Registration Dossier

Administrative data

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

Information is available from four GLP-compliant screening studies (see section 7.8.2) that evaluated the impact of Heavy Fuel Oil Components on reproduction in rats. Although the design of these investigations (where only females were treated with the test substance prior to mating) deviates from that of a guideline investigation, the design of the studies and reporting of the data is adequate for an assessment of potential effects on fertility.

 

Heavy Fuel Oil Components administered dermally to the skin of female rats from gestation days -7 through 20 at doses up to 1000 mg/Kg bw/day did not result in significant treatment-related effects on fertility parameters. However, vaginal discharge was consistently observed in the four studies (ARCO, 1994g, i, j, l) and appeared to increase in frequency at higher dosages. One study (ARCO, 1994i) reported pregnancy rates of 80%, 67%, 60% and 53% for the control, low (1 mg/kg bw/day), intermediate (250 mg/Kg bw/day) and high dose groups (1000 mg/Kg bw/day), respectively while another study (ARCO, 1994j) reported pregnancy rates of 80%, 60%, 60% and 80% for the control, low (1 mg/Kg bw/day), intermediate (250 mg/Kg bw/day), and high dose groups (1000 mg/Kg bw/day), respectively. In a third study (ARCO, 1994j), overall fertility rates were observed to be low for all groups (including controls), with only 40-50% of females continuing to pregnancy. In all of the above studies, none of the high dose females delivered a litter although the number of implantation sites was observed to be comparable to that of the controls.

 

Systemic toxicity (effects on food consumption, body weight, bodyweight gain, clinical effects, and reduced thymus) was observed in some of the

studies. No adverse histopathological alterations in male or female gonadal tissue or changes in sperm/spermatid parameters were found in the screening tests or in dermal sub-chronic toxicity studies (API, 1985a; ARCO, 1993a; 1994d; Mobil, 1985a; 1988l; 1992e; 1994a; 1994b; 1995a; Feuston, 1994; and Feuston, 1997) conducted on a range of Heavy Fuel Oil Components. However, one study (Cruzan et al., 1986) reported smaller ovaries and accessory sex organs in male and female rats post sub-chronic dermal administration of Catalytic Cracked Clarified Oil (CAS# 64741-62-4) at doses up to 2000 mg/Kg bw/day.

Short description of key information:

In accordance with column 2 of REACH Annex X, the study does not need to be conducted if the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented.  Heavy Fuel Oil Components do not specifically target the reproductive system of male and female rats.

Effects on developmental toxicity

Description of key information

The available data indicate that Heavy Fuel Oil Components adversely affect foetal development.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.05 mg/kg bw/day
Species:
rat
Quality of whole database:
Decreased gravid uterine weight, increased resorptions, decreased live litter size, decreased foetal weight
Additional information

Extensive information is available from a large number of predominantly GLP-compliant studies that have assessed the potential developmental toxicity of Heavy Fuel Oil Components. The design of several investigations conformed to international guideline standards while several of the remainder were near-guideline. Overall, therefore, confidence in the reliability of the database is considered to be high.

The developmental toxicity of clarified slurry oil (0, 0.05, 1, 10, 50 or 250 mg/Kg bw/day) was investigated in groups of pregnant SD rats after dermal application on GD 0-19 (Hoberman, et al., 1995). The dams were housed individually and fitted with collars to minimise ingestion during the 6 hr exposure period, and the test site wiped clean (acetone) at the end of the exposure.

There were no maternal deaths, abortions, premature deliveries or any irritation of the test site in any group during the study, however red vaginal discharge (affecting 20-80% of animals) was observed at 1 mg/Kg bw/day and above. Maternal feed consumption and maternal body weight were significantly decreased, in a dose-related manner at 1 mg/Kg bw/day and above. Net maternal body weight and net body weight gain were also significantly decreased in a dose related manner at 1 mg/kg bw/d and above.Significant, dose-related reductions in gravid uterine weight (decreased 40-95%) and an increased incidence of early resorptions (elevated 8-24 fold) were apparent in dams receiving 1 mg/Kg bw/day and above. The number of dead or resorbed foetuses was increased 8-16 fold over that of the controls in the 1, 10 and 50 mg/Kg bw/day groups with total litter resorption in high dose dams. Foetal body weight was also significantly decreased (14-25%) at 1 mg/kg bw/day and above. There were no treatment-related gross external malformations, however the incidence delayed development in soft tissues (variations, including moderate dilation of the renal pelvis, slight dilation of the lateral ventricles of the brain) was stated to be increased significantly (data not presented in publication). A reduction in the extent of ossification of the caudal vertebrae, metacarpals and phalanges (defined as variations) was also apparent in the 1, 10 and 50 mg/Kg bw/day groups. No adverse or statistically significant foetal findings were apparent in 0.05 mg/Kg bw/day group.

The NOAEL for maternal toxicity was 0.05 mg/Kg bw/day (based on decreased net body weight/net body weight gain, a reduction in food intake and the occurrence of vaginal discharge); the NOAEL for developmental toxicity was also 0.05 mg/Kg bw/d (reflecting decreased gravid uterine weight, increased resorptions, decreased live litter size and a reduction in foetal weight).

  

In a second study (ARCO, 1994e), the developmental toxicity potential of atmospheric tower bottoms (0, 50, 333 or 1000 mg/Kg bw/day) was investigated in a screening study using groups of 12-15 female SD rats. Dose level selection was based on preliminary dermal irritation screening study, with neat test substance applied daily to clipped dorsal skin (6 hr, open contact) on GD 0-20. The dams were allowed to litter normally, and mothers and pups observed to PND 4.

There were no maternal deaths and no irritation of the test site in any treated animal. Maternal body weight gain was significantly decreased in high dose animals on GD 16-20, although maternal body weight toward the end of the study was highly comparable to that of the controls. Maternal body weight on the first day of lactation (PND 1) was highly comparable for dams from the control and treated groups. No gross maternal lesions were apparent at necropsy of the dams on LD 4. Gestational length was increased significantly for the high dose group relative to that of the controls with a significant reduction in mean body weight for the high dose litters at LD 0. Pup body weight at LD 4 was also decreased significantly in the low and high dose litters relative to the controls but unchanged in the intermediate dose group. Litter size (total, live), sex ratio and pup survival to LD 4 were highly comparable between control and treated litters.

The NOAEL for maternal toxicity was 333 mg/Kg bw/day (based on decreased body weight gain and increased gestational length); the NOAEL for developmental toxicity was also 333 mg/Kg bw/day (reflecting decreased pup body weights on PND 0 and PND 4).

Several GLP compliant studies are available that support the above data (Feuston, 1997, and 1989; ARCO, 1994f-p; 1993d,e, and 1989m; Mobil, 1994c; 1988m,n, and 1987b). Foetal effects observed following dermal application of Heavy Fuel Oil components included reductions in gravid uterine weight, a decrease in the number of implantation sites, increased number of resorptions, decreased litter size and decreased foetal weight. Delayed ossification of skeletal tissue was also reported in several studies with decrements in pup weight (at birth and at LD 4) recorded in some studies where the dams were allowed to deliver a live litter. However there was no indication of teratogenicity. Manifestations of maternal toxicity commonly observed after dermal treatment during pregnancy included decrements in food intake, body weight (and/or body weight gain) and the occurrence of vaginal discharge at low doses, with organ weight reductions, increased gestational length and variable degrees of skin irritation following higher exposures. It is not clear, however, whether the altered pre- and post-natal development described above was secondary to maternal toxicity or whether it was caused directly by treatment with Heavy Fuel Oil Components.

Justification for selection of Effect on developmental toxicity: via dermal route:

One of 22 available studies.

Justification for classification or non-classification

The available data demonstrate that Heavy Fuel Oil Components do not selectively target the reproductive system of male and female rats, and that no classification for reproductive effects is necessary. Results of developmental toxicity testing indicate alterations in foetal and pup development, which sometimes occurred in the presence of maternal toxicity. Classification of Heavy Fuel Components with Reproductive toxicity 2 (H361d) is considered appropriate under the EU CLP Regulation (EC No. 1272/2008).