Gas oils (petroleum), straight-run, high-boiling

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

This endpoint is not a REACH requirement.

Additional information

No guideline or near-guideline studies were located that have examined the potential impact of straight-run 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. Nevertheless, a testing proposal for a 2 generation study with a respresenative sample for the category is included.

Table 1. Summaries of data on reproductive organs from subchronic studies with SRGO.
Test Material	Route, Species, Doses, Exposure Regimen	Endpoints	Results	Reference
Straight run middle distillate (API 83-11)	Dermal. Rabbit. 0, 200, 1000, 2000 mg/kg, applied to skin, covered with gauze pad, and wrapped for 6 hr, 3 d/wk for 4 wk.	Weights of ovaries and testes. Histopathology of ovaries and testes at 2000 mg/kg.	No treatment-related effect on reproductive organs noted.	API, 1985
Intermediate gas oil (F-130)	Dermal. Rat. 0, 0.01, 0.10, 0.50 ml/kg, applied to skin, covered with gauze pad and wrapped for 6 hr, 5d/wk for 4 wk.	Weights of ovaries and testes. Histopathology of ovaries and testes at 0.50 ml/kg.	No treatment-related effect on reproductive organs noted.	ARCO, 1992
Heavy atmospheric gas oil	Dermal. Rat. 0, 30, 125, 500 mg/kg applied uncovered, 5 d/wk for 13 wk	Weights of ovaries, uterus, epididymides, prostate, and testes. Histopathology of ovary, testis, and epididymis at 500 mg/kg. Weight of cauda epididymis, number of sperm per gram of cauda epididymis, number of sperm per cauda epididymis, percent of normal sperm from the cauda epididymis, number of spermatids per gram of testis, and number of sperm per testis at 500 mg/kg.	No treatment-related effect on reproductive organs except for lower absolute weight of prostate at 500 mg/kg (78% of control). It appeared related to reduced body weight. Also, isolated, infrequent changes occurred histologically, but other organs were affected more severely.	Mobil, 1992

Short description of key information:
A two-generation reproduction toxicity test (OECD 416) is proposed. A supporting screening study (non-guideline) was identified in which rats were dermally administered VDF gas oil. Females began treatment one week prior to mating and treatment continued until gestation day 20. Based on these results, the authors of the study determined a NOAEL of 1 mg/kg body weight/day (i.e., the low dose) for effects of VDF gas oil on female fertility and maternal toxicity.

Effects on developmental toxicity

Description of key information

A key dermal developmental study (OECD 414) was identified.  The study authors reported a NOAEL of 30 mg/kg body weight/day for both maternal toxicity (decreased body weight, haematological changes) and foetal toxicity (increased resorption, incomplete skeletal ossification, decreased foetal weights, decreased litter size) following repeated dermal application of heavy atmospheric gas oil on GD 0-19. There were no adverse effects on postnatal development (LD 0-4).

Effect on developmental toxicity: via dermal route

Dose descriptor:

NOAEL

30 mg/kg bw/day

Additional information

In a key developmental study, the developmental NOAEL was 30 mg/kg bw/day based on increased resorption, incomplete skeletal ossification, decreased foetal weights and decreased litter size following repeated dermal application of heavy atmospheric gas oil on GD 0-19.

 

The developmental toxicity of heavy atmospheric gas oil (straight run, high boiling distillate) was investigated by Mobil (1991) using two sets of pregnant Sprague Dawley rats. Animals from the first experimental series (termed the prenatal group) were treated with the test material at doses of 0 (sham control), 8, 30, 125, or 500 mg/kg body weight/day on gestation days (GD) 0-19, and sacrificed on GD 20. The second experimental series (termed the postnatal group) received 0 or 125 mg/kg body weight/day on GD 0-19, were allowed to deliver their pups normally, and both dams and pups were sacrificed on lactation day (LD) 4. In all instances the test material was applied to clipped dorsal skin (area unspecified) commencing when the dams were 11 weeks old (GD 0). There were 12 animals per treatment level, and the dams wore cardboard ("Elizabethan") collars to minimise ingestion of test material. Toxicological evaluations performed during the study included clinical observations, measurement of organ and bodyweights, examination of reproductive organs, examination of uterine contents, serum chemical/haematological analyses and foetal evaluations (macroscopic, soft tissue, skeletal).

 

Daily application of heavy atmospheric gas oil produced dermal irritation (erythema, thickening of skin, oedema, flaking, scabbing) at the site of application in some animals (infrequent at the lowest dose), but no irritation scores were provided in the report, and hence the impact of these reactions on pregnancy outcome cannot be judged directly. Red vaginal discharge was observed in 7 pregnant females from the 500 mg/kg body weight/day dose prenatal group, and in 1 female given 125 mg/kg body weight/day from both the prenatal and postnatal groups. This finding was considered by the study authors to be test material-related and indicative of some degree of litter resorption.

 

Maternal body weights were decreased significantly by approximately 6% or 26% in dams from the prenatal groups treated with 125 or 500 mg/kg body weight/day, respectively, on gestation days 13 and 20. Females from the postnatal group receiving 125 mg/kg body weight/day also gained significantly less weight during the first half of the gestation period (26 to 75% reduction in body weight change relative to the controls). Mean relative thymus weight was significantly decreased (by approximately 53% compared to controls), and mean relative liver weight significantly increased (by approximately 17% compared to controls), in prenatal females from the 500 mg/kg body weight/day group. Serum chemistry parameters were altered in high dose animals from the prenatal series, and a linear relationship was observed between dose and serum level for triglycerides, total protein, albumin, calcium, urea nitrogen, and alkaline phosphatase (data tables unavailable for review). The study authors reported that dose-response curves for these parameters fell outside the normal range in comparison to historical data but no further details were provided. There was also a reduction of segmented neutrophils and platelets in animals treated with 125 and 500 mg/kg/bw/day heavy atmospheric gas oil, respectively (data tables unavailable for review).

 

Pre-implantation loss in both the 125 and 500 mg/kg body weight/day dose groups was more than twice that of the control group (16.1% and 17.6%, respectively, compared to 7.1% in controls) but did not achieve statistical significance. In contrast, a statistically significant increase in mean number/percent of resorptions (108/65.6%) with a corresponding decrease in mean litter size (3.6) was observed at the 500 mg/kg body weight/day dose level when compared to control animals (8/5.0% and 14.9, respectively). All foetuses from the 500 mg/kg body weight/day as well as the male foetuses from the 125 mg/kg bw/day groups (mean body weights 3.0 and 3.6 g, respectively) weighed significantly less than control foetuses (3.8 and 3.9 g, respectively).

 

Skeletal examination revealed incomplete ossification of a number of structures (nasal bones, thoracic centra, caudal centra, sternebrae, metatarsals, and pubis) in foetuses from the 125 mg/kg body weight/day (83% incidence) and 500 mg/kg body weight/day (100% incidence) groups, which were stated to be significantly increased relative to the controls (66% incidence). The incidence of all of these structural findings was significantly raised in the 500 mg/kg/day group while the occurrence of incompletely ossified nasal bones and thoracic centra was increased in the 125 mg/kg/day group. No visceral anomalies or adverse effects on pup development or survival were reported, however pup body weight and body weight gain were significantly lower in the 125 mg/kg body weight/day group from the postnatal phase of the study (5.8 g on LD 0; 8.7 g on LD 4) relative to the controls (6.2 g on LD 0; 9.7 g on LD 4).

 

The study authors reported a NOAEL of 30 mg/kg body weight/day for maternal toxicity (decreased body weight, haematological changes) and foetal toxicity (increased resorption, incomplete skeletal ossification, decreased foetal weights, decreased litter size) following repeated dermal application of heavy atmospheric gas oil on GD 0-19. There were no adverse effects on postnatal development (LD 0-4).

 

In a supporting developmental toxicity study, gas oil intermediate was dermally administered to 12 to 15 Sprague-Dawley rats/dose at dose levels of 0, 50, 150, or 500 mg/kg bw/day from days 0 through 20 of gestation (ARCO 1994b). There was a significant reduction in maternal body weight and body weight gain in the high-dose group. Dermal irritation occurred in all dose groups. There were no treatment-related effects in survival, clinical signs, or caesarean parameters. The maternal LOAEL was 50 mg/kg/day, based on dermal irritation. The maternal NOAEL was > 50 mg/kg/day. Pup body weight was significantly reduced at lactation days 0 and 4 in the mid- and high-dose group. In the high-dose group, there was a decrease in pup survival on lactation day 4. There were no treatment-related effects noted in external abnormalities. The developmental LOAEL was 150 mg/kg/day, based on reduced pup weight. The developmental NOAEL was 50 mg/kg/day.

 

In additional supporting developmental toxicity studies, straight-run petroleum gas oil (F-193 and F-215) in acetone was dermally administered to 25 presumed pregnant rats/dose at dose levels of 0, 50, 250, or 500 mg/kg bw/day from days 0 through 19 of gestation (ARCO, 1993a; ARCO, 1993b). For F-193, Skin reactions (erythmea, oedema, atonia, and desquamation) occurred in all treatment groups. There was a significant reduction in body weight and feed consumption in the 250 - and 500 -mg/kg/day groups. There was also a significant reduction in average litter size and live foetuses, increased resorptions in these groups. The maternal LOAEL was 50 mg/kg/day, based on dermal effects. There was no maternal NOAEL. There was a significant decrease in pup body weight and increase in external, visceral, and skeletal malformations in the mid- and high-dose groups. The developmental LOAEL was 250 mg/kg/day, based on pup body weight and malformations. The developmental NOAEL was 50 mg/kg/day. For F-215, skin reactions occurred in the mid- and high-dose groups with vocalization occurring in eight of the high-dose animals. There was a significant reduction in body weight and body weight gain in the 250 - and 500 -mg/kg/day groups, but food consumption was only affected in the high-dose group. There were no biologically significant changes in any reproduction or developmental parameters. The maternal LOAEL was 250 mg/kg/day, based on dermal effects and body weight/body weight gain. The maternal NOAEL was 50 mg/kg/day. There was no developmental LOAEL, based on the lack of effects at the high dose. The developmental NOAEL was greater than or equal to 500 mg/kg/day.

 

Additional data support that straight run gas oils are not developmental toxicants (UBTL, 1994). This information is presented in the dossier.

Toxicity to reproduction: other studies

Additional information

This endpoint is not a REACH requirement.

Justification for classification or non-classification

No two -generation reproductive toxicity data are available for straight run gas oils. Therefore, there is insufficient data to classify straight run gas oils as toxic for reproduction under the EU CLP Regulation (EC No. 1272/2008). A testing proposal for a two-generation reproductive study has been submitted.

A key developmental study on heavy atmospheric gas oil was identified. The NOEL for both maternal and foetal toxicity was 30mg/kg. No classification for effects on development is proposed however since it is not possible to separate out the ‘indirect’ effects of maternal toxicity from any direct effects on the foetus.