Distillates (petroleum), sweetened middle

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 studies were located that have examined the potential impact of Other 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, which did not show any treatment related effects on reproductive (Table 1). Nevertheless, a testing proposal for a 2-generation study with a representative sample for the category is included.

Table 1. Summaries of data on reproductive organs from subchronic studies with OGO (Robust study summaries are provided in IUCLID Section 7.5 Repeated Dose Toxicity)
Test Material	Route, Species, Doses, Exposure Regimen	Endpoints	Results	Reference
API 81-09 Hydrodesulfurized middle distillate CAS 64742-80-9	Inhalation. Rat. 23 mg/m^3, 6 hr/day, 5 days/wk, 4 wk	Weight of ovaries and testes. Histopathology of ovary, uterus, prostate, and testis.	No treatment-related effect except for “variation” in “absolute and/or relative” weight of testis. Body weight was unaffected. No further details were in summary report for Group III.	API, 1986
API 81-09 Hydrodesulfurized middle distillate CAS 64742-80-9	Dermal. Rabbit. 200, 1000, or 2000 mg/kg/day, 3 days/wk, 4 wk	Weight of ovaries and testes. Histopathology of ovaries, vagina, uterus, testes, epididymides, prostate, and seminal vesicles.	No observed treatment-related effect on reproductive organs.	API, 1983

Short description of key information:
Study proposal to fulfil the information requirements of REACH Annex IX (8.7.3). In a number of repeat dose (dermal) and several OECD 414 developmental toxicity studies there were no effects observed on development. In addition, no effects were observed on reproductive organs in sub chronic studies with OGO and an assessment of the overall weight of evidence (as outlined in the attached testing proposal) concludes that it is unlikely that the primarily aliphatic OGOs have an adverse effect on fertility.

Effects on developmental toxicity

Description of key information

In a read across developmental study from heavy atmospheric gas oil, authors reported a NOAEL of 30 mg/kg body weight/day for maternal toxicity and foetal toxicity applicable to Other Gas Oils.

Effect on developmental toxicity: via dermal route

Dose descriptor:

NOAEL

30 mg/kg bw/day

Additional information

No studies were located for OGO substances. However information from a dermal study in rats on a Straight-run gas oil (Heavy atmospheric gas oil; CAS 68915-97-9) may be used as a source of information for read across. Straight run gas oil data can be used as read-across data for OGO substances due to similar physical/chemical properties and composition. 

 

The developmental toxicity of heavy atmospheric gas oil (Straight-run, high boiling distillate) was investigated using two sets of pregnant SD 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.

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 approx. 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 (26-75% 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. 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.

 

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). Although limited reporting means it is not possible to determine whether dermal irritation contributed to these findings, results from a sub-chronic dermal toxicity study on heavy atmospheric gas oil suggest this would not have been expected to have been present to any significant extent in dams from the 125 mg/kg body weight/day groups, indicating the effects observed at this dose level were test substance-related.

Toxicity to reproduction: other studies

Additional information

This endpoint is not a REACH requirement.

Justification for classification or non-classification

No reproductive toxicity data are available for other gas oils so there is insufficient information to classify this category as toxic for reproduction under the EU CLP Regulation (EC No. 1272/2008).

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 there was no evidence of foetal effects in the absence of significant maternal toxicity.