Document ID: EPA-HQ-OPP-2013-0165-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-06-05T04:00Z

i

 EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

 EPA Registration Division contact: P.V. Shah, 703-308-1846

 INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

 TEMPLATE: BASF Corporation PP IN-10545
       EPA has received a pesticide petition (IN-10545) from BASF Corporation, c/o Lewis &
 Harrison, LLC, 122 C Street NW, Suite 740, Washington DC 20001, requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish an exemption from the requirement of a tolerance for Alkyl (C8-C10) polyglucosides (CAS Reg. No. 68515-73-1) under §180.940(a) when used as an inert ingredient as a surfactant without limitation in antimicrobial pesticide formulations. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

 A. Residue Chemistry

 Residue data, including an analytical method, is not pertinent or required for this petition since an exemption from tolerance is requested.

 B. Toxicological Profile

 An extensive safety data base has been complied on the alkyl polyglycosides. The safety data base includes acute, subchronic, developmental toxicity, mutagenicity, and metabolism studies.

       1.   Acute toxicity

 Alkyl polyglycosides are of low toxicity via the oral and dermal route. At high concentrations, the alkyl polyglycosides can be irritating to eyes and skin. The alkyl polyglycosides are not dermal sensitizers.

             a.	Acute oral toxicity

 Primary limit tests were performed with various alkyl polyglycosides, using doses of 2,000 or
 5,000 mg/kg bw in three groups of animals. These doses were chosen to comply with the regulatory requirements in Europe and the United States used to define individual classification limits for chemical substances. The acute toxicity test results are shown below.

                 Acute Oral Toxicity of Alkyl Polyglycosides
    Chain Length
                                        C8-10
    C12-14
     C10-16
    Polymerization
                                          1.6
                                         1.5
                                         1.6
   Percent Substance
                                          50
                                         60
                                          50
   Dose (mg/kg bw)
                                      >5,000
     >2,000
     >5,000

     Test Animals
                               Sprague-Dawley rat
                                 5 male/5 female
                                    Wistar rat
                                2 male/2 female
                              Sprague-Dawley rat
                                5 male/5 female
     Mortalities
                                         0/10
                                         0/4
                                        0/10
  Animals with Gross
  Necropsy Findings

                                         0/10

                                         0/4

                                        0/10

 Chemical structure appears to have little influence on the acute oral toxicity of alkyl polyglycosides with all testing showing an LD50 of greater than 2,000 mg/kg bw at a minimum. The products tested covered a broad range of linear C8-16, with degrees of polymerization between 1.5 and 1.6. For the dose range used, none of the animals showed any adverse effects in response to alkyl polyglycoside challenge, irrespective of fine chemical structure. Thus ingestion of alkyl polyglycosides does not represent an acute health risk.

             b.	Acute dermal toxicity.

 Five male and female New Zealand white rabbits received single limit doses of either 2,000 mg/kg bw of C8-10 or C10-16 Alkyl Polyglycosides applied dermally. For C8-10 alkyl polyglycosides, clinical signs recorded in individual animals during the observation period of 14 days included mild to moderate irritating effects due to the high concentration. One animal receiving the test substance died. This was not test-substance related but rather was due to Tyzzer's disease, an infectious disease condition that was confirmed by microscopic examination. At the end of the 14-day observation period, all surviving animals were killed. Gross necropsy revealed spotty areas of hemorrhage on the lungs of five rabbits. The same protocol was applied using C10-C16 alkyl polyglycosides. No deaths occurred and no pathological findings were reported.
 The effects on the lung with C8-10 alkyl polyglycosides were not seen with the closely related C10-16 alkyl polyglycosides in the acute dermal toxicity study (see above), neither with C8-10 alkyl polyglycosides in a subacute dermal study, nor with C12-16 alkyl polyglycosides in a subchronic oral study. As a consequence, the effects observed in the lung in the acute dermal study are assessed as being a single observation, possibly due to an unintended exposure via inhalation, or due to the high pH of the product without relevance to the human exposure scenario.

             c.	Eye irritation.

 An in vivo study was carried out according to OECD Guideline 405 using an aliquot of 0.1 mL
 aqueous solution of C12-C16 alkyl polyglycoside (50% active substance). Eyes were scored at
 24, 48, and 72 hours after application. The conjunctivae displayed moderate to strong reactions that did not abate completely after 21 days in two animals.
 Another series of validated eye irritation tests using C12-16 Alkyl Polyglycoside (a dose of 0.1 mL of lauryl glucoside [neutralized, 12.5% active substance]) found no irritant reactions and only slight corneal reactions which persisted for less than 48 hours in one animal.

             d.	Dermal irritation.

 The table below summarizes the results of skin irritation tests undertaken according to OECD Guideline 404, using linear Alkyl Polyglycosides as the test substance. Short-chain (C8-10) Alkyl Polyglycosides are significantly less of an irritant than their corresponding long chain (C10-16 or C12-16) homologues. The primary dermal irritation index (PDII) and mean values for the 24-, 48-, 72-hour erythema data reveal an almost linear increase with increasing concentration, a relationship independent of the degree of polymerization. Even mixtures of short-chain and long-chain Alkyl Polyglycosides fit this scenario well, allowing meaningful extrapolations for labeling issues. A product tested at both pH 7 and pH 11 revealed that irritating properties were almost unaffected by alkalinity. Systemic toxicity after a single dermal application in rabbits was not observed in any of the tests with linear Alkyl Polyglycosides. Furthermore, it has been shown in dermatological studies that Alkyl Polyglycosides used as secondary surfactants significantly enhance the skin compatibility of primary surfactants.

              Dermal Irritation of Alkyl Polyglycosides
  Chain
  Length

 Polymerization
                                     Percent
                                   Substance

  PDII
                                    Erythema
                                     (Mean)
  Edema
  (Mean)
  C8-10
                                        1.6
                                        70
                                       0.8
                                       0.9
                                       0.0
  C8-10
                                        1.6
                                        35
                                       1.3
                                       1.1
                                       0.3
  C8-10
 Not specified
                                        15
                                       0.0
                                       0.0
                                       0.0
 C10-16
                                        1.4
                                        60
                                       4.6
                                       2.9
                                       2.1
 C12-16
                                        1.4
                                        50
                                       3.7
                                       2.2
                                       1.6
 C12-16
                                        1.4
                                        50
                                       3.0
                                       2.1
                                       0.9
 C12-16
                                        1.6
                                        50
                                       3.0
                                       1.9
                                       1.1
 C12-16
                                        1.4
                                        30
                                       2.8
                                       1.7
                                       0.9
 C10-16
                                        1.4
                                        20
                                       0.4
                                       1.2
                                       1.1
  C8-10/
 C12-16
 Mixture

 Not specified

 35 (C12-16)
 21 (C8-10)

                                       2.7

                                       1.8

                                       0.8

             e.	Skin sensitization.

 Both animal (guinea pig) and human skin sensitization tests were conducted. None of the tests with C12-16 Alkyl Polyglycosides displayed significant potential for skin sensitization either with the Buehler test or the Magnusson-Kligman protocol.

                Skin Sensitization for C12-16 Alkyl Polyglycosides
   Test Protocol
    Induction
  Challenge
   Positives
  Sensitizer
      Buehler
 Epidermal: 20%
Epidermal: 20%
                                        1/20
                                         No

Magnusson-Kligman
                              Intracutaneous: 1%
                                 Epidermal: 60%

Epidermal: 10%

                                        0/20

                                         No

         2.   Genotoxicity

   No evidence of genotoxicity or chromosomal effects was observed in mutagenicity studies conducted with the alkyl polyglycosides.

               a.	Reverse Mutation.

   A related compound containing C12-16 alkyl polyglycosides, was tested on Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537 and TA 1538 in two independent experiments, both with and without S9 mix metabolic activation according to the OECD guideline 471. Test concentrations were: 8, 40, 200, 1000, and 5000 ug/plate (1st test). Due to cytotoxic effects starting at 900 ug/plate, test concentrations were adjusted to 11.1, 33.3, 100,
   300 and 900 ug/plate (2nd test) according to the test guideline. Solutions of the Alkyl Polyglycosides were prepared in deionized double distilled water prior to use. Compared with concurrent negative controls, no precipitations or enhanced revertant rates were observed in all strains tested in the presence or absence of metabolic activation. 4-Nitro-ophenylenediame, 9- aminoacridine, and sodium azide controls were positive without S9 activation, and the aminoanthracene control was positive with S9 activation. C12-16 Alkyl Polyglycoside did not induce reverse mutations and were not mutagenic in this test system (Willing, Messinger and Aulmann, 2004).

   Based on the fact that different Alkyl Polyglycosides show a similar metabolic pathway resulting in the occurrence of sugar and different fatty alcohols and fatty alcohols can be seen as a
   category with comparable toxicological properties with regard to mutagenicity, Alkyl Polyglycosides is regarded as a group with similar toxicological properties. As a consequence, results from the mutagenicity studies obtained with C12-16 Alkyl Polyglycosides  are representative for the whole group of Alkyl Polyglycosides including C8-C10, the subject of this petition.

               b.	Chromosomal Aberration.

   Cultured Chinese hamster V79 lung fibroblasts were exposed repeatedly to C12-16 Alkyl Polyglycosides every 4 hours per OECD Guideline No. 473 (EU Guideline B10). No biological effects, with respect to aberration induction, were observed at any time, either with or without S9 activation. Thus it was concluded that C12-16 Alkyl Polyglycosides were not clastogenic under the conditions of the test design (Willing, Messinger and Aulmann, 2004).

   Based on the fact that different Alkyl Polyglycosides show a similar metabolic pathway resulting

 in the occurrence of sugar and different fatty alcohols and fatty alcohols can be seen as a category with comparable toxicological properties with regard to mutagenicity, Alkyl Polyglycosides is regarded as a group with similar toxicological properties. As a consequence, results from the chromosome aberration study obtained with C12-16 Alkyl Polyglycosides are representative for the whole group of Alkyl Polyglycosides including C8-C10, the subject of this petition.

       3.   Reproductive and developmental toxicity.

 No reproductive or developmental effects were noted in any of the tests conducted.

             a.	Reproductive toxicity.

 Using OECD Guideline No. 421, an assessment of the reproductive toxicity of C12-16 Alkyl Polyglycosides was conducted in 10 male and 10 female rats/group following daily administration by oral gavage of 100, 300, and 1000mg/kg bw/day doses (Willing, Messinger and Aulmann, 2004). No effects indicative of general toxicity were observed in parental animals. Relative and absolute weights of testes, epididymides and seminal vesicles did not differ between test and control animals. With regard to reproductive parameters, no test substance-related symptoms were observed. Mean litter weights, pup weights, sex ratios, and gestation periods did not differ significantly among all groups. No clinical pre-weaning
 effects were noted and necropsy or histological examination did not reveal any effects in parental or F1 pups. On the basis of these results, a NOAEL of 1,000 mg/kg bw/day was determined.

             b.	Developmental toxicity.

 C12-16 Alkyl Polyglycosides were tested in a segment II study per OECD Guideline No. 414 at dose levels of 0, 100, 300, and 1,000 mg/kg bw/day in pregnant CD-Rats. The substance was administered daily by gavage from days 6 to 15 of gestation. A standard dose volume of 10 mL/kg bw was used. Clinical condition and reaction to treatment were recorded at least once daily. Maternal weights were reported on days 0, 6, 16, and 20 of gestation. All dams tolerated the applied dose levels of up to 1000 mg/kg bw/day without lethality. Maternal body weight gain was not affected by treatment. For maternal toxicity a NOAEL of 1,000 mg/kg bw was deduced. All females had viable fetuses, and pre- and post-implantation losses as well as mean numbers of resorptions were not affected by treatment at any dose. Skeletal and visceral examinations also did not detect any treatment-related malformations. For embryo/fetotoxicity and teratogenicity, the NOAEL was also determined to be 1,000 mg/kg bw with no effect observed at any dose level tested.

 Both the developmental toxicity and teratogenicity NOAEL far exceed any reasonable foreseeable exposure to Alkyl Polyglycosides in humans. Furthermore, the data for these surfactants provide assurance of a lack of effect on maternal toxicity or reproductive capacity. Based on the fact that different Alkyl Polyglycosides discussed in this document show a similar metabolic pathway resulting in the occurrence of sugar and different fatty alcohols and that fatty alcohols can be seen as a category with comparable toxicological properties with regard to systemic toxicity, Alkyl Polyglycosides are regarded as a group with similar toxicological properties on repeated dose toxicity. As a consequence, results from repeated application studies

 obtained with C12-16 Alkyl Polyglycosides are representative for the whole group of Alkyl Polyglycosides including C8-C10, the subject of this petition.

       4.   Subchronic toxicity

 Based on the fact that different Alkyl Polyglycosides show a similar metabolic pathway resulting in the occurrence of sugar and different fatty alcohols and fatty alcohols can be seen as a
 category with comparable toxicological properties with regard to mutagenicity, Alkyl Polyglycosides is regarded as a group with similar toxicological properties. As a consequence, results from repeated application studies obtained with C12-16 Alkyl Polyglycosides are representative for the whole group of Alkyl Polyglycosides including C8-C10, the subject of this petition.

             a.   Subchronic oral toxicity.

 C12-16 Alkyl Polyglycosides were investigated in compliance with OECD Guideline 408 for subchronic toxicity (Willing, Messinger and Aulmann, 2004). Ten male and 10 female Sprague- Dawley rats per dosage group were administered daily with 250, 500 and 1000 mg/kg bw/day by gavage for 90 days. An untreated group served as the control. No significant changes were seen due to treatment in body weight gain, food consumption, relative organ weights, biochemical, ophthalmological or hematological parameters due to treatment. Gross pathology at necropsy revealed ulcerations and edema restricted to the forestomach in the high-dose group.
 Pathological and histological examinations revealed that no statistically significant or biologically relevant substance-related changes had occurred in any of the organs except the forestomach. Histopathology revealed dose-dependent manifestation of ulcers and inflammatory edema accompanied by acanthosis and proliferation of the mucosa confined to the mucous membrane of the forestomach of both male and female high-dose group and to a lesser extent in the mid-dose group. No substance-specific histopathology was evident in the forestomachs of the low-dose group. Examination of the forestomachs of a recovery group from the high-dose
 showed that these effects were reversible albeit slowly. Since eye contact with Alkyl Polyglycosides produces irritation, irritative effects on the mucous membranes of the gastrointestinal tract were not unexpected and this was confirmed in the 90-day study. After discontinuation of sample application (recovery group), examination of the forestomachs gave evidence that the effects were reversible. The inherent irritation potential requires special thought in the risk assessment process. Based on the dosing regime used in the 90-day oral toxicity study, specific problems can arise if the dosing regime is bolus-like, as was the case in this study. Other authors have previously reported that results from gavage studies differ from those of a more continuous intake (diet, drinking water) (Hayes, 1994; Greaves, 1990; and ECETOC, 2003).
 They demonstrated that gavage administration of irritating substances produced local ulcerations in the rodent forestomach due to peak concentrations of a test substance. If the same dose was applied in feeding or drinking water studies, or incorporated into the diet via microencapsulation as has been reported for Citral (Dieter, 1993) and  cinnamaldehyde (Hebert, 1994), no lesions were observed in the forestomach. In all these cases, dilution of the substance provides a good explanation for the different responses. Although feeding studies would mimic dietary exposure more realistically, bolus-likeapplications are a state-of-the-art technique to ensure accurate dosing. In other words, the boluslike application reflects a more severe than worst-case food exposure condition.

 Furthermore, the pH of the raw Alkyl Polyglycoside material is adjusted to a pH 12 to avoid microbial contamination which further enhances the irritation potential. Thus, since only local reversible effects on the forestomach based on irritation were observed, the No-Observed- Adverse-Effect Level (NOAEL) for systemic oral toxicity was therefore calculated to be 1,000 mg/kg bw/day.

             b.   Subchronic dermal toxicity.

 A dermal study for subacute toxicity with C8-10 Alkyl Polyglycoside (60% active substance) was conducted in New Zealand white rabbits with doses between 60 mg and 3000 mg /kg bw/day applied to the intact skin for 14 days. Doses at 1500 mg/kg bw/day and above induced severe skin irritation after repeated application as well as several changes in hematological and clinical parameters and testicular atrophy. Minimal to mild skin irritation was seen in dose groups starting from 540 mg/kg bw/day, whereas no clinical, hematological or organ changes were reported at this dose. At and below 180 mg/kg bw/day, none of the described adverse events were observed. A NOAEL for systemic effects was set at 540 mg/kg bw/day.

       5.   Chronic toxicity.

 There are no chronic/oncogencity studies available on the alkyl polyglycosides. However, chronic studies should not be required for the alkyl polyglycosides since:  1) there was no systematic toxicity observed in the sub-chronic studies; 2) the alkyl polyglycosides rapidly degrade to sugar and fatty acids, both of which do not present any toxicity issues of concern; and the alkyl polyglycosides are not mutagens, reproductive toxins or endocrine disruptors. There is nothing to indicate that C8-10 alkyl polyglycosides will have any adverse chronic effects on humans or the environment. C8-10 alkyl polyglycosides are already cleared for use and are exempt from tolerance without numerical restriction under 40 CFR §§180.910 and 180.930. Other alkyl polyglycosides (C10-16-alkyl glycosides and C9-11-alkyl glycosides) are likewise cleared under 40 CFR §§180.910 and 180.930 without numerical restriction.

 Further, several FDA clearances for alkyl polyglycosides exist including those for meat-room degreasing, pesticide adjuvants under 21 CFR §182.99 (C8-10 and C9-11 alkyl polyglycosides), and indirect food contact (felt cleaning operations) under 21 CFR Part 176.

       6.   Animal metabolism.

 Animal metabolism studies show that the alkyl polyglycosides are rapidly hydrolyzed into sugars and long-chain alcohols.

 Weber and Benning (1984) evaluated the metabolism of three alkyl glycosides: octyl glucoside (carbon chain of alcohol is C8), dodecyl maltoside (carbon chain of alcohol is C12), and hexadecyl glucoside (carbon chain of alcohol is 16). The radiolabeled substances were administered by gavage to female NMRI mice. Two hours after treatment the animals were sacrificed and relevant organs were analyzed to determine distribution in specific organs. Stomach, intestines, liver, and kidney showed the highest concentrations of radioactivity for the compounds. Using extraction methods, it was shown that Alkyl Polyglycosides are readily

 cleaved into glucose and fatty alcohol, which is further oxidized to the corresponding fatty acid and partly incorporated in normal fat metabolism. Octyl glucoside was rapidly transformed into hydrophilic metabolites during intestinal and liver passage, whereas hexadecyl glucoside showed a much greater tendency towards lipophilic metabolism, resulting, e.g., in preferential identification in the liver of radiolabeled palmitoyl glycerides. These findings are underlined by the fact that D-oxidation occurs more easily in medium-chain fatty acids than in long-chain fatty acids (Scheig (1968) and Petit et al., (1982)).

 The following summarizes the metabolic pathway of Alkyl Polyglycosides. First, the 8- glycosidic bond between glucose and long-chain alcohol is hydrolyzed. Glucose and glucose oligomers enter the carbohydrate metabolic pathway and are catabolized. Long-chain alcohols are acylated to wax esters, then either incorporated into ether glycerolipids or oxidized to fatty acids. Finally, the fatty acids are either esterified to ester glycolipids or oxidized to acetate. These test substances (C8-, C12- and C16-Alkyl Glycosides) represent the whole range of possible chain length of non-branched fatty alcohols (C8-16) for commercial Alkyl Polyglycosides which are characterized in Table 1 A. Alkyl Polyglycosides with branched fatty alcohols (C9, C11) will also rapidly degrade after oral intake due to the hydrolysis of the D- glycosidic bond. The branched fatty alcohol will not influence the hydrolysis. Thus, all Alkyl Polyglycosides are transformed into glucose and fatty alcohol (branched or non-branched). The metabolism of fatty alcohols is discussed in more detail in the following paragraph while the metabolism of glucose is not further discussed. Glucose is regarded as safe after oral intake.

 Fatty alcohols represent the main difference in the structure of the different Alkyl Polyglycosides. Therefore, different fatty alcohols occur after hydrolysis of Alkyl Polyglycosides. The metabolism of these fatty alcohols is described in more detail to show that the resulting fatty alcohols (C8 linear, C9 branched, C10 linear, C11 branched, C12 linear, C14 linear and C16 linear) belong to a category with comparable toxicological properties. The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrial P-oxidation process. This mechanism removes C2 units in a stepwise process and linear acids are more efficient in this process than the corresponding branched acids. In the case of unsaturated carboxylic acids, cleavage of C2-units continues until a double bond is reached. Since double bonds in unsaturated fatty acids are in the cis-configuration, whereas the unsaturated acyl-CoA intermediates in the P-oxidation cycle are trans, an auxiliary enzyme, enoyl-CoA isomerase catalyses the shift from cis to trans. Thereafter, β-oxidation continues as with saturated carboxylic acids [WHO, 1999]. An alternative metabolic pathway for aliphatic acids exists through microsomal degradation via ω or ω-1 oxidation followed by β-oxidation. This mechanism provides an efficient stepwise chain-shortening pathway for branched aliphatic acids (Verhoeven, et al., 1998). The acids formed from the longer chained aliphatic alcohols can also enter the lipid biosynthesis and may be incorporated in phospholipids and neutral lipids
 (Bandi et al, 1971a&b and Mukherjee et al, 1980). A small fraction of the aliphatic alcohols may be eliminated unchanged or as the glucuronide conjugate (Kamil et al, 1953). Similar to the dermal absorption potential, orally administered aliphatic alcohols also show a chain-length dependant potential for gastro-intestinal absorption, with shorter chain aliphatic alcohols having
 a higher absorption potential than longer chain alcohols. With regards to the blood-brain barrier,

 a chain-length dependant absorption potential exists with the lower aliphatic alcohols and acids more readily being taken up than aliphatic alcohols/acids of longer chain-length (Gelman, 1975). The long chain aliphatic carboxylic acids are efficiently eliminated so that aliphatic alcohols will not have a tissue retention or bioaccumulation potential (Bevan, 2001). Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides)
 (Kabir, 1993; 1995a,b). In summary, long chained alcohols are efficiently metabolised and there is limited potential for retention or bioaccumulation for the parent alcohols and their biotransformation products.

       7.   Metabolite toxicology.

 There are no metabolites of toxicological concern.

       8.   Endocrine disruption.

 Based on available studies, there is no information or evidence to indicate that the alkyl polyglycosides (C8-C10) are endocrine disruptors.

             a.   Impairment of Hormonal Functions-E-screen and reporter gene assay.

 The MCF-7 proliferation assay (E-Screen Assay) and the MCF-7 reporter gene assay were used as predictors of potential estrogenic activity (Willing, Messinger and Aulmann,  2004). In the E- screen, the induction of cell proliferation (mitogenic effect) in MCF-7 cells, an estrogendependent human breast tumour cell line, is determined. A wide range of concentrations
 of the test substance is compared to a negative control (medium) and to reference substances (17-
 0-estradiol and bisphenol A). C12-16 alkyl polyglycoside concentration ranges of 0.1-10,000 nmol were tested in this assay. No effects were noted with Alkyl Polyglycoside concentrations up to 10 times higher than the 0.1 nmol positive control.

 The effects of C12-16 Alkyl Polyglycosides were also investigated in a reporter gene assay. In this assay, the induction of luciferase activity in stably transfected MCF-7 cells (plasmid pVIT-tk-Luc), which express the luciferase gene under the control of wild type vitellogenine A2 promoter (derived from Xenopus laevis), is assayed. The luciferase activity correlates directly with the estrogenic potency of the tested ligand (test substance). In contrast to the E-Screen assay in which only cell proliferation is analysed, in this assay an estrogen-specific response on the gene expression level is measured. Transgene reporter gene systems are considered superior to the human MCF-7 cell line systems due to their better specifity and higher throughput. In the gene reporter assay, no concentration-dependent induction of luciferase was noted with the C12-16 Alkyl Polyglycosides at concentrations up to 100,000 times higher than the positive control.

 Based on these results, there is no indication that Alkyl Polyglycosides, including C8-10 alkyl polyglycosides, might act as an endocrine modulator.

 C. Aggregate Exposure

 As part of the tolerance reassessment process for the alkyl polyglycosides, the Agency reviewed the safety data base and concluded that the alkyl polyglycosides are lower toxicity substances. Ingredients that the Agency classifies as being of lower toxicity are generally considered to pose no concerns to humans or the environment. Adding uses in antimicrobial formulations will add little if any incremental risk compared to the unrestricted use of C8-10 alkyl polyglycosides in pesticide products applied directly to food crops both pre- and postharvest.

    1.   Dietary exposure.

 Dietary (food and drinking water) and residential (dermal and inhalation) exposures are possible from the use of C8-10 alkyl polyglycosides as an inert ingredient in antimicrobial formulations. Alkyl polyglycosides, including C8-10, have been demonstrated to be readily biodegradable, which reduces the likelihood of residues on food. For the same reason, no significant contributions to drinking water are expected from the use of C8-10 alkyl polyglycosides as inert ingredients in pesticide products. Alkyl polyglycosides have low toxicity and exposure to residues above toxicity levels of concern are not anticipated.

 A quantitative dietary risk assessment for the alkyl polyglycosides is not necessary since there are no toxicity endpoints of concern that are associated with dietary ingestion of the alkyl polyglycosides. The gastric irritation that resulted in the subchronic oral study is particular to the nature of the study (dosing by gavage with a surfactant) and would not occur from dietary intake of low levels of the alkyl polyglycosides.

 Nontheless, a quantitative risk assessment has been conducted using the systemtic NOEL from the subchronic study.  Specifically, a Reference Dose (RfD) of 10 mg/kg/day was calculated based on a NOAEL of 1,000 mg/kg/day in the subchronic oral toxicity study in rats using a 10x uncertainty factor for inter- and intra-species extrapolation. The chronic Population Adjusted Dose (cPAD) is also 10 mg/kg/day. No additional uncertainty factor was added to the cPAD calculation as the reproductive and developmental toxicity studies do not indicate any additional susceptibility for infants and children.

 The chronic dietary exposure due to C8-10 alkyl polyglycosides use as an inert ingredient in disinfectants (sanitizer) used on food-contact surfaces was assessed. This assessment calculated the Daily Dietary Dose (DDD) and the Estimated Daily Intake (EDI). The assessment considered: application rates, residual solution or quantity of solution remaining on the treated surface without rinsing with potable water, surface area of the treated surface which comes into contact with food, pesticide migration fraction, and body weight. These assumptions are based on FDA guidelines (FDA, 2003).

 The EDI calculations presented in this assessment assume that food can contact either 2,000 cm2 or 4,000 cm2 (50% and 100% of the FDA worst-case scenario) of treated surfaces, and that 10% of the material would migrate to food. The 10% migration rate is based on Agency Residential Standard Operation Procedures. These daily estimates were conservatively used to assess chronic dietary risks (i.e., percent chronic population adjusted dose or %cPAD).

 Assuming a level of 2,100 ppm of C8-10 alkyl polyglycosides in the use dilution solution, the following EDI is calculated:

 EDI: 100% FDA Worst Case

             2	x
EDI	=   1 mg/solution cm

2,100 ug
1,000 mg	x

4,000 cm 2
person/day	x   10%	=
                              840 ug/person/day
                                         OR
                              0.84 mg/person/day
                                       

 EDI: 50% FDA Worst Case

             2	x
EDI	=   1 mg/solution cm

2,100 ug
1,000 mg	x

2,000 cm 2
person/day	x  10%	=
                              420 ug/person/day
                                         OR
                              0.42 mg/person/day
                                       

 The above calculation is for use of the substance in products that are used in public-eating facilities, which is worst-case. Use in food-processing plants would yield dramatically lower exposures.

 Assuming body weights for men (70 kg), women (60 kg), and infants and children (15 kg), the following percent DDD values are calculated:

 DDD: 100% FDA Worst Case

    ::	Male:	0.84 mg/person/day / 70 kg/person = 0.012 mg/kg/day
    ::	Female:	0.84 mg/person/day / 60 kg/person = 0.014 mg/kg/day
    ::	Infants/Children:	0.84 mg/person/day / 15 kg/person = 0.056 mg/kg/day

 DDD: 50% FDA Worst Case

    ::	Male:	0.42 mg/person/day / 70 kg/person = 0.006 mg/kg/day
    ::	Female:	0.42 mg/person/day / 60 kg/person = 0.007 mg/kg/day
    ::	Infants/Children:	0.42 mg/person/day / 15 kg/person = 0.028 mg/kg/day

 Based on the calculated DDDs and the cPAD value of 10 mg/kg/day, the following percent cPAD estimates are derived:

 % cPAD: 100% FDA Worst Case

    ::	Male:	0.012 mg/kg/day / 10 mg/kg/day = 0.12% cPAD
    ::	Female:	0.014 mg/kg/day / 10 mg/kg/day = 0.14% cPAD
    ::	Infants/Children:	0.056 mg/kg/day / 10 mg/kg/day = 0.56% cPAD

 % cPAD: 50% FDA Worst Case

    ::	Male:	0.006 mg/kg/day / 10 mg/kg/day = 0.06% cPad

    ::	Female:	0.007 mg/kg/day / 10 mg/kg/day = 0.07% cPad
    ::	Infants/Children:	0.028 mg/kg/day / 10 mg/kg/day = 0.28% cPad i.		Food.
 Food contact exposures are well below 100% of the cPAD, and are therefore below EPA's established level of concern for all U.S. subpopulations. The combined exposure for males, females, and infants and children is < 1% of the cPAD, even for the 100% worst case scenario.

    ii.	Drinking water.

 Drinking water exposure is highly unlikely from the use of Alkyl (C8-C10) Polyglycosides as an inert ingredient in antimicrobial pesticide products. Moreover, alkyl polyglycosides are readily biodegradable according to OECD criteria, which reduce the likelihood of residues on food. Furthermore, the Agency did not anticipate significant contributions to drinking water when assessing the risks from these chemicals as inert ingredients in pesticide formulations applied to growing crops and animals. Exposures to residues above toxicity levels of concern are not anticipated.

 D. Cumulative Effects

 Alkyl (C8-C10) polyglycosides do not share a common mechanism of toxicity with any other pesticide active and/or inert ingredient.

 E. Safety Determination

 The proposed use of alkyl (C8-C10) polyglycosides will not increase the current exposure due to other non-pesticide exposures. The food-contact sanitizer use for all population subgroups combined is <1% of the cPAD.

 As part of the tolerance reassessment process for the alkyl polyglycosides, the Agency reviewed the safety data base and concluded that the alkyl polyglycosides are lower toxicity substances. With the exception of localized irritation at high concentrations, the safety test data clearly shows that the alkyl polyglycosides are practically non-toxic after both acute and repeated exposures. The one effect that was observed in the sub-chronic study  -  irritation of the forestomach  -  is typical of surfactants, such as the soap salts, which are listed in §180.950.

 Ingredients that the Agency classifies as being of lower toxicity are generally considered to pose no concerns to humans or the environment. Adding uses in antimicrobial formulations will add little if any incremental risk compared to the unrestricted use of C8-10 alkyl polyglycosides in pesticide products applied directly to food crops both pre- and postharvest.

 Additionally, alkyl polyglycosides surfactants in the range of C6-C16 (CAS Nos. 68515-73-1,
 132778-08-6, 110615-47-9) are classified as Generally Recognized as Safe (GRAS) by FDA for
 use in the cleaning of food products; the cleaning of equipment used to process food; the manufacture of products that come in contact with food, fruits and vegetables including meat and poultry carcasses; the cleaning of materials that subsequently come in contact with food, paper,

 cardboard, plastic or stainless steel lines and or production vessels; and the cleaning and sanitizing of surfaces in food preparation areas.

       1.	U.S. population.

 The % cPAD calculated for males (0.06-0.12%) and females (0.07-0.14%) is below the level of concern. Based on these conservative exposure estimates, there is a reasonable certainty that no harm will result to the U.S. population from the aggregate exposure to alkyl (C8-C10) polyglycosides.

       2.	Infants and children.

 FFDCA Section 408 requires an additional tenfold margin of safety for the protection of infants and children in case of threshold effects to account for prenatal and postnatal toxicity, and an inadequate toxicity database. Where an adequate and reliable database is available and there is a lack of evidence for increased susceptibility, the FQPA safety factor may be reduced or removed.

 An evaluation of susceptibility and uncertainty issues associated with alkyl (C8-C10) polyglycosides
 has been performed, and EPA has previously reduced the FQPA safety factor from the default 10x to
 1 for the following reasons:
       ::	The availability of a substantial and scientifically sound mammalian toxicology database that includes acute, repeat dose, reproduction, developmental, and endocrine data for alkyl polyglycosides, including C8-C10;
    ::	OECD  testing  indicating  that  there  was  no  evidence  of  developmental  toxicity  or
       malformations in the developing offspring;
       ::	There is no evidence to suggest that alkyl polyglycosides, including C8-C10, would have an adverse effect on the reproductive organs;
       ::	Alkyl polyglycosides, including C8-C10, do not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system. Alkyl polyglycosides, including C8-C10, have been evaluated in acute, repeated dose, developmental, and chronic toxicity studies capable of detecting effects on endocrine mediated events and have not demonstrated any endocrine-related effects.

 The % cPAD calculated for infants and children (0.28-0.56%) is below the level of concern. Based on these conservative exposure estimates, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure to alkyl (C8-C10) polyglycosides.

 F. International Tolerances

 There are no CODEX MRLs established for alkyl (C8-C10) polyglycosides.