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 recovery group following an additional twentyeight 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 offspring 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 

study 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 alleviated 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 in 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 toxicity 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 with 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 C30-C35 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 lengths of C32-C35, they are not absorbed to any significant extent. Since the FischerTropsche derived hydrocarbons have chain lengths in the range of C40-C70 (similar to the petroleum derived 

materials) they are unlikely to be absorbed. Consequently, when administered orally, Fischer-Tropsche derived 

hydrocarbons in the range of C40-C70 are likely to be excreted, unabsorbed, in the feces. It should be noted that 

the Applicant described CASRN 848301-69-9 as being C18-C50.

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

lack of genotoxicity 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 distillates 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 have 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 an Unknown or Variable Composition, Complex Reaction Products and Biological Materials

(UVCB) substance composed of saturated linear or branched hydrocarbons with general formula CnH2n. None 

of the constituents contains functional groups associated with the susceptibility to undergo hydrolysis under 

typical environmental 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 solvent 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. INTRODUCTION

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 inert ingredient in pesticide 

products. Specifically, the substance is a product of petroleum distillation using the Fishcher-Tropsch process. 

The substance is described as GTL petroleum distillates (Fishcher-Tropsch), heavy, C18-C50, branched, cyclic 

and linear. The CASRN is 848301-69-9. GTL petroleum distillate products differ from conventionally 

derived sources in that GTL petroleum distillates 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 hydrogenation 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 hydrocarbons having carbon 

numbers in the range of C18-C50. 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 existing 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 petroleum 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 Structures.

Table 1. Physical/Chemical Properties

Property GTL Petroleum Distillate

Physical Form Liquid

Physical Appearance Clear colorless slightly viscous

liquid

Molecular Weight 114 -226 g/mol

Boiling Range 198- 361°C(Ref 1)

300- 570°C (see comment below)*

Relative Density 0.809 at 20°C

Water Solubility < 1.0 mg/L at 20'C

Partition Coefficient Log Pow > 6.5

Adsorption Coefficient Log Koc >5.63

Flash Point 187 ± 2'C
Page 5 of 17

Vapor Pressure 0.0028 Pa at 25'C

Auto ignition 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 by 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 Days 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 

macroscopic 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 (LD50) of the test material 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 an acute dermal toxicity test, 2,000 mg/kg bw of 

test material [distillate] would 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 without 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 the 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 Zealand White rabbits using a 4-hour, 

semi-occluded application test 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. 

Immediately 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 first 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 from 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 considered 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 concentrations 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 material 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 approximately 

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 for 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 the 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 nonnecrotizing 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 preliminary 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 chosen for the MNIC (maximal 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 sighting 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 topical challenge 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 nonsensitizer to guinea pig skin (MRID 488429-06).

B. Repeat Dose Toxicity 

Ninety-day Oral Toxicity

GTL petroleum distillates 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 ninety 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 recovery 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 day 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 alveolar 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/day. 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 488429-07).

Two-generation Reproductive Toxicity Study
Page 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 anogenital distance 

(AGD) in F1 females born from dams given 250 and 1000 mg/kg/day. Test item-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 

(renal tubule hyaline droplets likely representing α2μ-globulin) of the F1 males only. The renal effects are well 

known male rat specific effects 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) group 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 established. (MRID 48842908).

The Agency noted similar test-substance related effects described in the 90-day oral toxicity (gavage) study and 

in the two-generation reproduction 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 adverse 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 toxicity 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 HanTM:RccHanTM: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 3rd 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 measured 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 histopathologic changes 
Page 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 the 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) (RccHanTM:WIST(SPF) strain) were 

exposed daily by oral gavage to 0, 50, 200 and 1000 mg/kg/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 food consumption. 

Mean absolute body weight and body weight gain were not affected by treatment with the test material. Postimplantation 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 fetal 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 considered 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 Escherichia coli WP2 uvrA. 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 4994209).

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 mammalian cells was negative with and without activation in human 

lymphocytes (OECD draft Guideline 487) (MRID488429-10). 

In Vitro Micronucleus
Page 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 

activation) 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 normal 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 (MRID488429-10).

Carcinogenicity

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

lack of genotoxicity 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 did 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-day 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 

vacuolation of alveolar macrophages in the lung were 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 to carbon chain length and is independent of 

isomeric form, preparation process or type of product. Materials with carbon chain lengths of C30-C35 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 lengths of C30-C35, they are not absorbed to 

any significant extent. Since the Fischer-Tropsche derived hydrocarbons have chain lengths in the range of

C40-C70 (similar to the petroleum derived materials) they are unlikely to be absorbed. Consequently, when 

administered orally, Fischer-Tropsche derived hydrocarbons in the range of C40-C70 are likely to be excreted, 

unabsorbed, in the feces. 

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

similar to GTL petroleum distillates. 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 includes FQPA evaluations for five aliphatic hydrocarbon fluids in the 

C8-C20 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. In 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 material (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 mesenteric 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 was no systemic 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 unless 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 studies 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 studies

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 

adverse 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, startle reflex, grip strength and motor activity were evaluated in the 90-day 
Page 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 document to refer to nonoccupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and 

flea and tick control on pets). GTL petroleum distillates 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 EXPOSURE/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.

VIII. 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 Address 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 consumption, 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 are 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 lifestyle and traditional dietary patterns among specific subgroups. 

IX. 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 distillates is an Unknown or Variable Composition, Complex 

Reaction Products and Biological Materials (UVCB) substance composed of saturated linear or branched 

hydrocarbons with general formula CnH2n. 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 predominantly 

domestic sewage. The concentration of inoculum in the test 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 CO2 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 Accommodated 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 carbon present with the 100 mg/L load rate 
Page 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 insufficient evidence of stability of the test 

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 Method 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 material 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 were recorded at 3, 6, 24, 48, 72 and 96 hours after exposure. Samples 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 greater 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 spiked with test item over 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 on Day 10 of the exposure period to determine the 10-Day larval 

survival and growth data. The 28-day ECSO (reduction in emergence) based on nominal test concentrations was 

greater than 1000 mg/kg. The NOEC was 560 mg/kg. The EC50 (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 exposed (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 (P1) and that there were no significant 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 this 

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: oat (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 mortalities and or morphological 

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

EC50 (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, respectively, 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, C18-C50, branched, cyclic and linear) (CASRN 

848301-69-9) are approved for use as inert ingredients in pesticide products without limitation when used as a 

solvent, diluent and/or dust suppressant in pesticide formulations. 

. 
Page 16 of 17

REFERENCES

MRID 488429-01: White, D.F and Mullee, D.M. (2006) Distilates (Fischer- Tropsch), heavy,

C18-50 branched, cyclic and linear: Determination of General Physico-Chemical Properties. 

Safepharm Laboratories Limited Project No. 20411007, 2006.

MRID 488429-02: Tremain, S.P. (2006) Distillates (Fischer-Tropsch), heavy,Cl8-

50 branched, cyclic and linear: Determination of Hazardous Physico-Chemical

Properties. Safepharm Laboratories Limited Project No. 20411008, 2006.

MRID 488429-03: Sanders, A. (2006) Distillate (Fischer-Tropsch), heavy C18-50 branched, cyclic

and linear: Acute oral toxicity in the rat-fixed dose method. Safepharm Laboratories Limited

Project No. 2041/0048, 2007.

 

 MRID 488429-04: Sanders, A. (2008) Distillate (Fischer-Tropsch), heavy C18-50 branched, cyclic

and linear: Acute dermal irritation in the rabbit. Safepharm Laboratories Limited Project No.

2041/0058, 2008

 MRID 488429-05: Sanders,A. (2008) Distillate (Fischer-Tropsch), heavy C18-50 branched,

cyclic and linear: Acute eye irritation in the rabbit. Safepharm Laboratories Limited-Project No.

2041/0059, 2008

 MRID 488429-06: Richeux, F. (2008) Distillate (Fischer-Tropsch), heavy,C18-50- branched, cyclic

and linear:- Skin sensitisation in the guinea pig -Magnusson and Kligman maximisation method.

Undertaken under Study No. SMK-PH-07/0420 by Phycher Bio Developpement, France for Safepharm

Laboratories Limited Project No.

2041/0060

 MRID 488429-07: Dunster JS, 2009: Distillate (Fischer-Tropsch), heavy, C18-50- branched, cyclic

and linear aliphatic - Ninety day repeated dose oral (gavage) toxicity study in the rat (with recovery

period). Harlan, Switzerland. Project Number

2041/0061

 MRID 488429-08: RTI (2010) Two-generation Reproductive Toxicity Evaluation of Shell GTL

Base Oil Administered Via OralGavage to CD® (Sprague-Dawley) Rats. RTI Project No.: 

0212131.000.001

MRID 488429-09: Bowles, A. (2006) Distillate (Fischer-Tropsch), heavy C18-50 branched,

cyclic and linear: Salmonella typhimurium and Escherichia coli/mammalian-microsome reverse

mutation assay. Safepharm Laboratories Limited Project No. 2041/0021, 2006.

MRID 488429-10. Durward, R. (2006). Distillate (Fischer-Tropsch), heavy C18-50 branched, 

cyclic and linear: Micronucleus test in human lymphocytes in vitro: draft OECD method 487. 

Safepharm Laboratories Limited Project No. 2041/0037, 2006.

MRID 488429-15. Han, X. (2009). Biodegradation Test of Distillates (Fischer-Tropsche), heavy, 

C18-50 – branched, cyclic and linear (301B) Protocol Number GP080021, Study Number: 

G0840A0099, Report Number R0840A0099, Supervision and Test Center for Pesticide Safety 
Page 17 of 17

MRID 494505-02. GTL Base Oil 3 28-Day Oral Toxicity in the Rat ()CSPP 870.3050; OECD 

407). Summitec Corporation, 9724 Kingston Pike, Suite 602 Knoxville, TN 37922, Task Order 

2014-11, unpublished study.

MRID 494505-03. GTL Base Oil Distillate Prenatal Developmental Toxicity Study – Rat, OCSPP 

870.3700a [§ 83.3a]; OECD 414. Summitec Corporation, 9724 Kingston Pike, Suite 602 

Knoxville, TN 37922, Task Order 2014-11, unpublished study.

MRID 494505-02. McRae, L. (2014). GTL Base Oil 3: Twenty-Eight Day Repeated Dose Oral 

(Dietary) Toxicity Study in the Rat. Unpublished. Harlan Laboratories Ltd., Harlan Study No. 

41302691; 11 AUG. 2014.

MRID 494505-03. Senn, C. (2014). GTL base oil distillate (Distillates (Fischer-Tropsch), heavy, 

C18-50-branched, cyclic and linear): Prenatal Developmental Toxicity Study in the Han Wistar 

Rat. Unpublished, Harlan Laboratories Ltd., Harlan Study No. D80072. 16 April 2014.

Wagner, J. M. 2012. Petition Proposing an Exemption from the Requirement of a Tolerance Under 

40 CFR § 180.910 for the Inert Ingredient Distillates (Fishcher-Tropsch), Heavy, C18-C50, 

Branched, Cyclic and Linear, CAS No. 848301-69-9 When Used in Pesticide Formulations. 

Unpublished document submitted for Pennzoil-Quaker State Company c/o Wagner Regulatory 

Associates, Inc. Hockessin, DE 

 

:M.Dow/L.Austin(CITAB)

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

M.I.Dow:S7958:PY1:(703)305-5533:CITAB:7505P