Page 2 of 17 In a 90

- day oral toxicity study, GTL petroleum distillates administered by gavage resulted in a statistically significant increase in the incidence and severity of alveolar macrophage accumulations and increased vacuolation of alveolar macrophages in the lung in rats at the lowest observed adverse effect level (LOAEL) >200 mg/kg/day (LOAEL). These effects were still present in a recove ry group following an additional twenty

eight days without treatment. The 'No Observed Adverse Effect Level' (NOAEL) was 50 mg/kg/day.

In a two

- generation reproductive toxicity study via gavage in rats, GTL petroleum distillates caused maternal and offsp ring toxicity at 1000 mg/kg/day. Toxicity was manifested as chronic interstitial/alveolus inflammation in the lungs. The NOAEL was 50 mg/kg/day since animals in the mid dose (250 mg/kg/day) group were not analyzed. The reproduction NOAEL was 1000 mg/kg/ day, the highest dose tested.

Based upon subsequent studies conducted to evaluate the lung effects, the Agency determined that the effects were caused by gavage administration error and were not test material (dose) related. In a 28

- day oral feeding

stud y at doses > 1,000 mg/kg/day, no adverse effects were observed. In a prenatal developmental toxicity study

in the rat (by oral gavage) at doses up to 1,000 mg/kg/day, no adverse toxicological effects were seen. The

results of the two recent studies allev iated the Agency’s concern for the lung effects seen in the 90

- day oral toxicity study and the 2

- generation reproduction study.

GTL petroleum distillates were evaluated for mutagenic potential using the Ames test, micronucleus assay, and gene mutation i n mammalian cells. These studies were negative for the induction of mutations and aberrations. Therefore, GTL petroleum distillates are considered non

- mutagenic.

A neurotoxicity study was not conducted with GTL petroleum distillates. However, acute tox icity tests (i.e. doses up to 5000 mg/kg bw/day) in the rat using GTL petroleum distillates did not produce any neurotoxicity. Also, functional observation parameters were evaluated in the 90

- day oral toxicity study in rats and in the 28

- day oral feeding study . Evidence of neurotoxicity was not observed.

An immunotoxicity study was not conducted with GTL petroleum distillates. However, alveolar macrophage accumulations and increased vacuolation of alveolar macrophages in the lung was observed in rats at >200 mg/kg/day in both the 90

- day oral and 2

- generation reproduction toxicity studies. However, these effects were determined to be caused by gavage technique error rather than the test substance.

The Applicant asserts that w ith regards to absorption, metabolism, distribution and elimination, it is noted that with various complex mixtures of normal, branched and cyclic petroleum derived hydrocarbons absorption is inversely related to carbon chain length and is independent of isomeric form, preparation process or type of product. Materials with carbon chain lengths of C 30

- C 35 are typically absorbed in the gastro

- intestinal tract at

rates of 2

- 20%. However, when present as mineral oil hydrocarbons of higher molecular weights with approximate chain leng ths of C 32

- C 35 , they are not absorbed to any significant extent. Since the Fischer

Tropsche derived hydrocarbons have chain lengths in the range of C 40

- C 70 (similar to the petroleum derived materials) they are unlikely to be absorbed. Consequently, when administered orally, Fischer

- Tropsche derived hydrocarbons in the range of C 40

- C 70 are likely to be excreted, unabsorbed, in the feces. It should be noted that the Applicant described CASRN 848301

- 69

- 9 as being C 18

- C 50

.

Carcinogenicity studies with GTL petroleum distillates are not available for review. However, based on the

lack of genotoxic ity and lack of any systemic toxicity at the limit dose (1000 mg/kg/day) , GTL petroleum distillates are not expected to be carcinogenic.

EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF were reduced to 1X.Page 3 of 17 Available toxicity data on GTL petroleum dis tillates demonstrated no toxicity at doses up to 1,000 mg/kg/day. Therefore, since there are no endpoints of concern for GTL petroleum distillates a qualitative dietary exposure risk assessment is appropriate.

GTL petroleum distillates are expected to ha ve negligible effects upon the environment

. Abiotic degradation in water, sediment or soil is not anticipated, on the basis of the chemical structures present. The GTL petroleum

distillates is a n Unknown or Variable Composition, Complex Reaction Products and Biological Materials (UVCB) substance composed of saturated linear or branched hydrocarbons with general formula C
n H 2n. None of the constituents contains functional groups associated with the susceptibility to undergo hydrolysis under typical environ mental conditions. Phototransformation is not expected in water or in soil based upon the chemical structures. A study of aerobic biodegradation using municipal sludge determined that there was an

absence of inhibition of micro

- organisms by GTL petroleum distillates at a concentration of 30 mg suspended

solids/L.

The petition is for an exemption from the requirement of a tolerance when used as an inert ingredient in pesticide formulations as described in 40 CFR § 180.910. In mixtures in pesticide formulations, the GTL petroleum distillates serve as a diluent, a so lvent or as a dust suppressant.

Based upon the discussion presented in the summary of toxicological effects and the discussion presented under toxicological endpoint, as well as the discussion of environmental fate and effects, the Agency concludes that

GTL petroleum distillates ((Fishcher

- Tropsch), heavy, C18

- C50, branched, cyclic and linear) (CASRN

848301

- 69

- 9) are approved for use as an inert ingredient in pesticide products without limitation.

II. I NTRODUCTION

The Wagner Regulatory Associates, Inc. (P.O. Box 640, 7217 Lancaster Pike, Suite A, Hockessin, DE 19707)

on behalf of Pennzoil

- Quaker State Company (a subsidiary of Royal Dutch Shell ; 700 Milam Street, Houston,

TX 77002 ) has submitted a request to use a GTL petroleum distillates as an ine rt ingredient in pesticide products. Specifically, the substance is a product of petroleum distillation using the Fis h cher

- Tropsch process.

The substance is described as GTL petroleum distillates (Fis h cher

- Tropsch), heavy, C 18

- C 50 , branched, cyclic

and linear. The CASRN is 848301

- 69

- 9. GTL petroleum distillate products differ from conventionally

derived sources in that GTL petroleum distillate s contain negligible quantities of aromatic, sulphur or nitrogen compounds. The GTL petroleum distillates function as a solvent, diluent and/or dust suppressant in pesticide

formulations.

The submitter describes GTL petroleum distillates as: “A complex combination of hydrocarbons obtained from a feedstock derived from the catalytic hydr ogenation of carbon monoxide (the Fischer

- Tropsch process), optionally followed by one or more of the following processes: hydrotreatment, hydroisomerisation and/or hydrocracking. It consists predominantly of branched, cyclic and linear aliphatic hydroca rbons having carbon numbers in the range of C 18

- C 50 . It is a base oil that boils approximately in the range of 300 o C to 570 o C with a viscosity of at least 4.0 cSt at 40o C and an approximate pour point of less than 0o C.

The Registrant cites an exis ting regulation at 40 CFR 180.910 for ‘Petroleum hydrocarbons, light odorless conforming to 21 CFR 172.884 for use as solvent and/or diluent’. The referenced regulation at 21 CFR 172.884 specifies: ‘(a)...mixture of liquid hydrocarbons derived from petroleu m or synthesized from petroleum gases. The additive is chiefly paraffinic, isoparaffinic, or naphthenic in nature. (b) The additive meets the following specifications: (1) Odor is faint and not kerosenic. (2) Initial boiling point is 300 oF minimum. (3 ) Final boiling point is 650 oF maximum.’Page 4 of 17 III. PHYSICAL AND CHEMICAL PROPERTIES

Exemplary Chemical Structure s

.



### Table 1. Physical/Chemical Properties
Property GTL Petroleum Distillate

Physical Form Liquid

Phy s i cal Appearance Clear colorle s s sligh t l y viscous

liquid

Molecular W e i g h

t 114

- 226 g/ m o l

Boiling Range 198

- 36 1 ° C (Ref 1)

300

- 57 0 ° C ( see comment belo w )*

Relative Density 0.809 at 20°C

Water Solubility < 1.0 mg/L at 2 0 ' C

Partition Coefficient Log P ow > 6

. 5

Adsorption Coeffi c i ent Log K oc > 5

. 63

F la s h Point 187 ± 2 ' CPage 5 of 17

Vapor Pressure 0

. 0028 Pa at 25 ' C

Auto igniti o

n temp 348 ± 5 ' C

IV

. TOXICOLOGY PROFILE

A. Acute Toxicity

Acute Oral Toxicity

– A preliminary acute oral toxicity study was conducted on rats given a single dose of 5000 mg/kg bw of distillates. No toxicity was observed. Therefore, four female Sprague

- Dawley CO (Crl : CD® (SD) IGS BR) strain rats were administered a single oral dose of 5000 mg/kg bw b y gavage. Clinical observations were made 1/2, 1, 2, and 4 hours after dosing and subsequently once daily for fourteen days. Morbidity and mortality checks were made twice daily.

Individual bodyweights were recorded on Day 0 (the day of dosing) and on Da ys 7 and 14. At the end of the study the animals were sacrificed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any

m acroscopic abnormalities was recorded. No tissues were retained.

There were no clinical signs of toxicity noted nor were there any mortalities noted. There were no internal signs of abnormality. The acute oral median lethal dose (LD 50 ) of the test mater ial in the female Sprague

- Dawley CD strain rat was estimated to be greater than 5000 mg/kg bodyweight (MRID 488429

- 03).

Acute Dermal Toxicity

- The submitter states that: “In a n acute dermal toxicity test, 2,000 mg/kg bw of

test material [distillate] wou ld be applied to the skin of the animals. Because dermal absorption of distillate is expected to be less than intestinal absorption, the concentration of material systemically available after dermal administration will be significantly less than following oral administration. Even if all of the dermal applied test substance (2,000 mg/kg bw) would be absorbed through the skin, the amount of bio

- available material would be less than in the acute oral toxicity studies, where 5,000 mg/kg was administered with out signs of toxicity. As a consequence, an acute dermal toxicity study with distillates is deemed unnecessary and unethical from an animal welfare point of view.”

Acute Inhalation

– No data were reported regarding acute inhalation exposure. However t he Agency notes the low vapor pressure of GTL petroleum distillates (0.0028 Pa at 25oC) indicating negligible volatility.

Dermal Irritation

– Dermal irritation was evaluated on three New Ze a land White rabbits using a 4

- hour,

semi

- occluded application te st method. No corrosive effects were noted (MRID 848429

- 04).

Acute Eye Irritation

- Initially, a single rabbit was treated. A volume of 0.1 ml of the test material was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The upper and lower eyelids were held together for about one second immediately after treatment, to prevent loss of the test material, and then released. The left eye remained untreated and was used for control purposes.

Immedi ately after administration of the test material, an assessment of the initial pain reaction was made according to a six point scale. All animals were scored as showing a slight initial pain.

After consideration of the ocular responses produced in the fir st treated animal, two additional animals were treated. Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment, according to a numerical evaluation (Draize J H (1977) "Dermal and Eye Toxicity Tests " In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC pA8 to 49).Page 6 of 17 Any other ocular effects were also noted. Examination of the eye was facilitated by the use of the light source f

r om a standard ophthalmoscope. No corneal or iridial effects were noted. Minimal conjunctival irritation was noted in all treated eyes one hour after treatment and in two treated eyes at the 24

- hour

observation. One treated eye appeared normal at the 48

- hour observation. The test material produced a maximum group mean score of 6.0 and was classified as a minimal irritant (Class 3 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.

Distillates are not c onsidered to be irritating to the eyes (MRID 488429

- 05).

Skin Sensitization

- Female albino Dunkin Huntley guinea pigs were used to test dermal sensitization. Intradermal injections (0.1 ml/injection site) were made on the clipped shoulder of two guinea pigs, at the concentrations of 100%, 50%, 25%, 12.5%, 6.25% and 3.125% by successive dilution (v/v) in olive oil. A macroscopic evaluation of the injection sites was conducted approximately 24 hours after injection to determine

whether these concentration s caused necrosis. Any evidence of systemic toxicity was also recorded. The highest concentration which did not cause necrosis was selected for the intradermal induction stage of the main study.

Two guinea pigs were treated with preparations of the test m aterial at 100% and diluted at 50%

, 25% and 12.5% by successive dilution (v/v) in liquid paraffin. Applications were made to the clipped flanks under occlusive dressings for an exposure period of 24 hours. The degree of erythema and edema was evaluated app roximately 24 hours after dressing removal. The highest concentration producing only moderate dermal irritation was selected for the topical induction stage of the main study.

Four preparations of the test material at 100% and diluted at 50%, 25% and 12.5 % by successive dilution (v/v) in liquid paraffin were applied to the clipped flanks of three guinea pigs under occlusive dressings for an exposure period of 24 hours. These guinea pigs did not form part of the main study but had been treated identically to the control animals of the main study, up to Day 14.

The degree of erythema and edema was evaluated approximately 24 hours after dressing removal. The highest

non

- irritant concentration of the test material and one lower concentration were selected fo r the topical challenge stage of the main study.

A group of fifteen guinea pigs was used for the main study, ten tests and five controls. The bodyweight of each animal was recorded at the start and the end of the study.

No skin reactions were noted at th e intradermal induction sites of the preliminary sighting test animals following treatment with the test material at the concentrations of 100%, 50%, 25%, 12.5%, 6.25% and 3.125%. The concentration chosen for use in the intradermal induction phase of the main test was 100% (maximal non

necrotizing concentration (MNNC)).

Individual skin reactions at the topical induction sites of the preliminary sighting test animals were recorded. No skin reactions were noted at the topical induction sites of the prelimi nary sighting test animals following treatment with the test material at concentrations of 100%, 50%, 25% and 12.5%.

The concentration chosen for use in the 2nd topical induction of the main test was 100% and the 1st

concentration c hosen for the MNIC (max imal non

- irritant concentration) determination was 100%. Individual skin reactions at the topical challenge sites of the preliminary sighting test animals are recorded. No skin reactions were noted at the topical challenge sites of the preliminary sighti ng test animals following treatment with the test material at concentrations of 100%, 50%, 25% and 12.5%.Page 7 of 17 The concentrations chosen for use in the t opical c hallenge phase of the main test were 100% (maximal non

- irritant concentration (MNIC)) and 50% (1/2 MNIC) in liquid paraffin.

Skin Reactions Observed After Topical Challenge:

100% : No skin reactions were noted at the topical challenge site of the test or control group animals

at the 24 and 48

- hour observations. 50% in liquid paraffin : No skin reactions were noted at the topical challenge site of the test or control group

animals at the 24 and 48

- hour observations.

Under the conditions of the test, the test material produced a 0% sensitization rate and was classified as a non

sensitizer to guin ea pig skin (MRID 488429

- 06).

B. Repeat Dose Toxicity

Ninety

- day Oral Toxicity

GTL petroleum d istillates were administered by gavage to three groups, each of ten male and ten female Sprague

- Dawley Crl:CD® (SD) IGS BR strain rats, for up to ninet y consecutive days, at dose levels of 50, 200

and 1000 mg/kg/day

. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP (a peanut oil)). Two recovery groups, each of ten males and ten females, were treated with the high dose (1000 mg/kg/day ) or the vehicle alone for ninety consecutive days and then maintained without treatment for a further twenty

- eight days.

Clinical signs, functional observations, bodyweight development and food and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all non

- recovery animals at the end of the treatment period and for all recove ry group animals at the end of the treatment

- free period. Ophthalmoscopic examination was also performed on control group and high dose animals. All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues was performed.

There were no treatment related effects observed on clinical signs, functional observations, bodyweight, food and water consumption, hematology, blood chemistry and opthalmoscopic examination.

One male treated with 200 mg/kg/day was killed in extremis on d ay 88. Histopathological examination of the respiratory tissues for this animal revealed peripheral inflammatory cell infiltrations and pleural adhesions indicating that the animal had been mal

- dosed into the thorax. There were no further unscheduled deaths.

Microscopic examination revealed a greater incidence of higher grades of severity of alveolar macrophage accumulations in the lung of animals of either sex treated with 1000 mg/kg/day (P<0.01 for males and for females) or at 200 mg/ kg/day for males (P<0.05). The cytoplasm of macrophages seen in the lungs of animals of either sex treated with 1000 mg/kg/day (P<0.001) or at 200 mg/kg/day (P<0.001 for males and p<0.01 for females) was generally more vacuolated than that seen in alveola r macrophages in control animals.

Following an additional twenty

- eight days without treatment, the condition of the lungs had not regressed to any extent among the group of recovery rats of either sex at 1000 mg/kg/da y

. Therefore, the LOAEL is 200 mg/kg/ day based on the increased incidence and severity of alveolar macrophage accumulations and increased vacuolation in alveolar macrophages in the lung

. The 'No Observed Adverse Effect Level' (NOAEL) for this study was considered to be 50 mg/kg/day

. (MRID 48 8429

- 07).

Two

- generation Reproductive Toxicity StudyPage 8 of 17 GTL petroleum distillates at doses of [0 (vehicle), 50, 250, or 1000 mg/kg/day)] were given by oral gavage to F0 and F1 parental male and female rats for at least 70 days prior to mating and throughout the 14

- day mating, postmating holding (for males), and gestation and lactation (for females) periods. There were no adverse effects observed on clinical signs, body weight, body weight gain, food consumption, male or female reproductive parameters, and pup viability. There was a test item

- related, non

- adverse decrease in anogen i tal distance (AGD) in F1 females born from dams given 250 and 1000 mg/kg/day. Test it em

- related histopathological lesions were identified in the lungs (chronic interstitial/alveolus inflammation) of both males and females of the F0 and F1 generations with corresponding macroscopic findings and/or increased lung weights and the kidneys (ren al tubule hyaline droplets likely representing α2μ

- globulin) of the F1 males only. The renal effects are well known male rat specific effect s which are induced by hydrocarbons and has no relevance for humans. A decrease in F2 pup brain weights was observed in male pups at 1000 mg/kg/day. While this effect is considered treatment related, it is not considered adverse.

The NOAEL for this study was 50 mg/kg/day since animals in the mid dose (250 mg/kg/day) gro up were not analyzed. The LOAEL was 1000 mg/kg/day based on chronic interstitial/alveolus inflammation in the lungs. The offspring and reproduction NOAELs were 1000 mg/kg/day, the highest dose tested. The offspring and reproduction LOAELs were not estab lished. (MRID 48842908).

The Agency noted similar test

- substance related effect s described in the 90

- day oral toxicity (gavage) study and

in the two

- generation reproducti on toxicity study namely, chronic interstitial/alveolus inflammation due to

alveolar macrophage accumulations in the lungs of males and females. Since the same effects were seen in two different repeat

- dose studies, there was uncertainty regarding the choice of NOAEL for use in risk assessment. The uncertainty was whether or not the ad verse lung effects were test

- substance related per se or due to aspiration from gavage error. By policy, the Agency would normally use 50 mg/kg/day as the NOAEL for risk

assessment purposes

.

As a result, the petitioner conducted two repeat

- dose toxicity studies according to OECD guidelines. One study

is a 28

- day repeated dose oral (dietary) toxicity study in the rat and the other is a prenatal developmental toxicity study in the rat.

28

- Day Repeat Dose Oral Toxicity Study

The 28

- day repeat

- dose oral t oxicity study was conducted according to OECD Guidelines for Testing of Chemicals No. 407 “Repeated Dose 28 Day Oral Toxicity Study in Rodents”. Twenty male and twenty female

Wistar Han TM :RccHan TM :Wist strain of laboratory rats were used. Animals were housed in groups of 5 by sex. The test substance (GTL Base Oil 3; distillates (Fischer

- Tropsch), heavy, C18

- C50

– branched, cyclic and linear) (purity not specified) was administered as free access in the diet at 0, 750, 3750, and 15000 ppm

concentration which equates to 0, 63, 308 and 1267 mg/kg/day. At study termination, all animals were subject to gross necropsy and histopathological evaluation of select organ tissues for the high dose group and control group. There were no deaths during the study. There were no clinical signs in any of the animals throughout the treatment period. There were no changes in behavioral patterns. There were no treatment related changes in the functional performance parameters measured. There were no treatment

- related changes in sensory activity. There were no changes in body weight gain. There were no changes in food consumption or food efficiency.

At the 3 rd week of treatment, males at all doses showed increases in levels of water consumption. There was no change in water consumption in the females at any dose. There were no changes in hematological parameters measured. There were no changes in blood parameters measured. There were no macroscopic changes noted. There were no treatment related changes in measure d organ weights. In males at the highest dose, there were microscopic findings characterized by apoptosis/single cell necrosis in the lamina propria/crypt in the duodenum, jejunum, ileum, Peyer’s patches, spleen and mesenteric lymph nodes. No histopathol ogic changesPage 9 of 17 were noted in males treated at 750 ppm or 3750 ppm and no histopathologic changes were noted in females at any dose . The study authors concluded that the NOAEL for males was 3750 ppm (308 mg/kg/day) based on the microscopic findings in lower gut (MRID 49450502).

Prenatal Developmental Toxicity Study in the Rat

A prenatal developmental toxicity study was conducted to determine any effects on pregnant rats and the development of the embryo and fetus as a result of exposure of the female to t he test material (GTL Base Oil 3; distillates (Fischer

- Tropsch), heavy, C18

- C50

– branched, cyclic and linear) (purity not specified). The exposure of the female to the test material was from gestation day 6 post coitum (implantation) to gestation day

20 post coitum (the day prior to Caesarean section). The study was conducted according to OECD test guideline 414. Twenty

- two mated female rats per group (88 females) ( RccHan TM :WIST(SPF) strain ) were exposed daily by oral gavage to 0, 50, 200 and 1000 mg/k g/day of the test material administered in a corn oil

vehicle . Results of the study are as follows. All females survived until scheduled necropsy. There were no

test

- item related clinical signs observed at any dose. There were no changes observed in fo od consumption. Mean absolute body wei g ht and body weight gain were not affected by treatment with the test material. Post

implantation loss and the number of fetuses per dam were not affected by treatment with the test material.

There were no macroscopic findings at any dose level. There were no test

- item related findings upon external examination of fetuses. At the 200 mg/kg/day dose, one pup had a short lower jaw confirmed by fetal pathology. There were not test item related changes in fet al sex ratios in any group. There were no test

- item related changes in fetal body weights. Incidentally, mean body weights of live fetuses calculated on litter and individual basis were statistically significantly increased at 1000 mg/kg/day. There were no fetal visceral abnormalities or variations. One fetus at 50 mg/kg/day had a severely dilated renal pelvis. At 200 mg/kg/day one fetus had a malpositioned subclavian artery and at 1000 mg/kg/day one fetus showed a situs inversus.

These are considered incidental and not treatment related. There were no test item related findings regarding bone abnormalities or variation. At 50 and 200 mg/kg/day there were two fetuses that showed similar findings. One had fused mandibles and lower incisors, misshapen exoccipital/basisphenoid and absent/reduced in size cervical vertebral arches. Another fetus showed a short lower jaw, fused mandibles, lower incisors and misshapen basisphenoid. In the absence of any dose treatment relationship, these are not considere d an adverse treatment related effect. There was no maternal toxicity noted at any dose level. Under the conditions of this study, the GTL Base Oil 3; distillates (Fischer

- Tropsch), heavy, C18

- C50

– branched, cyclic and linear did not reveal teratogenic potential up to and including doses of 1000 mg/kg/day, which is considered the NOAEL (MRID 49450503).

Mutagenicity

Distillates were evaluated for mutagenic potential using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA1537 and Escherich ia coli WP2 uvr A. Distillates were dissolved in tetrahydrofuran at concentrations up to 5000 μg/plate. Appropriate solvent and positive controls were included which exhibited expected results. No toxicity to bacterial cells was observed. No significant increase in the number of revertants was observed at any concentration with and without metabolic activation in any of the strains tested. The results were confirmed with a repeat experiment. Both tests used the direct plate incorporation method (MRID 4 994209).

Gene mutation (Bacterial reverse mutation assay/ Ames Test). The test was negative with and without

activation in Salmonella typhimurium strains TA 98, 100, 1535, 1537 and Escherichia coli WP2uvrA (OECD 471) (MRID 488429

- 09). Cytogenicity in ma mmalian cells was negative with and without activation in human lymphocytes (OECD draft Guideline 487) (MRID488429

- 10).

In Vitro MicronucleusPage 10 of 17 An in vitro micronucleus study was conducted using GTL petroleum distillate using the OECD draft guideline 487. There was no increased incidence of micronuclei in duplicate cultures of human lymphocytes at any concentration in either the initial experiment (4 hr exposure, 16 hr expression, with and without metabolic

a ctivation) or the repeat experiment (20 hr exposure without metabolic activation; 4 hr exposure, 16 hr expression, with metabolic activation). There was no observed toxicity induced by the test material. The test

material was dissolved in acetone and the maximum concentration tested was 2500 μg/plate. Higher concentrations could not be tested due to difficulties in formulating the test material in the vehicle. The vehicle controls had frequencies of cells with micronuclei within the range expected for n ormal human lymphocytes. Appropriate positive controls were included and induced significant increases in the number of cells with

micronuclei. It was concluded that the test material is non

- clastogenic and non

- aneugenic to human lymphocytes in vitro (MR ID488429

- 10).

Carcinogenicity

Carcinogenicity studies with GTL petroleum distillates are not available for review. However, based on the

lack of geno toxicity at the limit dose (1000 mg/kg/day), GTL petroleum distillates are not expected to be carcinogenic.

Neurotoxicity

A neurotoxicity study was not conducted with GTL petroleum distillates. However, acute toxicity tests (i.e., doses up to 5000 mg/kg bw/day) in the rat using GTL petroleum d id not produce any neurotoxicity. Also, neurological parameters including: grasp response, vocalization, toe and tail pinch, finger approach, touch escape, pupil and blink reflex, startle reflex, grip strength and motor activity were evaluated in the 90

- d ay oral toxicity study in rats. Evidence of neurotoxicity was not observed following treatment with GTL petroleum

distillates.

Immunotoxicity

Evidence of potential immunotoxicity in the form of alveolar macrophage accumulations and increased

vacuolat ion of alveolar macrophages in the lung w ere observed in rats at >200 mg/kg/day in both the 90

- day oral toxicity and 2

- generation reproduction studies. However, these effects were determined to be caused by gavage technique error rather than the test substance.

Toxicokinetics (Absorption, Metabolism, Distribution and Elimination)

The Registrant notes that studies with various complex mixtures of normal, branched and cyclic petroleum derived hydrocarbons show that absorption is inversely related t o carbon chain length and is independent of isomeric form, preparation process or type of product. Materials with carbon chain lengths of C 30

- C 35 are typically absorbed in the gastro

- intestinal tract at rates of 2

- 20%. However, when present as mineral oi l hydrocarbons of higher molecular weights with approximate chain lengths of C 30

- C 35 , they are not absorbed to any significant extent. Since the Fischer

- Tropsche derived hydrocarbons have chain lengths in the range of

C 40

- C 70 (similar to the petroleum de rived materials) they are unlikely to be absorbed. Consequently, when administered orally, Fischer

- Tropsche derived hydrocarbons in the range of C 40

- C 70 are likely to be excreted, unabsorbed, in the feces.

In this vein, the Registrant notes that the Ag ency has previously assessed compounds that are structurally

similar to GTL petroleum d istillates . They are:Page 11 of 17 1) “Inert Reassessments: Five Exemptions from the Requirement of a Tolerance for Petroleum Hydrocarbons” (August 2, 2006) The reassessment inc ludes FQPA evaluations for five aliphatic hydrocarbon fluids in the

C 8

- C 20 chain length. The substances include normal paraffins, branched, (iso) paraffins, and cycloparaffins.

2) “Revised Reregistration Eligibility Decision for Aliphatic Solvents” (29 November 2007). The RED document assesses the available data that support the re

- regisration of a range of aliphatic hydrocarbons used and approved by the Agency as pesticide active ingredients. The RED evaluated substances with carbon ranges

of C20

- C50 carbon chain lengths

– i.e., similar to GTL petroleum Distillate.

V. END POINT SELECTION

The Agency has determined, based on the weight of the evidence, that a quantitative exposure and risk assessment is not necessary and a toxicological endpoint was not identified. No toxicity was observed following an acute oral dose of 5,000 mg/kg/day. I n a 90

- day oral toxicity study and a two

- generation reproduction study there were no adverse toxicological effects at doses up to 1,000 mg/kg/day. Effects were seen in the lungs of both sexes in both studies at 1,000 mg/kg/day. The effects were chronic interstitial/alveolus inflammation in the lungs and macrophage accumulations. Based upon subsequent studies conducted to evaluate the lung effects, the Agency determined that the effects were caused by gavage administration error

and were not test materia l (dose) related. In a 28

- day oral feeding study , in males at the highest dose, there were microscopic findings characterized by apoptosis/single cell necrosis in the lamina propria/crypt in the duodenum, jejunum, ileum, Peyer’s patches, spleen and mesen teric lymph nodes. No histopathologic changes were noted in females at any dose. However, these effects were not seen in the 90

- day study and reproduction study in rats so they were not considered as adverse. So there were no treatment related effects in 28

- day toxicity study in rats at doses up to 15,000 ppm; equal to 1267 mg/kg/day. In a prenatal developmental toxicity study in the rat (by oral gavage) at doses up to 1,000 mg/kg/day, no adverse toxicological effects were

seen. Since there w as no sys temic toxicity at or above the limit dose of 1000 mg/kg/day, the Agency concluded that it is not necessary to conduct quantitative risk assessment.

Special Consideration for Infants and Children (FQPA Safety Factor)

Section 408 of the FFDCA provides that EPA shall apply an additional margin of safety for infants and children in the case of threshold effects to account for prenatal and post natal toxicity and the completeness of the database on toxicity and exposure un less EPA determines that a different margin of safety will be safe for infants and children. EPA concludes that the FQPA safety factor could be reduced to 1X for GTL petroleum distillates for the following reasons:

i. The database is considered adequate for FQPA assessment. The following acceptable stud ies are available:

2

- Generation Reproduction toxicity study via gavage

- rat (1) Developmental toxicity study

- rat (1)

ii. Fetal susceptibility was not observed in the 2

- generation reproduction or developmental toxicity stud ies in rats. Maternal and offspring effects (chronic interstitial/alveolus inflammation) were observed at the same dose, 1000 mg/kg/day. However, these effects were due to gavage technique error rather than treatment. No

ad verse toxicological effects were noted at doses up to 1,000 mg/kg/day in the developmental toxicity study.

iii. Neurological parameters including: grasp response, vocalization, toe and tail pinch, finger approach, touch escape, pupil and blink reflex, s tartle reflex, grip strength and motor activity were evaluated in the 90

- dayPage 12 of 17 oral toxicity study in rats. Evidence of neurotoxicity was not observed. EPA concluded that the developmental neurotoxicity study is not required at this time.

iv. Evidence of potential immunotoxicity in the form of alveolar macrophage accumulations and increased vacuolation of alveolar macrophages in the lung was observed in rats at >200 mg/kg/day in both the 90

- day oral toxicity and 2

- generation reproduction studies. However, these effects were determined to be caused by gavage technique error rather than the test substance.

Taking into consideration the available information, EPA concludes the additional 10X FQPA safety factor can

be reduced to 1X.

IV. EXPOSURE

As noted above, based on the toxicological database for the GTL petroleum distillates , the Agency has determined that no toxicological endpoint of concern (for risk assessment) has been identified. Therefore, a quantitative assessment of exposure and risk are not necessary and have not been conducted.

Dietary Exposure/Risk Characterization

Dietary exposure can occur from eating foods containing residues of GTL petroleum distillates . Because no hazard endpoint of concern was identified for the acute and chronic dietary assessment (food and drinking water), a quantitative dietary exposure risk assessment was not conducted.

Residential (Non

- Occupational) Exposure/Risk Characterization

From non

- dietary exposure . The term “residential exposure” is used in this doc ument 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). GTL petroleum d istillates may be used in inert ingredients in pesticide products that are registered for specific uses that may result in both indoor and outdoor residential exposures.

V. AGGREGATE RISK AND DETERMINATION OF SAFETY

Based on the lack of any endpoints of concern, EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure GTL petroleum

distillates residues.

VI. OCCUPATIONAL EX POSURE/RISK PATHWAY

A quantitative exposure and risk assessment was not conducted. Based on the complete toxicological database, a toxicological endpoint of concern (for risk assessment) had not been identified. Quantitative assessments of occupational exposure and risk are not necessary.

VII. CUMULATIVE EXPOSURE

Cumulative effects from substances with a common mechanism of toxicity: Section 408(b)(2)(D)(v) of 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.”Page 13 of 17 For 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

.

VII I

. ENVIRONMENTAL JUSTICE

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Ad dress Environmental Justice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

.

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to

well

- established procedures. In line with OPP policy, RD estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consum ption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under CSFII and are used in pesticide risk assessments for all registered

food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments ar e performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifesty le and traditional dietary patterns among specific subgroups.

I X. ENVIRONMENTAL FATE AND EFFECTS

Hydrolysis

– Abiotic degradation in water, sediment or soil is not anticipated, on the basis of the chemical structures present. The GTL petroleum d istill ates is a n Unknown or Variable Composition, Complex Reaction Products and Biological Materials (UVCB) substance composed of saturated linear or branched hydrocarbons with general formula C
n H 2n. None of the constituents contains functional groups associated with the susceptibility to undergo hydrolysis under typical environmental conditions. Quantification of abiotic degradation is therefore not necessary.

Phototransformation

– Phototransformation is not expected in water or in soil based upon the chemical

structures.

Aerobic Biodegradation

– A study of the ready biodegradation of Fischer

- Tropsch Distillates (C18

- 50 branched, cyclic and linear) has been conducted according to the OECD Guideline 301B. The test substance was introduced into the test system absorbed on silica gel at a concentration of 15.2mg C/l. The inoculum was

non

- adapted activated sludge sampled from a municipal waste water treatment plant treating predomin antly domestic sewage. The concentration of inoculum in the t e st system was 30 mg suspended solids/l. The study determined, as far as possible, the absence of inhibition of microorganisms by the test substance. Assessment of biodegradation in both tests was made by CO 2 analysis. At the end of the 28 day test period, 30.5 % degradation was reported (MRID 488429

- 15).

An acute toxicity study was conducted using Daphnia magna . Twenty daphnids (4 replicates of 5 animals) were exposed to a Water Accommodate d Fraction (WAF) of the test material at a single nominal loading rate of 100 mg/L for 48 hr at 21°C under static conditions. Total Organic Carbon analysis of the test preparations at 0 and 48 hours showed no significant differences in the amount of carbo n present with the 100 mg/L load ratePage 14 of 17 WAF vessels compared to the control vessels. Since the levels of carbon in the control and test vessels were below the limit of quantitation it was concluded that there was insuffic i ent evidence of stability of the te st preparations. Under the condition of the test the 48 hr no observed effect loading rate was 100 mg/L (loading rate WAFG).

The acute toxicity of GTL petroleum distillates was studied on the zebra fish, Brachydanio rerio . The test used

the OECD Test M ethod 203. Ten fish were exposed to a Water Accommodated Fraction of the test material, at a single nominal loading rate of 1000 mg/L for 96 hours under semi

- static renewal conditions. Exposure is stated in terms of the original concentration of test mat erial in water at the start of the mixing period (loading rate) irrespective of the actual concentration of test material in the WA. The fish were observed daily and

abnormalities or deaths wer e recorded at 3, 6, 24, 48, 72 and 96 hours after exposure. S amples were taken from the control and test vessels at the first and third 24 hour period and concentrations of Total Organic Carbon were determined. The measured amount of TOC was determined to be 0.09 mg/L and the 96 hour NOEC was > 0.09 mg/L (TOC) or g reater than 1000 mg/L WAF.

A study was conducted of the toxicity of GTL petroleum distillates to the sediment

- dwelling larvae of Chironomus riparius. Eighty fly larvae (four replicates of 20 larvae/concentration) were exposed to formulated sediment spike d with test item ov er a range of concentrations of 100, 180, 320, 560 and 1000 mg/ kg for 28 days.

The numbers of emerged adult midges were recorded daily. A further 40 larvae (two replicates of 20 larvae) of each test group were prepared and sacrificed o n Day 10 of the exposure period to determine the 10

- Day larval survival and growth data. The 28

- day EC SO (reduction in emergence) based on nominal test concentrations was greater than 1000 mg/kg. The NOEC was 560 mg/kg. The EC 50 (development rate) based on nominal test concentrations was greater than 1000 mg/kg.

A study was performed to assess the effect of GTL petroleum distillates on the reproduction of Daphnia magna

over a 21

- day period using the OECD Test Method 211. In this study Daphnia were expo sed (10 replicates of a single daphnid per group) to WAFs of the test item over a range of nominal loading rates of 10, 32, and 100 mg/L for 21 days. The number of live and dead adult daphnids and young daphnids (live or dead) were determined daily. The “lowest observed effect loading rate” was considered to be greater than 100 mg/L: loading rate WAG on the basis that at this loading rate no significant mortalities (immobilization) were observed in the parental generation (P 1 ) and that there were no signi ficant differences between the control and the 100 mg/L loading rate WAF test group in terms of numbers of live young produced per adult by day 21. The no observed effect loading rate was considered to be 100 mg/L loading rate WAF on the basis that at thi s loading rate no significant mortalities were observed in the parental generation and that there were no significant difference between the control and the 100 mg/L loading rate WAF test group in terms of numbers of live young produced per adult by day 21

.

The GTL petroleum distillates were tested for effects on terrestrial plant seedling emergence and seedling growth test. Five species of plants were evaluated. The test method followed the DECO Guideline for the Testing of Chemicals No. 208: Terrestrial (Non

- target) Plant Test: Seedling Emergence and Seedling Growth Test. Three species of dicotyledons were tested: soybean ( Glycine max ), tomato ( Lycopersicon esculentum ) and mustard ( Sinapis alba ). Two monocotyledonous species were tested: oa t ( Avena sativa ) and perennial ryegrass ( Lolium perenne ) were exposed to concentrations of 0, 100, 180, 320, 560, and 1000 mg/kg GTL petroleum distillates test substance. The number of seedling emerged and any mo r talities and or morphological

abnormalitie s were determined daily for 21 or 22 days after 50% emergence in the control for each species. The

EC 50 (emergence and EC 50 (growth based on final dry weight) for the test item based on nominal test concentrations were > 1000 mg/kg and >1000 mg/kg, respe ctively, for each of the five species tested.Page 15 of 17 X

. CONCLUSION

Based upon the discussion presented in the summary of toxicological effects and the discussion presented under toxicological endpoint, and based upon the discussion of environmental fate and effects, the Agency concludes

that GTL petroleum distillates ((Fishcher

- Tropsch), heavy, C 18

- C 50, branched, cyclic and linear) (CASRN

848301

- 69

- 9) are approved for use as inert ingredient s in pesticide products without limitation when used as a solvent, diluent and/or dust suppressant in pesticide formulations.

.Page 16 of 17 REFERENCES

MRID 48842 9

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:M.Dow /L.Austin ( CITAB )

RDI: P. Shah, K .Leifer, L. Austin , D. Lieu, W. .Cutchin

M.I.Dow:S7 958 :PY1:(703)305

- 5533: CITAB :7505P