Registration Dossier

Administrative data

Description of key information

A number of subacute and subchronic studies with kerosines and jet fuels are available (OECD 410, 412, 413, and other non-guideline protocols). The repeated inhalation and oral studies of kerosine in rats produced no consistent toxicological effects other than changes in male rat kidneys that are not considered relevant to humans. The NOAEC for inhalation exposure is greater than or equal to 1000 mg/m3 (vapour).  The systemic dermal NOAEL is greater than or equal to 495 mg/kg bw/day, based on a well conducted 90-day study in rats.  The NOAEL for systemic effects of oral exposure is 750 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 000 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
six well conducted studies available on representative sampeles from the category

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 000 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
six well conducted studies available on representative sampeles from the category

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
495 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
One of 15 well conducted studies with representatives of the kerosine category, covering sub-acute and sub-chronic eposure

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
1 mg/cm²
Study duration:
subchronic
Species:
rat

Additional information

A number of subacute and subchronic studies with kerosines and jet fuels are available. The repeated inhalation and oral studies of kerosine in rats produced no consistent toxicological effects other than changes in male rat kidneys that are not considered relevant to humans. The male-rat specific nephropathy, evident at exposures from 500 mg/m3(inhalation), or 750 mg/kg/day (oral gavage) is not taken into account for risk assessment purposes. The nephropathy in inhalation studies coincided with a decreased bodyweight gain in male rats. No other signs of toxicity were observed. The NOAEC for inhalation exposure is greater than or equal to 1000 mg/m3 (vapour). The systemic dermal NOAEL is greater than or equal to 495 mg/kg bw/day). The NOAEL for systemic effects of oral exposure is 750 mg/kg/day.

 

Oral Exposure

In the key oral subchronic study (Klimisch score=1; Mattie et al., 2000), male rats were treated for 70 to 90 days with 0 (1mL of distilled water), 750, 1500, or 3000 mg/kg/day of undiluted JP-8 jet fuel, then mated to untreated females (one female at a time). Males were gavaged throughout the cohabitation period and were returned to their individual cage after successful mating. In the second part of the study, female rats were administered the test compound at doses of 0 (1mL of distilled water), 375, 750, or 1500 mg/kg/day undiluted JP-8 jet fuel for 90-day prior to mating, through mating, gestation, delivery, and lactation for a total of 21 week. During mating, they were housed with untreated males. 

There were no effects on clinical signs or mortality in either sex. Haematology, clinical chemistry, and urinalysis were measured only in females without any effects noted. Body weights in male rats were decreased in a dose-dependent manner and was likely related to nephropathy, which is specific in male rats treated with hydrocarbons, and not relevant for human exposure. In females, body weight was only significantly reduced in the high-dose group. Absolute and relative liver weights were increased in mid- and high-dose females, but were not likely biologically significant due to the lack of changes in clinical chemistry or histopathology in the liver. The test compound caused perianal dermatitis (high-dose only) and stomach hyperplasia (mid- and high-dose) in the female rats. There was a dose-related decrease in pup weight that was significant in the 750 mg/kg/day group on postnatal day 4 only and in the 1500 mg/kg/day group from postnatal day 4 through postnatal day 21 but had recovered by postnatal day 90. There were no treatment-related effects on reproduction or sperm parameters in males. There were no effects on reproduction, gestation, or litter size in females.

The study LOAEL for systemic effects is 1500 mg/kg/day and the NOAEL for systemic effects is 750 mg/kg/day, based on reduced body weight in dams and in pups. The LOAEL for adult males rats exposed to JP-8 orally was 750 mg/kg/day due to changes in clinical pathology, body weight, organ weights and the same irritation seen in female rats. The decrease in male rat bodyweight is very likely due to the male rat-specific nephropathy and is therefore not taken into account for the derivation of the oral NOAEL. The reproduction NOAEL was 3000 and 1500 mg/kg/day in males and females, respectively. 

 

Inhalation Exposure

In a key subchronic inhalation toxicity study (Klimisch score=1; Mattie et al., 1991), JP-8 jet fuel was administered to 95 male Fisher 344 rats, 75 female Fischer 344 rats, and 100 male and female C57BL/6 mice by dynamic whole body vapour exposure at concentrations of 0, 500 or 1000 mg/m3(0, 0.5, or 1.0 mg/L) as a vapour for 24 hours per day, 7 days/week for a total of 90 days. The male rats developed hydrocarbon-induced nephropathy at both treatment concentrations. Male rats had decreased body weight and decreased absolute and relative kidney weight at both treatment concentrations.  Female rats were unaffected by treatment. In mice, no significant clinical signs of toxicity were noted that differentiated the groups that were treatment-related. The NOAEC for male rats is difficult to establish, since potential adverse effects may be masked by male rat specific hydrocarbon nephropathy. However, based on the hydrocarbon-induced nephropathy and reduced body weights and increased kidney weights, the LOAEC in male rats is 500 mg/m3. The LOEC for male mice is also 500 mg/m3, but it was not treatment related. The NOAEC for female rats and mice is greater than or equal to 1000 mg/m3.  This was the highest dose tested in the study.

In a subacute inhalation toxicity study (Klimisch score = 1; API, 1986), hydrodesulfurised kerosine vapour was administered to 20 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at a concentration of 24 mg/m3(0.024 mg/L) for 6 hours per day, 5 days/week for 4 weeks. There were no compound related effects in mortality, clinical signs, body weight, haematology, clinical chemistry, organ weights, or gross and histologic pathology.  Therefore, the NOAEC is greater than or equal to 24 mg/m3. This was the highest dose tested in the study.

 

Dermal Exposure

In a key sub-chronic dermal study hydrodesulfurized kerosine was applied at concentrations of 20, 40 or 60% (v/v) at a rate of 1 ml/kg/day to the shorn intrascapular region of groups of 12 individually housed male and female, Sprague-Dawley rats (aged 7-9 weeks). This was equivalent to doses of test material of 165, 330 or 495 mg/kg/day. Dosing was continued for five days a week for 13 weeks. In addition a group of 12 male and 12 female rats of similar age were administered mineral oil at a dose rate of 1 ml/kg/day; these animals served as vehicle controls. 12 rats/sex/group each in the vehicle controls and high dose group were maintained for a 4-week recovery period. Ingestion of the test material was prevented by using a collar and removal of any residual test or control material from the skin. Animals were observed for clinical signs prior to dosing and 1, 6 and 24 hours after the first dose. Subsequently, observations were made prior to each dose being applied.

Prior to the administration of each dose, the treated skin site was evaluated for dermal irritation using the Draize scoring method. Body weights were recorded prior to the first dose and weekly thereafter. An ophthalmic examination was conducted on each rat prior to application of the first dose and again prior to sacrifice at the end of the study. During the week prior to the first dose, each rat was subjected to a functional observation battery (FOB). The FOB was conducted again 1, 6 and 24 hours after the first dose and at 7 and 14 days. During the study, the FOB, motor activity and startle response testing was conducted on all rats at weeks 4, 8 and 12. At week 14 blood samples were collected from 12 animals/sex/group. Full necropsies were performed at week 14 on 6 rats/sex/group and at week 18 on the recovery rats (vehicle and high dose groups). Each full necropsy included an examination of the external surface of the body and its contents.The remaining six rats of each group were anesthetized with an intraperitoneal injection of Pentothal and transcardially perfused in-situ using 10% neutral-buffered formalin and given a limited necropsy. For these rats, no organs were weighed and specific tissues were also collected for subsequent microscopic testing.

There was a generally dose-related increase in the incidence and severity of various skin conditions at the treated site. Males seemed to be more sensitive than females as they were affected at all doses, however, the effects indicated very little irritation. Recovery group animals revealed complete recovery in the females and minimal hyperkeratosis in the high dose group males. At necropsy no substance-related observations were made for males in any group. In the females there was a suggestion of a possible treatment-related effect which occurred in 7 rats across all groups and consisted of skin crusts or ulceration at the site of application of test material. Haematological and serum clinical parameters were unaffected by treatment. 

All animals survived until scheduled termination. There were no test substance-related effects on survival, clinical observations (apart from skin irritation), neurobehavioral signs or ophthalmological findings. The NOEL for systemic toxicity was >495 mg/kg/day. The LOEL for slight dermal irritation was 165 mg/kg/day, equivalent to ~ 1mg/cm2.

Summary

A NOAEC for inhalation exposure of greater than or equal to 1000 mg/m3(vapour) was established. Considering an average breathing rate for female rats of 0.182 m3/day and the average female rat bodyweight of 0.258 kg, the NOAEC of greater than or equal to 1000 mg/m3corresponds with a calculated NOAEL of greater than or equal to 705 mg/kg/day. This is well in agreement with the experimentally determined oral NOAEL of 750 mg/kg/day for female rats.  The repeat dose toxicity of kerosine is not classified using EU CLP Regulation (EC No. 1272/2008).

Additional data support that kerosines are not classified as harmful to health after prolonged exposure (inhalation:Carpenter et al., 1976; Shell, 1979; dermal: API, 1980a; API, 1983b; Freeman et al., 1990; CONCAWE, 1991; CONCAWE 1993; Batelle, 1997). This information is presented in the dossier.

 

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

One of 6 repeat dose inhalation studies covering sub-acute and sub-chronic exposure.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

well conducted 90-day dermal study

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

slight dermal irrition seen at all dose levels

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

Based on the lack of adverse systemic effects even with the highest doses administered, kerosines are not classified under the EU CLP Regulation (EC No. 1272/2008).