative effect is transient, and recovery is rapid and is usually observed only when following acute exposures to high concentrations (e.g., pharmacological uses). 

The OECD Test Guideline 422 study showed no adverse effect at the No Observed Adverse Effect Level (NOAEL) of 450 mg/kg/day, the highest dose tested. In addition, there was no evidence of carcinogenicity or neuropathological changes or effects reported in any of the studies. The Agency therefore does not believe magnesium sulfate is carcinogenic or neurotoxic. 

Magnesium sulfate is currently approved for use under 40 CFR §180.910 and a review of currently approved pesticide products containing magnesium sulfate found that the majority of products were lawn care products and products used in swimming pools. Ecolab, Inc. is requesting that EPA establish an exemption from the requirement of a tolerance for magnesium sulfate for use in antimicrobial pesticide formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils at a maximum concentration of 4400 ppm. Based on the current and proposed use patterns of magnesium sulfate, dietary and residential exposure from pesticidal uses are expected. However, no toxicological endpoint of concern was identified in the database; therefore, a quantitative risk assessment was not necessary. As part of its qualitative assessment, the Agency did not use safety factors for assessing risk, and no additional safety factor is needed for assessing risk to infants and children. 

Magnesium sulfate is found naturally in water, and based on various aquatic studies, it does not present a hazard for aquatic systems or the environment. Overall, the widespread use of magnesium sulfate in foods, drugs, and cosmetics, in combination with the natural occurrence of both magnesium and sulfate in the body, indicate that this compound does not pose a safety risk from these uses. 

Based upon the factors summarized above, the Agency has determined that there is a reasonable certainty that no harm to the general population or any population subgroup, including infants and children, will result from aggregate exposure to magnesium sulfate residues. Therefore, the Agency is establishing exemptions from the requirement of a tolerance for residues of magnesium sulfate under 40 CFR § 180.940(a) when used as an inert ingredient in antimicrobial pesticide formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils at a maximum end-use concentration of 4400 ppm. 

 BACKGROUND

In June 2019 Ecolab, Inc. submitted a petition (IN-11325) to the Environmental Protection Agency (herein referred to as EPA or the Agency) requesting an exemption from the requirement of tolerance for magnesium sulfate anhydrous (CAS Reg. No. 7487-88-9) and its hydrated forms: magnesium sulfate monohydrate (CAS Reg. No. 14168-73-1); magnesium sulfate trihydrate (CAS Reg. No. 15320-30-6); magnesium sulfate tetrahydrate (CAS Reg. No. 24378- 31-2); magnesium sulfate pentahydrate (CAS Reg. No. 15553-21-6); magnesium sulfate hexahydrate (CAS Reg. No. 17830-18-1); and magnesium sulfate heptahydrate (CAS Reg. No. 10034-99-8) as inert ingredients in pesticide formulations under 40 CFR § 180.940 (a) at a maximum of concentration of 4400 parts per million (ppm) when used in antimicrobial formulations applied to food-contact surfaces in public eating places, dairy processing equipment, food-processing equipment and utensils. For ease of reading this group of chemicals will be referred to as magnesium sulfate throughout the document. Magnesium sulfate is currently approved for use as a food use inert ingredient (solid diluent, carrier, safener) in pesticide products under 40 CFR § 180.910 for use pre- and post-harvest. 

In addition to its natural abundance in the enviroment, magnesium sulfate is broadly used in pharmaceuticals, foods and beverages, dietary supplement, fertilizers, and cosmetics. Magnesium sulfate is used in both human and animal pharmaceutical products for its effect as an analgesic, anesthetic, anti-arrhythmia agent, anticonvulsant, calcium channel blocker, cathartic, tocolytic agent, bronchodilator, electrolyte replacement aid, laxative, and treatment of cardiac arrhythmias and malignant hypothermia. It is commonly administered by injection or intravenously for the prevention and control of seizures in preeclampsia and eclampsia in pregnant women. Magnesium sulfate heptahydrate, known as Epsom salt, is an over-the-counter (OTC) drug and cosmetic ingredient. It is commonly dissolved in bathwater as an analgesic soaking agent. As a cosmetic, it is used at concentrations up to 11% and 25% in leave-on and rinse-off products, respectively (MRID 50871303).

In 2007, the Food and Agricultural Organization of the United Nations (FAO) and the World Health Organization (WHO) Joint Expert Committee on Food Additives (JECFA) concluded that the Acceptable Daily Intake (ADI) of magnesium sulfate was "not specified": 

	Taking into consideration 1) the widespread occurrence of magnesium and
      sulfate in the food supply from natural sources and use of other magnesium
      salts as additives, 2) the uses of magnesium sulfate as a flavour enhancer,
      firming agent, fermentation aid and nutrient and 3) the previous guidance of
      the Committee regarding various cation and anion combinations, the Committee 
      allocated an ADI "not specified" for magnesium sulfate.  (MRID 50871309)

Magnesium and sulfate are ubiquitous in the earth's crust representing the 8[th] and 14[th] most abundant elements, respectively. Both magnesium and sulfate are essential for the human body. 

 PHYSICAL/CHEMICAL PROPERTIES 

Below are the available physical and chemical properties for magnesium sulfate. Table 1 list the anhydrous and hydrated forms of magnesium sulfate supported by this petition. Table 2 outlines some of the physical/chemical characteristics of magnesium sulfate anhydrous. 

           Table 1: Chemical Identity of Magnesium Sulfate Compounds
Chemical Name
Chemical Formula
CAS Reg. No.
Molecular Weight
Magnesium sulfate anhydrous
MgSO4
7487-88-9
120. 37
Magnesium sulfate monohydrate
MgSO4·H2O
14168-73-1
138.38
Magnesium sulfate trihydrate
MgSO4·3H2O
15320-30-6
174.41
Magnesium sulfate tetrahydrate
MgSO4·4H2O
24378-31-2
192.42
Magnesium sulfate pentahydrate
MgSO4·5H2O
5553-21-6
219.44
Magnesium sulfate hexahydrate
MgSO4·6H2O
7830-18-1
228.46
Magnesium sulfate heptahydrate
MgSO4·7H2O
10034-99-8
246.47

Magnesium sulfate is freely soluble in water and will dissociate into magnesium and sulfate ions. Magnesium (Mg[2+]) is likely to form complexes with ligands like organic matter. Sulfate (SO4[2-]) may reduce under anaerobic conditions to sulfide ion, which in turn will reach an equilibrium with hydrogen sulfide. Indices of environmental fate such as log Kow, log Koc, biodegradation and photolysis do not apply to inorganic substances like magnesium sulfate.

     Table 2: Physical/Chemical Properties of Magnesium Sulfate Anhydrous
Characteristic
Value
Source
Structure


MRID 50871314
Appearance
White crystalline powder or needle-like colorless crystals
MRID 50871314
Density (g/cm[3])
 2.66
MRID 50871314
Melting point
1124 °C
MRID 50871314
Water Solubility (g/L)
357 at 25˚C
MRID 50871314

Based on the solubility of magnesium sulfate in water the anhydrous and hydrated forms would be indistinguishable in the environment. 

 METABOLISM
                                                                               
Magnesium sulfate dissociates into magnesium and sulfate ions in the gastrointestinal tract after reaction with gastric acids. Magnesium is a macronutrient and serves vital functions in the human body. It is ubiquitous in the environment and all living things. According to the National Institutes of Health (MRID 50871311), "magnesium is a cofactor for over 300 metabolic enzyme systems that regulate diverse biochemical reactions in the body including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation. It is required for energy production, oxidative phosphorylation, and glycolysis, contributes to the structural development of bone, and is also required for the synthesis of DNA, RNA, and the antioxidant glutathione. "Magnesium also plays a role in the active transport of calcium and potassium ions across cell membranes, a process that is important to nerve impulse conduction, muscle contraction, and normal heart rhythm."  

Magnesium is absorbed primarily in the small intestine. Most magnesium in the body is found inside cells or in bone; however, some magnesium is present in every cell of the body. In blood plasma, about 65 percent is the ionic form while the remainder is bound to protein. The balance in the body is regulated by intestinal absorption, exchange with bone, and renal excretion (MRID 50871317). Urine is the major route of excretion under normal conditions, although excretion through sweat and milk is also possible (MRID 50871314). Magnesium is filtered by the glomeruli and reabsorbed by renal tubules. Unabsorbed magnesium is excreted primarily in the feces. 

Sulfates are naturally occurring abundant substances that are found in minerals, soil, and rocks. They are present in ambient air, groundwater, plants, and food. Sulfate is also an important macronutrient, necessary for the normal function of cells. Sulfate absorption is determined by the dose and the accompanying anion, with magnesium being poorly absorbed in general. It is the fourth most abundant anion in human plasma (300 μM) (MRID 50871321) and all cells have sulfate transporters for the influx/efflux of sulfate.

According to the 2005 US Institutes of Medicine "Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (MRID 50871307)": 

      Inorganic sulfate (SO4[2−]) is required for the synthesis of 3′-phosphoadenosine-5′-phosphosulfate (PAPS). PAPS is required for synthesis of many important sulfur-containing compounds, such as chondroitin sulfate and cerebroside sulfate. While significant levels of sulfate are found in foods and various sources of drinking water, the major source of inorganic sulfate for humans is from biodegradation due to body protein turnover of the sulfur amino acids methionine and cysteine. Dietary sulfate in food and water, together with sulfate derived from methionine and cysteine found in dietary protein and the cysteine component of glutathione, provides sulfate for use in PAPS biosynthesis. Sulfate requirements are thus met when intakes include recommended levels of sulfur amino acids. For this reason, neither an Estimated Average Requirement (and thus a Recommended Dietary Allowance) nor an Adequate Intake for sulfate is established.

Sulfate is absorbed from the intestine by an active transport system. Low doses of sulfate are generally absorbed well while high doses, such as those used medicinally to soften stool, probably exceed absorptive capacity, so that much of the dose is excreted in the feces. Sulfate is also used for detoxification of compounds to sulfate esters, which can be excreted in the urine. Sulfate is eliminated by the kidney, and levels are regulated by the kidney through a reabsorption mechanism. (MRID 50871321).

 TOXICOLOGY

Available toxicity data for magnesium sulfate are summarized below. The primary adverse health effect associated with magnesium sulfate is an osmotic laxative effect at high doses. The laxative effect is transient, and recovery is rapid and is usually only observed when following acute exposures to relatively high concentrations (e.g., pharmacological uses). 

 Acute Toxicity

Data on acute toxicity, as well as data on eye and skin irritation and skin sensitization, are discussed in this section. 

 Acute Oral Toxicity 
An acute oral toxicity study (Organization for Economic Cooperation and Development (OECD) Test Guideline 423) on magnesium sulfate anhydrous was performed with female Sprague-Dawley rats (MRID 50871314). Magnesium sulfate was administered at 300 and 2,000 mg/kg via gavage and animals (6/dose) were observed for 14 days. Clinical signs of toxicity were recorded at 30 minutes, 1, 2, 3, 4 and 8 hours after administration, then once per day until the end of testing. No deaths were observed, and bodyweights increased normally. At the high dose, diarrhea and watery diarrhea were present for the first 8 hours. No clinical signs of toxicity were noted at 300 mg/kg. No reduction in body weight or macroscopic abnormalities were noted at either dose. The oral median lethal dose (LD50) value was determined to be >2,000 mg/kg for female rats. 
 Acute Dermal Toxicity
No acute dermal toxicity studies were available for magnesium sulfate; however, magnesium sulfate heptahydrate (i.e., Epsom salts) has a long history of over the counter use as an analgesic via full body soaking which would indicate that this compound is not likely to be toxic via the dermal route.

 Acute Inhalation Toxicity
           
No acute inhalation toxicity studies are available for magnesium sulfate. 
 Skin Irritation 
A preliminary skin irritation study (MRID 50871303) was performed in mice prior to a skin sensitization study described in Section 5.1.6. A 50% solution of anhydrous magnesium sulfate was applied to the ears of two animals on three consecutive days. Observations were recorded at approximately 3-4 hours after the last application. No skin irritation or macroscopic abnormalities were observed in any of the animals.
 Eye Irritation 
There are no eye irritation studies available for magnesium sulfate. However, the widespread use of magnesium sulfate in foods, drugs, and cosmetics, in combination with the natural occurrence of both magnesium and sulfate in the body, indicate that this compound is unlikely to have strongly irritating or sensitizing properties.
 Skin Sensitization 
Magnesium sulfate anhydrous was evaluated using an OECD Test Guideline 429 mouse local lymph node assay (MRID 50871303). According to the Cosmetic Ingredient Review (CIR) Expert Panel which reviewed the study, the dorsal surface of both ears of 5 mice/dose were treated with magnesium sulfate at concentrations of 10%, 25%, and 50% plus a vehicle control, using a dose volume of 25 μL/ear. Mice were then injected intravenously with 3H-methyl thymidine, sacrificed, and lymph nodes collected. The stimulation index (SI) was calculated for each group. Magnesium sulfate did not elicit an SI of >= 3 at any concentration tested; therefore, it was considered a non-sensitizer.

 Repeat Dose Toxicity
        
 Combined Repeated Dose Range-Finding Toxicity Study (Oral Toxicity Study in Rats) 

An OECD Test Guideline 422: Combined Repeat Dose Reproduction/Developmental Toxicity Screening Test was carried out on magnesium sulfate anhydrous and the results were reported and reviewed in the OECD Screening Information Dataset (SIDS) for magnesium sulfate (MRID 50871314). Male and female Sprague Dawley rats (13/sex/dose) received 0, 50, 150 or 450 mg/kg/day magnesium sulfate in water. An additional 6 animals (3/sex) per group were used in a 2-week recovery group and dosed at 0 or 450 mg/kg/day. 

Males of the main group and both sexes of the recovery group were dosed two weeks each prior to, during and post mating. Females of the main group were dosed two weeks prior to mating, throughout gestation and for 5-6 days after delivery until the day of sacrifice. 

According to the OECD SIDS assessment:  

      All animal were observed for mortality, general condition and gross evidence of clinical signs and symptoms daily throughout the study. Individual body weights of both sexes were measured once a week
      throughout the dosing period. Food consumption was recorded. Sensory function and motor activity,
      urinalysis, hematology, blood chemistry, organ weights and histopathology were examined. In the
      main and recovery groups, there were no mortalities during the study. No abnormalities in clinical
      signs were observed in 50 and 150 mg/kg main groups. However, soft stool was sporadically or
      frequently observed in most animals in 450 mg/kg main group, and it was recovered in all animals
      of both sexes in recovery period. No dose-related changes in detailed clinical observations such as
      detailed physical examinations for signs and symptoms of adverse effects, including central and
      autonomic nervous system effects, motor activity and behavior, body weights and food
      consumption were noted. In addition, no dose-related changes in sensory function, motor activity,
      urinalysis, hematology, blood chemistry and organ weights were noted. No effects were evident at
      necropsy and histopathology.

In both sexes of 150 mg/kg group, soft stool was observed 1-2 times in 1-3 animals. This was noted by OECD to be "no effect of toxicity." The occurrence of soft stool increased in the high dose group and was either sporadically or frequently observed in 10-11 animals of both sexes; this effect was considered dose related. Soft stool did not last after the first day of the recovery period. One female had stomach ulcers and hyperplasia; however, no other animals showed evidence of stomach histopathology. In the absence of other adverse effects of treatment, the Agency does not consider soft stool alone to be an adverse effect of treatment and therefore considers the NOAEL to be 450 mg/kg/day. A Lowest Observed Adverse Effect Level (LOAEL) could not be determined.

 Reproductive and Developmental Toxicity
As noted in the section 5.2 above "Repeated Dose Toxicity," an OECD Test Guideline 422: Combined Repeat Dose Reproduction/Developmental Toxicity Screening Test was carried out for magnesium sulfate anhydrous (MRID 50871314). Male and female Sprague Dawley rats (13/sex/dose) received 0, 50, 150 or 450 mg/kg/day magnesium sulfate anhydrate in water and an additional 6 animals per group were used in a 2-week recovery group. Males of the main group and both sexes of the recovery group were dosed two weeks each prior to, during, and post mating. Females of the main group were dosed two weeks prior to mating, throughout gestation, and for 5-6 days after delivery until the day of sacrifice. In addition to the endpoints noted in section 5.2.1 above, the following parameters were examined in F1 offspring: number and sex of pups, number of corpora lutea and uterine implants, mean litter size, live births, postnatal mortality, body weights of pups on postnatal day (PND) 0 and 4, and external examination of all pups on delivery day and on PND 4.

No significant dose-related effects were observed on reproductive function or development. The gestation indices were 100% and the pre-implantation loss rates were 10.5% and 4.8% in the control and 450 mg/kg/day groups, respectively. The post-implantation loss rates and the live birth indices were not affected nor were viability indices on postnatal day 0 and 4. Furthermore, no effects were noted in live birth index, sex ratio, mean litter size, and external findings including eye, ear, mouth, palate, absence of limbs and tail, position, size and shape on PND 0 and 4. Finally, as noted above, there were no significant changes in weight or histopathological findings in testes, epididymides, ovaries, or uterus. The NOAEL for reproductive and developmental effects was the highest dose tested, 450 mg/kg/day. A LOAEL could not be determined.
 Genotoxicity and Mutagenicity
        
 Bacterial Reverse Mutation Test 

A reverse mutation assay was carried out with magnesium sulfate at concentrations of up to 100 mg/plate (MRID 50841308). Magnesium sulfate did not induce an increase in the frequency of revertant colonies in Salmonella typhimurium strains TA92, TA1535, TA100, TA1537, TA94 and TA98 with or without metabolic activation from S9 mix. 

In a second study outlined in the SIDS report on magnesium sulfate (MRID 50871314), an OECD Test Guideline 471 bacterial reverse mutation assay was performed with S. typhimurium strains TA 1535, TA 1537, TA 98, and TA 100 and Escherichia coli WP2uvrA in the presence and absence of metabolic activation (S9 mix). The plate incorporation method was used employing three replicates at each dose level. Based on preliminary test results, magnesium sulfate doses ranged from 156.3 to 5,000 ug/plate by a factor of two. The test substance did not induce an increase in the frequency of revertant colonies in a dose-dependent manner under any condition tested. Based on the results, magnesium sulfate was not considered to be genotoxic under the test conditions. 
 In Vitro Mammalian Chromosome Aberration Test

An in vitro chromosomal aberration test was performed on magnesium sulfate using a Chinese hamster fibroblast cell line. Cells were exposed to three different doses for 24 and 48 hours in the absence of metabolic activation. The maximum dose was 4 mg/mL and was selected in a preliminary test that determined the dose needed for 50% cell-growth inhibition. No polyploid cells or cells with structural aberrations were observed at any dose. The results of this study indicate that magnesium sulfate was not clastogenic under these conditions (MRID 50841308).

In a second study outlined in the SIDS report on magnesium sulfate (MRID 50871314), an OECD Test Guideline 473 in vitro mammalian chromosome aberration test using Chinese Hamster Lung (CHL) cells was performed both in the absence and the presence of metabolic activation system (S9 mix). Cells were treated with 1000, 2000, or 5000 ug/mL for 6 hours followed by 18 hours of recovery period. There was no significant increase in the number of structural aberrations or numerical aberrations compared to controls at any dose level with and without metabolic activation. These results indicate the substance is not clastogenic.
 Carcinogenicity
The carcinogenicity of magnesium sulfate was tested via inhalation exposure in male Wistar rats (MRID 50871305). Rats (27/group) were exposed for one year (5 days per week, 6 hours per day) to long and short magnesium sulfate whiskers (diameter 1.8 μm and 1.5 μm, respectively). A subchronic 4-week study co-occurred with this yearlong study using an additional 124 animals (42, 42, and 40 rats per group for short whiskers, long whiskers, and controls, respectively). Long and short whiskers were tested at mean concentrations of 4.0 mg/m[3] and 2.3 mg/m[3], respectively. There were few whiskers detected in rat lungs, even immediately following exposure indicating the substance dissolved and was eliminated quickly. A parallel study in hamsters indicated the half-life of whiskers in lungs was 17.6 minutes. Histopathological examination of the rats indicated that the lung tumor incidence was not significantly different from that of control rats. Based on the results of this study, magnesium sulfate is unlikely to be carcinogenic. 

Although no oral or dermal cancer or long-term studies are available to evaluate the carcinogenic potential of magnesium sulfate, no target organ toxicity was seen in the repeat dose study and no genotoxic or mutagenic effects were seen in the bacterial reverse mutation test and the in vitro mammalian chromosome aberration test (Section 5.4). It is therefore, unlikely that magnesium sulfate is carcinogenic.

 Neurotoxicity

No neurotoxicity studies are available for magnesium sulfate. Functional Observational Battery (FOB) tests were carried out as part of the OECD Test Guideline 422 study (MRID 50871314) described above in section 5.2.1. FOB observations included: clinical observations on central and autonomic nervous system effects, motor activity and behavior examination of all dosed animals once before dosing and once per week throughout the dosing and recovery periods. There were no effects of magnesium sulfate noted on sensory functions or motor activities when compared to control animals. 
                                                                               
 Immunotoxicity

No immunotoxicity studies are available for magnesium sulfate; however, no effects were seen in the OECD Test Guideline 422 study (MRID 50871314), described above in section 5.2.1, that would indicate that magnesium sulfate would be immunotoxic. Furthermore, considering magnesium and sulfate are both essential nutrients in the diet and endogenous compounds, it is unlikely that they are immunotoxic.


 TOXICITY ENDPOINT SELECTION

Magnesium and sulfate are both abundant in the natural enviroment and are necessary for human life. Magnsium sulfate is commonly found in our food and water either as a naturally occuring element or as an additive. It is also broadly used in pharmaceuticals, fertilizers, and cosmetics. No toxicological endpoint of concern has been identified in the database; therefore, a quantitative assessment of human exposure is not necessary.

 SPECIAL CONSIDERATION for INFANTS and CHILDREN

FFDCA Section 408(b)(2)(c) provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA safety factor (SF). In applying this provision, EPA either retains the default value of 10X or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor. 

As part of its qualitative assessment, the Agency did not use safety factors for assessing risk, and no additional safety factor is needed for assessing risk to infants and children. The available acute and repeat dose toxicity studies on magnesium sulfate indicate that it has low toxicity. There is also no indication, based upon the available data, that magnesium sulfate is neurotoxic or immunotoxic, and it therefore would not result in increased susceptibility in infants or children. Taking into consideration all available information, there is no concern, at this time, for increased sensitivity to infants and children to magnesium sulfate.

 EXPOSURE

Magnesium sulfate is currently approved for use under 40 CFR §180.910 as an inert ingredient pre- and post-harvest. A review of currently approved pesticide products containing magnesium sulfate found that the majority of products were lawn care products and products used in pools. Ecolab, Inc. is requesting that EPA establish an exemption from the requirement of a tolerance for magnesium sulfate under 40 CFR §180.940(a) for use in antimicrobial formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, and food-processing equipment and utensils at a maximum concentration of 4400 ppm. 
Based on the current and proposed use pattern of magnesium sulfate, dietary and residential exposure from pesticidal uses are expected. In addition, humans are constantly exposed to magnesium sulfate as it is ubiquitous in the environment. However, no toxicological endpoint of concern was identified in the database; therefore, a quantitative risk assessment was not necessary.  
 Dietary Exposure
Dietary exposure to magnesium sulfate may occur from eating foods treated with pesticide formulations containing this inert ingredient and drinking water containing runoff from soils containing the treated crops. In addition, magnesium sulfate is also used as an additive in food and beverages and in dietary supplements. However, no toxicological endpoint of concern was identified, and therefore a quantitative dietary exposure assessment for magnesium sulfate was not conducted. 

 Residential Exposure

The term "residential exposure" is used in this document to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Magnesium sulfate is currently used in both pesticide products and non-pesticidal products (e.g., cosmetics, pharmaceuticals, and fertilizers) that can result in residential exposure.  Although the current and proposed uses of magnesium sulfate can result in residential exposures to magnesium sulfate, there are no toxicological effects of concern in available studies, and therefore it is not necessary to conduct a quantitative assessment of residential (non-occupational) exposures and risks. 

 Occupational Exposure/Risk
The Agency has reviewed the available toxicological information for magnesium sulfate and found that there are no adverse toxicological effects observed; therefore, a quantitative occupational risk assessment is not necessary. 

 AGGREGATE EXPOSURE

The Federal Food, Drug, and Cosmetic Act (FFDCA) section 408  directs EPA to consider available information concerning exposure from the pesticide residue in food and other non-occupational exposures to determine that "there is a reasonable certainty  that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.

Because no adverse effect was seen in the toxicity database for the magnesium sulfate a qualitative risk assessment was conducted and subsequently, it is not necessary to aggregate dermal and inhalation residential exposures with estimated dietary exposures. 

    CUMULATIVE EXPOSURE

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity."

EPA has not found magnesium sulfate to share a common mechanism of toxicity with any other substances, and magnesium sulfate does do not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA assumed that magnesium sulfate does not have a common mechanism of toxicity with other substances. For further information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative.

    ENVIRONMENTAL FATE & EFFECTS 

Magnesium sulfate is expected to have a minimal impact on the environment based on its physical and chemical characteristics and the fact that magnesium and sulfate are found naturally in the environment. Magnesium sulfate occurs naturally in sea water, mineral springs and in minerals such as kieserite (i.e., magnesium sulfate monohydrate) and epsomite (i.e., magnesium sulfate heptahydrate). Magnesium is one of the 10 most common elements in the Earth's crust.  

 Environmental Fate
        
Magnesium sulfate is ubiquitous in the environment and living things. According to the OECD (MRID 50871314): 

      Environmental fate analysis based on log Kow and log Koc and typical fugacity modelling are not applicable to magnesium sulphate due to its inorganic properties. Photodegradation and biodegradation are also not applicable to an inorganic metal salt like magnesium sulfate. Given its high solubility in water, magnesium sulfate will dissociate and release Mg2+ and SO4[2-] ions. The dissociated Mg[2+] cation can then transform and form complexes with dissolved ligands present in natural waters. Under anaerobic conditions, the dissociated sulfate ion is reduced to sulfide ion, which establishes an equilibrium with hydrogen ion to hydrogen sulphide. As a macronutrient, magnesium is widespread in living cells and so it is not expected to bioconcentrate in aquatic organisms. 

 Ecotoxicity Data

Magnesium and sulfate occur in natural water systems and are found abundantly in the earth's crust. Ecotoxicity studies conducted with magnesium sulfate showed that it was not toxic to fish, invertebrates, or algae. The ecotoxicity data presented below has been taken from the 2010 OECD review of magnesium sulfate (MRID 50871314) and the 2010 Van Dam study (MRID 50871320) in which he looked at the effect of magnesium sulfate on six freshwater species. 

The results of these studies are summarized in Table 3 and detailed in the sections below.

Table 3: Toxicity of Magnesium Sulfate to Aquatic Species 
Species
Endpoint
LC50/IC50*(mg/L)
Source
 Fish
Oryzias latipes
 96-hr survival
 >96.4
 MRID 50871314
Pimephales promelas
 96-hr survival
 2820
 MRID 50871314
Mogurnda mogurnda 
 96-hr survival
 198 
 MRID 50871320
 Water Flea 
Daphnia magna
 48-hr mobility
 >88.7
 MRID 50871314
Daphnia magna
 48-hr survival
 1820
 MRID 50871314
Moinodaphnia macleayi 
 3 brood reproduction
 312
 MRID 50871320
 Snail
Amerianna cumingi 
 96-hr embryo production
 64
 MRID 50871320
Algae
Chlorella sp. 
 72-hr cell division
 6014
 MRID 50871320
Pseudokirchnerella
subcapitata
 72-hr growth rate
 72-hr yield
 >99.2 ErC50
 >99.2 EyC50
 MRID 50871314
 Aquatic Plants
Hydra viridissima 
 96-hr growth
 54
 MRID 50871320
Lemma aequinoctialis
 96-hr growth
 22
 MRID 50871320
*acute median lethal concentration (LC50)/ chronic median inhibition concentration (IC50)

    Fish

The test substance was not toxic to fish in the three studies described below. The first two studies listed below are outlined in the OECD SIDS document on magnesium sulfate (MRID 50871314). 
                                                                               
In an acute toxicity study (OECD Test Guideline 203), groups of 7 Japanese rice fish (Oryzias latipes) were exposed under static conditions to 100 mg/L of magnesium sulfate for 96 hours. There were no mortalities or adverse effects observed in any of the fish. The 96 hr-LC50 was greater than 96.4 mg/L (measured concentration).

A fish toxicity study (96 hours) in Fathead minnows (Pimephales promelas) was conducted under static conditions. The LC50 was 2,820 mg/L (nominal concentration).

Van Dam et al. (2010) tested the acute toxicity of magnesium sulfate (MRID 50871320)
in six tropical freshwater species (Chlorella sp., Lemna aequinoctialis, Amerianna cumingi, Moinodaphnia macleayi, Hydra viridissima, and Mogurnda mogurnda). The Northern Trout Gudgeon (Mogurnda mogurnda) showed a 96 hr-LC50 of 198 mg/L. 
    Aquatic Invertebrates: Water Flea
The test substance was not toxic to aquatic invertebrates in the three studies described below. The first two studies are outlined in the OECD SIDS document (MRID 50871314). 

Daphnia magna (groups of 20 organisms) were observed for immobilization at 24 and 48 hours following static exposure to concentrations of magnesium sulfate of 100 mg/L and control. The study was conducted according to OECD Test Guideline 202 "Daphnia sp., Acute Immobilization Test". No immobility was observed at the tested concentrations. Based on these results, the EC50 was >88.7 mg/L (measured concentration) after 48-hour exposure.
In an acute toxicity test in invertebrate, Daphnia magna were exposed under static condition to magnesium sulfate for 48 hours. The LC50 of magnesium sulfate was 1,820 mg/L (nominal concentration).
In the Van Dam study (MRID 50871320), Moinodaphnia macleayi showed little response to magnesium concentrations up to approximately 40 mg/L, with an IC50 of 63 mg/L and 312 mg/L for Mg and MgSO4, respectively.
 Algae
A 72-hour growth inhibition test (OECD Test Guideline 201) of 100 mg/L magnesium sulfate was conducted with Pseudokirchneriella subcapitata. Based on the results, the 72-hour ErC50 (average specific growth rate) and the EyC50 (yield) were > 99.2 mg/L (mean measured concentrations) (MRID 50871314).
Of the six freshwater organisms tested in the Van Dam study (MRID 50871320), Chlorella sp. was clearly the least sensitive species to Mg exposure showing little response to Mg concentrations of approximately 80 mg/L, with an IC50 of approximately 1,200 mg/L. The IC50 for MgSO4 was 6000 mg/L.

    RISK CHARACTERIZATION

Magnesium sulfate is ubiquitous in the environment and is currently approved for use as a food use inert ingredient (solid diluent, carrier, safener) in pesticide products under 40 CFR § 180.910 for use pre- and post-harvest. It is also used in various other non-pesticidal food and consumer products, including pharmaceuticals, dietary supplements, fertilizers, cosmetics, and as a food and beverage additive. One form, magnesium sulfate heptahydrate, also known as Epsom salt, has been used for centuries as an over the counter laxative and a soaking agent for aching joints.  

Available acute studies on magnesium sulfate include an oral toxicity study, a dermal irritation study, and a dermal sensitization study. Repeat dose toxicity testing for magnesium sulfate includes an OECD Test Guideline 422: Combined Repeat Dose Reproduction/Developmental Toxicity Screening Test and a 1-year inhalation cancer study in rats. Magnesium sulfate was also tested for genotoxic and/or mutagenic effects using a bacterial reverse mutation test and an in vitro mammalian chromosome aberration test. 

All studies showed low acute and repeat dose toxicity and no reproductive/developmental toxicity. The primary health effect associated with magnesium sulfate is an osmotic laxative effect at high doses. The laxative effect is transient, and recovery is rapid and is usually observed only when following acute exposures to high concentrations (e.g., pharmacological uses). In the acute oral study, diarrhea was seen at the highest dose tested (2000 mg/kg/day); however, this effect was seen above the limit dose of 1,000 mg/kg/day and therefore would not be used as point of departure for determining risk.

The OECD Test Guideline 422 study showed no adverse effect at the NOAEL of 450 mg/kg/day, the highest dose tested. In addition, there was no evidence of carcinogenicity or neuropathological changes or effects reported in any of the studies. The agency does not believe magnesium sulfate is carcinogenic or neurotoxic. 

Based on the current and proposed use patterns of magnesium sulfate, dietary and residential exposure from pesticidal uses are expected. However, no toxicological endpoint of concern was identified in the database; therefore, a quantitative risk assessment was not necessary. As part of its qualitative assessment, the Agency did not use safety factors for assessing risk, and no additional safety factor is needed for assessing risk to infants and children. 

Magnesium sulfate is found naturally in water, and based on various aquatic studies, it does not present a hazard for aquatic systems or the environment. Overall, the widespread use of magnesium sulfate in foods, drugs, and cosmetics, in combination with the natural occurrence of both magnesium and sulfate in the body, indicate that this compound does not pose a safety risk from these uses. 

                                 Bibliography


(MRID 50871303) Cosmetic Ingredient Review (CIR). 2014. Safety Assessment of Magnesium Sulfate as Used in Cosmetics. Expert Panel Review - Final Report, Release Date: June 26, 2014, Panel Date:  June 9-10, 2014. Expert Panel: Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Ronald A Hill, Ph.D. James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D.

(MRID 50871305) Hori, H. Kasai T. Haratake J. Ishimatsu S. Oyabu T. Yamato H. Higashi T. and Tanaka T. Biological effects of inhaled magnesium sulphate whiskers in rats. Occup.Environ.Med. 1994;51(7):492-499.

(MRID 50871307) Institute of Medicine (IOM). 2005. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC, USA, The National Academies Press, https://doi.org/10.17226/10925.

(MRID 50871309) Joint FAO/WHO Expert Committee on Food Additive (JECFA). 2007. Sixty-eighth report of the Joint FAO/WHO Expert Committee on Food Additives. WHO technical report series: no. 947.

(MRID 50871311) Office of Dietary Supplements (ODS). 2018. Dietary Supplement Fact Sheet: Magnesium. Office of Dietary Supplements, US National Institutes of Health. Updated: September 26, 2018.

(MRID 50871314) Organization for Economic Cooperation and Development (OECD). 2010. Magnesium sulfate. SIDS Initial Assessment Report for SIAM 31. 19-20 October 2010, Paris. Sponsor Country: Republic of Korea, Date of submission: July 14, 2010.

(MRID 50871317) Seo, JW and Park, TJ. 2008. Magnesium metabolism. Electrolyte & Blood Pressure 6:86-95.

U.S. Environmental Protection Agency (EPA). 2003. Drinking Water Advisory: Consumer Acceptability Advice and Health Effects Analysis on Sulfate. Office of Water (4304T). Health and Ecological Criteria Division. EPA 822-R-03-007. February 2003.

(MRID 50871320) Van Dam RA, Hogan AC, McCullough CD, Houston MA, Humphrey CL, Harford AJ. 2010. Aquatic toxicity of magnesium sulfate, and the influence of calcium, in very low ionic concentration water. Environ Toxicol Chem. 2010 Feb;29(2):410-21.

(MRID 50871321) World Health Organization (WHO). 2004. Sulfate in Drinking-water Background document for development of WHO Guidelines for Drinking-water Quality. WHO/SDE/WSH/03.04/11


