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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No guideline or near-guideline studies were located that have examined the potential impact of gas oils on reproductive function. Some indication of the likely effect of a test substance on reproductive organs can be gained from the results of repeated-dose toxicity studies with members of this category, as summarized in Table 1.

  

Table 1. Summaries of data on reproductive organs from subchronic studies with VHGOs. (Robust study summaries are provided in Section 7.5 Repeated Dose Toxicity)

Test Material

Route, Species, Doses, Exposure Regimen

Endpoints

Results

Reference

Diesel fuel

Inhalation. Rat.

350, 880, 1710 mg/m3

4 hr/day, twice/wk, 13 wk

Weight and histopathology of testes

No treatment-related effect noted

Lock et al, 1984

Cherry point diesel fuel No. 2

CAS 68476-34-6

Dermal. Rat.

0.5, 2.0, 5.0 ml/kg

5 d/wk, 4 wk

Weight and histopathology of testes and ovaries

No treatment-related effect noted

ARCO, 1986a

Naval distillate Watson

CAS 68334-30-5

Dermal. Rat.

0.25, 2.0, 5.0 ml/kg

5 d/wk, 4 wk

Weight and histopathology of testes and ovaries

No effect noted. Testicular degeneration in 2/10 males considered spontaneous.

ARCO, 1986b

Watson diesel fuel #2

68476-34-6

Dermal. Rat.

0.5, 2.0, 5.0 ml/kg

5 d/wk, 4 wk

Weight and histopathology of testes and ovaries

No treatment-related effect noted

ARCO, 1986c

Diesel fuel

CAS 68476-34-6

Dermal. Rat.

0.5, 1.0, 2.5, 5.0, 10.0 ml/kg

5 d/wk, 4 wk

Weight and histopathology of testes and ovaries

No treatment-related effect noted

ARCO, 1988

Vacuum tower overheads

CAS 64741-49-7

Dermal. Rat.

30, 125, 500 mg/kg,

5 d/wk, 13 wk

Weight of epididymides, ovaries, prostate, testes, uterus. Histopathology of ovaries and testes. Number of epididymal sperm, sperm/g cauda epididymis, number of abnormal and normal sperm, number of testicular spermatids, and sperm/g testis

No treatment-related effect noted

Mobil, 1989

Naval distillate

CAS 68334-30-5

Dermal. Rat.

0.0001, 0.005, 0.5 ml/kg

5 d/wk, 4 wk

Weight and histopathology of testes and ovaries

No treatment-related effect noted

ARCO, 1992a

Sweet distillate

(light hydro-cracked distillate)

CAS 64741-77-1

Dermal. Rat.

0.05, 0.25, 1.0 ml/kg

5 d/wk, 4 wk

Weight and histopathology of testes and ovaries

No treatment-related effect noted

ARCO, 1992b

Light vacuum gas oil

CAS 64741-58-8

Dermal. Rat.

0.05, 0.25, 1.0 ml/kg

5 d/wk, 4 wk

Weight and histopathology of testes and ovaries

No treatment-related effect noted

ARCO 1993a

Naval distillate

CAS 68334-30-5

Dermal. Rat.

0.50 ml/kg

5 d/wk, 4 wk

Weight of testes and ovaries. No histopathology was done.

No treatment-related effect noted

ARCO, 1994a

Diesel fuel

(F-237)

68334-30-5

Dermal. Rat.

0.01, 0.10, 1.00 ml/kg,

5 d/wk, 13 wk

Weight of testes and ovaries. Histopathology of testis, ovary, prostate, uterus

No treatment-related effect noted

ARCO, 1994b

Based on the test results from these 11 studies, it is considered unlikely that exposure to substances in this category will affect reproductive performance. However, an extended one-generation reproductive toxicity test (OECD 443) is proposed to fulfil the data requirement on a representative sample of all category members. See attached testing proposal for more detailed information.

Short description of key information:

No guideline or near guideline studies were located on Vacuum Gas Oils, Hydrocracked Gas Oils & Distillate Fuels on reproductive function.

Gonadal histopathology and/or sperm parameters (counts; morphology) were among endpoints included in subchronic dermal evaluations of vacuum tower overheads and aerosol inhalation exposure to diesel fuel. Based on these data an inhalation reproductive toxicity NOAEL of 1710 mg/m3 (for aerosolised diesel fuel) and a dermal reproductive toxicity NOAEL of 500 mg/kg body weight/day (from studies performed using vacuum tower overheads) were determined.

 

Although an extended one-generation reproduction toxicity test (OECD 443) is proposed to fulfil the data requirement, the need for this study for this category is questionable based on the fact that there were no effects observed on development in repeated dose toxicity tests and prenatal developmental tests, and, as mentioned above and outlined below, no effects were observed on reproductive function (reproductive organs and sperm parameters) in repeated dose toxicity tests. An assessment of the overall weight of evidence concludes that it is unlikely that exposure to VHGOs will affect reproductive performance. More detail is given in the attached testing proposal.

Effects on developmental toxicity

Description of key information

Results of two inhalation developmental studies indicate a NOAEC >2,110 mg/m3. Maternal and foetal NOAELs of 125 mg/kg body weight/day were established from dermal prenatal developmental toxicity studies (equivalent or similar to OECD 414). There are no acceptable developmental studies following oral exposure.

 

Additional testing on four substances in this category is now proposed; dermal tests to be conducted in two species (rat and rabbit).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2 110 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
One of two inhalation studies investigating the developmental toxicity of VHGO category members
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
One of four dermal studies investigating the developmental toxicity potential of VHGO category members.
Additional information

Results are available from studies involving inhalation exposure of pregnant rats to either diesel oil or No.2 Home Heating Oil (a mixture of straight run gas oil and cracked gas oil) vapour. No treatment related effects on maternal health or foetal development were observed in either study, giving a NOAEC >2,110 mg/m3. The studies were well conducted and reported but the exposure period (GD 6-15) was less intensive than that recommended by current guidelines (GD 5-20) and only covered the period of organogenesis in the rat. The results do however indicate that inhalation exposure to gas oil vapour is unlikely to adversely impact foetal development.

 

In the first inhalation teratology study (API 1979a), diesel fuel was administered via whole body exposure of pregnant female (CRL: COBS CD (SD) BR) rats to graded measured airborne (vapour) of 0, 101.8, or 401.5 ppm (equivalent to 0, 530, and 2110 mg/m3, respectively) on days 6 through to 15 of gestation. The pregnant female rats were approximately 11 weeks of age at the time of the first dose and were assigned sequentially to treatment groups of 20 animals each. There were no deaths during the course of the study and all females were normal in appearance. Mean body weights indicated no significant differences between control and treated pregnant rats, although the food consumption of the high-dose group was significantly lower (p < 0.05) than the controls during treatment. Diesel fuel did not appear to have any effect on the uterus and examination of the offspring revealed no visible abnormalities except for the occurrence of subcutaneous haematomas in 1/188, 4/227 and 4/188 in the control, low-dose, and high-dose groups, respectively. All litters appeared normal and the sex ratio did not differ significantly between treated and control groups. The conclusion of the authors was that exposure of rats to diesel fuel (vapour) did not result in compound-induced terata, variation in sex ratio, embryo toxicity or inhibition of foetal growth and development. Therefore the NOAEC is >2,110 mg/m3 (401.5 ppm), the highest concentration tested.

 

In the second study, the effect of inhalation of No.2 Home Heating Oil, a mixture of straight run gas oil and cracked gas oil, ( API 1979b) vapour on foetal development was tested in three groups of pregnant female CRL; COBS CD (SD) BR rats. The 11 week old females were randomly assigned into groups of 20 animals each and treated (whole body) with measured concentrations of 0 (control group), 86.9 or 408.8 ppm (equivalent to 460 or 2,150 mg/m3) test substance from days 6 to 15 of gestation for 6 hours each day. There were no treatment related deaths or changes in appearance of dams throughout the duration of the study. One female delivered before the computed gestation day 20 and her pups were examined but not included in statistical analysis. There were no statistically significant changes in uterine contents. Subcutaneous haematomas were observed in all groups – 7, 4 and 3 in control, low-dose and high-dose groups respectively. There were no statistically significant or treatment related adverse effects on reproductive or developmental toxicity in this study leading to a NOAEC of > 2,150 mg/m3, the highest dose tested.

 

A recent study to OECD 414 (dermal) and GLP was conducted on a member of the VHGO category. This showed low systemic and developmental toxicity (NOAEL 600 mg/kg/day), with higher doses not possible due to excessive local irritation. This study was conducted on a substance in the category low in PAH content (the constituent expected to drive toxicological hazard).

 

There is one study in which the developmental toxicity of a vacuum gas oil has been investigated in pregnant rats following dermal exposure (Mobil 1989b). Substance-related effects in the dams commonly included varying degrees of skin irritation at the test site, with decreased body weight (including decreased net weight gain), increased resorption, decreased thymus weight and occasional alterations in haematological- and serum chemistry parameters. Findings in the foetuses (or pups in studies where dams were permitted to litter) included decreased body weight, decreased crown-rump length, decreased litter size and delayed ossification of some skeletal structures. It appears that decreases in maternal and foetal (or pup) body weight together with reductions in litter size and delayed skeletal development were sensitive indicators of developmental effects in these studies. However, the occurrence of skin irritation is a possible confounder in the interpretation of these findings since it is not known if chemical toxicity or maternal stress (due to repeated moderate-severe skin damage) was responsible for the effects observed in the dams and foetuses. Destruction of the barrier function of the skin may also affect absorption of the test sample across the skin, giving unrepresentative systemic exposures. Maternal and foetal NOAELs of 125 mg/kg body weight/day, obtained from a non-guideline study in which pregnant rats received daily dermal applications of vacuum gas oil on GD 0-19, will be used for the purposes of risk characterisation.

 

In a supporting developmental toxicity screening study, straight run diesel in acetone was dermally administered to 14 or 15 presumed pregnant rats/dose at dose levels of 0, 125, or 250 mg/kg bw/day from days 0 through 20 of gestation. Another group of 15 rats received 1000 mg/kg/day from days 0 to 5 of gestation ( ARCO 1994c). Dermal irritation occurred in all treatment groups. Body weight, body weight gain, and food consumption was reduced in the 250- and 1000 -mg/kg/day groups. The maternal LOAEL is 125 mg/kg/day, based on dermal irritation.  There is no maternal NOAEL. Pup weight was decreased on lactational days 0 and 4 in the 250 -mg/kg/day group. There were no developmental effects observed in the 1000 -mg/kg/day for 6 days. The developmental LOAEL is 250 mg/kg/day, based on reduced pup weight. The developmental NOAEL is 125 mg/kg/day.  

 

In an additional supporting developmental toxicity screening study, VDF diesel in acetone was dermally administered to 14 or 19 presumed pregnant rats/dose at dose levels of 0, 125, or 250 mg/kg bw/day from days 0 through 20 of gestation. Another group of 14 received 1000 mg/kg/day from days 0 to 5 of gestation (ARCO 1994d). Dermal irritation occurred in all treatment groups. Body weight, body weight gain, and food consumption was reduced in the 250- and 1000 -mg/kg/day groups. The maternal LOAEL is 125 mg/kg/day, based on dermal irritation. There is no maternal NOAEL. Pup weight was decreased on lactational day 0 in all dose groups and on lactational day 4 in the 250 -and 1000 -mg/kg/day groups. The developmental LOAEL is 125 mg/kg/day, based on reduced pup weight. There is no developmental NOAEL.

 

These studies were both classified as reliable with restriction, because the high-doses had to be discontinued due to maternal discomfort and were not available to determine developmental toxicity. The studies were well conducted and were GLP compliant.

 

In a developmental embryo-fetal toxicity and teratogenic potential study, straight run diesel in acetone was dermally administered to 25 presumed pregnant rats/dose at dose levels of 0, 50, 150, or 300 mg/kg bw/day from days 0 through 19 of gestation (ARCO 1993k). Skin reactions (erythema, oedema, atonia, and desquamation) occurred in all treatment groups. In the mid- and high-dose group, vocalization occurred in 5 or 6 of the animals. There was a slight decrease in body weight gain in the 50 mg/kg/day group with significant reductions occurring in the 150- and 300-mg/kg/day groups. Feed consumption was only reduced in the high-dose group. There were no treatment-related effects on reproduction or development (number of corpora lutea, implantations, litter size, live fetuses, resorptions, fetal body weight, or sex ratio). There were no gross external, skeletal, or visceral abnormalities observed. The maternal LOAEL is 50 mg/kg/day, based on dermal effects and reduced body weight gain. There is no maternal NOAEL. The developmental NOAEL is>300 mg/kg/day, based on no effects at the highest dose tested.

Justification for classification or non-classification

The information available currently on reproduction toxicity parameters is insufficient to determine the impact on human fertility. No classification is appropriate at this time but a testing proposal is included for an extended one generation fertility study to meet data requirements for this endpoint. 

Developmental studies only observed developmental effects at doses that caused maternal toxicity and the developmental effects cannot be separated from the maternal effects; therefore classification for developmental toxicity is not considered appropriate. Additional testing on four substances in this category is now proposed; dermal tests to be conducted in two species (rat and rabbit).