summary of the data used to reassess this chemical under the current proposed exemption, including data from the previous risk assessmen t along with two studies th at were not reviewed for the previous tolerance exemption, is provided below.

For ease of reading, alkyl polyglycosides will be collectively known thr oughout the document as “APGs” with the specific carbon chain length identified as “(C

x -C

x )”, when appropriate. As stated in the final rule for alkyl (C 10 -C 16 ) polyglycosides, “Alkyl (C 8 -C 10 ) polyglycosides and alkyl (C 12 -C 14 ) polyglycosides are structur ally related to the alkyl (C 10 -C 16 ) polyglycosides also known as D-glycopyranose, oligomeric, C 10 -C 16 - alkyl glycosides...These chemicals differ from one another only in the length of the alkyl chai n. Given these structural similarities, these chemicals have similar toxicological char acteristics.” Therefore, data on alkyl (C 8 -C 16 ) polyglycosides has been used to make a safe ty finding on D-Glucopyranose, oligomeric, decyl octyl glycosides also know as alkyl (C 8 -C 10 ) polyglycosides. Pl ease note the word “polyglucosides” is used thr oughout the document when the chemical has been derived from glucose.

In addition to their use in pesticide products AP Gs are used in laundry detergents, hard surface cleaners, other house hold cleaners, as rinse aids in dish washers and in personal care products. A Generally Recognized As Safe (GRAS) Noti ce (GRN 000237) was submitted to the Food and Drug Administration in 2007 for the use of alkyl polyglycosides 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, th e cleaning of materials that subsequently come in contact with food, pa per, cardboard, plastic or stainless steel lines and/or production vessels, and the cleaning and sa nitizing of surfaces in food preparation areas. It is anticipated alkyl polyglycos ide surfactants would be presen t in most final cleaning product

formulations at no more than 20% active and at final use levels less than 2% active. The FDA had no questions regarding the conclusion th at alkyl polyglycosides are GRAS under the intended conditions of use. The FDA has not, how ever, made its own determination regarding the GRAS status of the subject use of alkyl polyglycosides.

Acute studies indicate lo w acute oral and dermal toxicity (Table 1). C 10 -C 16 is likely to be an eye and skin irritant; however, studies using C 8 -C 10 did not show evidence of irritation.

Table 1. Acute Toxicity Studies* Study/Species Test Substance Results Acute oral toxicity/rat C 8 -C 14 Lethal Dose (LD) 50 > 5,000 milligrams/kilogram (mg/kg) Acute oral toxicity/rat C 12 -C 14 LD 50 > 5,000 mg/kg Acute oral toxicity/rat C 12 -C 14 LD 50 > 5,000 mg/kg Acute dermal toxicity/rabbit C 8 -C 10 LD 50 > 5,000 mg/kg Acute dermal toxicity/rabbit C 12 -C 14 LD 50 > 5,000 mg/kg Primary eye irritation/rabbit C 8 -C 10 No irritating effects Primary eye irritation/rabbit C 12 -C 14 Irritating to the eye Primary dermal irritation/rabbit C 8 -C 10 No irritating effects Primary dermal irritation/rabbit C 12 -C 14 No irritating effects at concentrations of up to 30% Irritating to the skin at concentrations > 30% to 100% Dermal sensitization/ guinea pig C 8 -C 10 Not a dermal sensitizer Dermal sensitization/ guinea pig C 12 -C 14 Not a dermal sensitizer *Adopted directly from FR(citation)Repeat dose studies (Table 2) for APGs in clude a 90-day gavage study, a 14-day dermal, a reproduction study, and a developmental study. In the 90-day rat oral (gavage) study, APG (C 12 - C 14 ) was administered at dose levels of 0, 250, 500, or 1,000 mg/kg/day for 5 days/week. (MRID 46090901) There were no treatment-related adve rse effects on body weight, body weight gain, food consumption, hematological or clinical ch emistry parameters or organ weights in any group. Adverse treatment-related effects were li mited to the forestomach in both males and females receiving 500 or 1,000 mg/kg/day. After 27 days, it was observed that forestomach effects were reversible following the cessation of treatment, but not reversible during treatment.

The no observed adverse effect level (NOAEL) in the 2005 Final Rule (FR) was determined to be 250 mg/kg/day and the lowest observed adve rse effect level (LOAEL) was 500 mg/kg/day based on acanthosis, subepithelial inflammatory edem a, and hyperkeratosis (females only) of the forestomach. However, “Humans do not have a fore stomach which serves as a storage reservoir in rodents; therefore effects seen in the rat forestomach are likely to be significantly more severe than what would be expected from the com pound in the glandular stomachs in humans and therefore, have less relevance to humans. ”(EPA 2009) The Toxicology Science Advisory Committee (ToxSAC), one of Office of Pesticide’s Health Effect Division ’s scientific peer review committees, recently concluded that these effects are local effects and not systemic and therefore, should not be the ba sis for the study LOAEL. Theref ore, EPA concluded that the NOAEL for the systemic toxicity is 1,000 mg/kg/ day. A LOAEL was not obs erved in this study.

A 14-day dermal study was conducted on APGs (C 8 -C 10 ). The information contained in this document was taken from a summary of the study which was published in the Handbook of Detergents, Part B. (Willing, 2004) While skin irritation was observed at doses above 180 mg/kg/day and changes in hematological and clin ical parameters and testicular degeneration were observed at the dose levels of 1,500 a nd 3,000 mg/kg/day, these effects are likely

attributable to stress and infl ammation due to the severe irrita tion caused by the test substance and therefore a NOAEL for systemic effects was not established.

...study for subacute toxicity is available for C 8

– 10 APG. The test substance (60% active substance) was applied openly to the intact skin of rabbits (New Zealand white) at doses between 0.06 and 3 g/kg b.w./ day, respectively. Each dose gr oup consisted of six male and six female animals, which received ali quots of 2 mL/kg once da ily over a treatment period of 14 days. After each daily 6-h exposur e time, the application sites were wiped. A control group was treate d with only water. The rabbits we re observed daily for clinical signs and skin irritation. Body weights were determined on days 5 and 9 of treatment, whereas hematological and clinical chemical parameters were determined prior to dosing and on termination of the study. Absolute and relative organ weights, necropsy observations, and histopathology of the testes and accessory sex glands were evaluated at the end of treatment. Doses at and above 1.5 g/ kg b.w./day induced se vere skin irritation after repeated application as well as several changes in hematological and clinical parameters and testicular dege neration. These effects were at least partly attributed to

stress and inflammation due to the severe ir ritation caused by the test substance. Minimal

to mild skin irritation was seen in dose groups starting from 0.54 g/kg b.w./day, whereas no clinical, haematological, or organ changes were reported at this dose. At and below 0.18 g/kg b.w./day, none of the described adverse effects was seen...A reproduction study summarized in the Handbook of De tergents, Part B is provided below. The full study is not available. (Willing, 2004)

C10/16 alkyl polyglycosides were investigated in male and female rats following daily administration by oral gavage of 100-, 300-, and 1000-mg/kg/day doses. Each group

contained 10 male and 10 female F0 rats. Da ms were allowed to litter and rear their offspring to post partum day 4. No effects indi cative of general toxicity were observed in parental animals. Relative and absolute we ights of testes, epididymides, and seminal

vesicles did not differ between test and control animals. A marginal reduction in absolute and relative prostate weights wa s seen in all treated males co mpared to the control group, being significant for the lo w-dose group only and not dose dependent. Therefore, this finding was not considered to be substan ce related. With rega rd to reproductive parameters, no test substance–related symp toms were observed. Mean litter weights, mean pup weights, sex ratios, and gestati on periods were similar among groups. Some variations in prebirth loss were seen in the high-dose gr oup without being dose dependent or significantly different to the controls. Pr e-weaning clinical signs showed no treatmentrelated effects in pups, nor did necropsy reveal any effects in decedent or Fl pups. Macroscopic examination revealed no differen ce between treated and control animals. On

the basis of the results obtained in this one-generation screen ing assay, a NOAEL of 1000 mg/kg/day for reproductive effect can be deduced.

In a rat developmental toxicity study, APGs (C 12 -C 14 ) was administered by gavage at dose levels of 0, 100, 300, and 1,000 mg/kg/day on gestation days 6 to 15. (MRID 46090902) No treatment related maternal deaths, clinical signs, or decreases in mean body weight, weight gain, corrected weight gain or gross lesions were observed in this study. In addition, there were no treatmentrelated developmental effects (e.g., external a bnormalities, visceral abnormalities or skeletal malformations/variations); therefore, the developmental and maternal NOAEL is 1,000 mg/kg/day. A LOAEL was not determined.

Table 2. Repeat Dose Studies
Study/Species Test
Substance Dose Results

90-day oral toxicity/rat C 12 -C 14 0, 250, 500, or 1,000 mg/kg/day NOAEL = 1,000 mg/kg/day (highest dose tested)

LOAEL not established

14-day

dermal/rabbit C 8 -C 10 60-3000 mg/kg/day Systemic NOAEL not established Systemic LOAEL not established Developmental toxicity/rat C 12 -C 14 0, 100, 300, or 1,000 mg/kg/day Maternal NOAEL = 1,000 mg/kg/day (highest dose tested)

Maternal LOAEL not established Developmental NOAEL = 1,000 mg/kg/day (highest dose tested) Developmental LOAEL not established Reproductive screening toxicity/rat C 10 -C 16 0, 100, 300, or 1,000 mg/kg/day Reproductive NOAEL = 1,000 mg/kg/day (highest dose tested)

LOAEL not established

An in vivo study is not available; however, an in vitro dermal penetration study using caprylyl/capryl glucoside on human skin showed that when the substance was diluted to 10% and tested the mean recovery was 0.52% of caprylyl/ capryl glucoside from two tape strips and 0.30%of caprylyl/capryl glucoside in the remaining 18 tape strips, after 24 hours. The mean amount of caprylyl/capryl glucosid e removed from the skin (by washing) ranged from 109-145% of the dose applied. The mean absorbed dose of capry lyl/capryl glucoside, as the sum of the amounts found in the viable epidermis, dermis, and receptor medium, was 0.01%. (Across Barriers GmbH, 2009). Full study re port not available.

Mutagenicity studies on various chain lengths of alkyl polyglucosides were negative indicating that APGs are not likely to be mutage nic. (Banduhn, 1994 and Banduhn, 1995) Table 3 was taken directly from the Final Rule for Alkyl (C 10 -C 16 ) Polyglycosides published in the Federal Register on September 14, 2005 (70 FR 54281). No carcinogenicity stud ies are available on APGs; however, APGs are not expected to be car cinogenic based on lack of mutagenicity, lack of any systemic toxicity at high doses (up to and includ ing 1,000 mg/kg/day) and rapid metabolism to sugars and alcohols in the body and excretion from the body.

Table 3. Mutagenicity Studies Type of Study Test Substance Results

Salmonella/Escherichia reverse gene mutation assay ) Ames Test C 12 -C 14 Negative. No evidence of induced mutant colonies over background. Salmonella typhimurium reverse (Ames Test) Not specified Did not induce reverse mutations in

tested strains of Salmonella typhimurium either with our without

metabolic activation

In vitro cytogenetic test in Chinese hamster V79 lung fibroblast Not specified Considered to be non-mutagenic.

In vitro mammalian cytogenetics assay C 12 -C 14 Negative with and without activation.

When evaluating inert ingredients for food use the agency is responsible for addressing the Food Quality and Protection Act (FQPA) safety factor to protect infants and children. Testicular atrophy was observed in the 14-day dermal study at 1,500 mg/kg/day; however, these effects are likely attributable to stress and inflammation due to the severe skin irritation caused by the test substance and therefore a NOAEL for sy stemic effects was not established. In addition, oral reproductive and developmental studies did not show any effects at does as high as 1,000 mg/kg/day. Based on the low acute and subchronic toxicity of th e chemical and the lack of endpoint of concern (including re productive and developmental) in repeat dose studies at doses as high as 1,000 mg/kg/day, the agency feels a safety factor analysis is not necessary.

APGs are currently approved under 40 CF R 180.910 and 180.930 without limitation which allows the inert ingred ient to be used on food both pre- and postharvest and use on animals. Subsequently, unrestricted nonfood use as an inert ingredient in pesticide products is permitted. Non-occupational exposure is possible via the oral route resulting from eating foods treated with the inert ingredient, consuming animal products fr om animals exposed to the inert ingredient, or by ingesting residues left on utensils and dish es treated with antimic robial food sanitizing solutions containing the inert ingredient. In additi on, there is a potential fo r residue transfers to

food that comes in contact with these treated areas (e.g., food-contact su rfaces in public eating places, dairy-processing equipment, or food-pr ocessing equipment). Dermal and inhalation exposure is also possible when applying the pestic ide formulation containing the inert ingredient in residential settings. Occupational exposure via the dermal and inhalati on route is possible.While oral, dermal, and inhalation exposures are possible there was no endpoint of concern identified in toxicity studies up to 1,000 mg/kg/day. In addition, metabolism studies on structurally-related chemicals indicate that the body can effec tively metabolize D-glucopyranose, oligomeric, C 10 -C 16 -alkyl glycosides to water-soluble substances (predominantly sugar and various alcohols) that are readily excreted from the body. (MRID 46059205) Based on the low acute toxicity, the body’s ability to rapidly metabo lize the inert ingredient , and the lack of an endpoint of concern for repeat dose studies at the limit dose (1,000 mg/kg/day) a qu alitative risk

assessment was conducted.

Predictive modeling (Federal Register, September 14, 2005 (70 FR 54281)) and various screening test for biodegradation (Willing, 2004; MRID 46059207) indicate that APGs are expected to undergo rapid degrada tion (estimated to be hours to days for primary degradation) and ultimate degradation to water and carbon dioxide in days to weeks. Therefore, it is unlikely that APGs will reach either gr ound or surface water or bioaccumulate in the environment. EPA previously assessed ecotoxicity for APGs using pr edictive models and SAR analysis which led to the conclusion that these chemicals were moderately to highly toxic to aquatic species. However, experimental studies for APGS have shown that alkyl (C 8 -C 10 ) polyglycosides are only slightly toxic to aquatic species (Table 4). (Willing, 2004)

Table 4. Acute Ecotoxicological Data of APG-Freshwater Organisms

Test Substance Endpoint OECD Method Duration C 8 -C 10 C 12 -C 14 C 16 -C 18 Fish 203 96-hr, LC 50 101 mg/L 3.0 mg/L 2.6 mg/L (48 hr) Daphnia 202/I 48-hr, EC 50 20 mg/L 7.0 mg/L n.d. Algae 201 72-hr, EC 50 47 mg/L 10 mg/L n.d.

Based on the low acute toxicity, th e lack of a toxic endpoint in av ailable studies at doses up to and including 1,000 mg/kg/day, the body’s ability to metabolize the inert ingredient, coupled with the low ecotoxicity; the agency believes ther e is reasonable certainty of no harm to human health and the environment by expanding the current approval under 40 CFR 180.910 and 180.930 to include an exemption under 40 CFR 180.940(a). Therefore an exemption from the requirement of tolerance under 40 CFR 180.940(a) fo r D-Glucopyranose, oligomeric, decyl octyl glycosides has been established.Bibliography

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