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Key value for chemical safety assessment

Effects on fertility

Description of key information

This endpoint is not a REACH requirement.  No information identified.

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 adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

In a non-guideline reproductive/developmental screening study (UBTL, 1994a; Klimisch score = 2), groups of female Sprague-Dawley rats received 0 (sham control), 1, 50 or 250 mg/kg body weight/day of light coker gas oil dermally. Treatment of the females commenced one week prior to mating with untreated males. Pregnant females were then assigned to the test (n = 12/dose level) and control groups (n = 15) and treatment continued until gestation day 20. None of the dams died during the course of the study. Slight to moderate erythema, oedema and eschar were present at the treatment site in the low- and mid-dose groups, with more severe responses (including slight to severe erythema, ulceration in one animal) recorded in the 250 mg/kg body weight/day group. Mean body weight was decreased by approximately 10% (significant) in high-dose animals throughout gestation, with a comparable (significant) reduction in weight gain on during gestational days 0 to 4. Maternal body weight at lactational day 4, and weight gain during the period lactational day 0 to 4 were also significantly decreased in postnatal dams from the 250 mg/kg body weight/day group. The only effect noted in the offspring was a significant decrease in mean pup weight at birth (-7%) and at lactational day 4 (‑14%) in the high-dose litters. Based on these results, the authors of the study determined a NOAEL of 50 mg/kg body weight/day for effects of light coker gas oil on foetal/pup development (reduced body weight of live pups/ litter) after administration to pregnant rats on gestational days 0 to 20. Skin irritation was observed at the test site in all treated animals, and a confounding effect on the mothers and/or foetuses cannot be excluded. There were no effects on reproductive parameters, so the NOAEL for toxicity to female reproduction is greater than or equal to 250 mg/kg bw/day.

 

In a reproductive/developmental screening study (UBTL, 1994b; Klimisch score = 2), light coker gas oil was applied neat to clipped dorsal skin (area unspecified) of female rats, at dose levels of 0 (sham control), 1, 250 or 1000 mg/kg body weight/day, commencing 1 week prior to mating. There were 20 controls and 15 test animals per group. Although it was intended that the animals would be treated from gestational day 0 until gestational day 20, extreme irritation was present at the test site in the 1000 mg/kg body weight group, which failed to mate and was sacrificed on gestational day 5. Similarly, treatment of the mid-dose group was halted between gestational days 8 and 11, again due to extreme dermal irritation, but the dams were allowed to deliver their litters. Irritation of the test site was present in all groups, and ranged from slight to moderate erythema, oedema and slight eschar for animals receiving 1 mg/kg body weight/day up to slight to extreme erythema, oedema and eschar with discharge and fissuring in the 250 and 1000 mg/kg/day groups. Maternal body weight, food consumption, and reproductive/developmental parameters were affected in the mid-dose group. A foetal/pup NOAEL of 1 mg/kg bw/day for developmental toxicity was identified, and a maternal NOAEL of 1 mg/kg body weight for toxicity to female reproduction was identified. The effects observed at 250 mg/kg/day were consistent with results observed in the previous study.

 

In a dermal sub-chronic study (Mobil, 1991; Klimisch score = 2), rats were administered 0, 30 or 125 mg/kg body weight/day of coker light gas oil for 13 weeks. The assessment of potential treatment-related effects on the reproductive system of male and female Sprague-Dawley rat was included as a part of the study. The reproductive assessment included wet whole organ weights for ovaries, uterus, testes, prostate and epididymides, histological examination of the epididymides, ovaries, prostate and seminal vesicles, testes (right only) and uterus (body and horns), and spermatozoa/spermatid evaluation (cauda epidiymides and testicular parenchyma were weighed and prepared for spermatozoa and spermatid counts.

 

Absolute and relative ovary and uterus weights were indistinguishable between control and treated female rats. Absolute epididymal, prostate and testes weights were also comparable between the groups, however the relative weight of these organs was increased significantly (10%, 18%, 10%, respectively) versus controls. This apparent increase in relative organ weight was likely a consequence of a significant 11-12% decrease in terminal body weight for these animals, since relative adrenal, brain, kidney, liver, spleen and thymus weights were also increased by a similar amount. No treatment-related microscopic changes were present in gonadal tissue from males or females. An assessment of epididymal sperm parameters demonstrated no alteration in weight of cauda epididymis, the number of sperm per cauda (both total and per g wet wt tissue) or the percentage of normal sperm. Testicular spermatid parameters showed no alteration in testis weight or spermatid numbers (both total and per gram testis).

 

Based on a lack of effects on reproductive organ weights and histology in male and female rats, or on sperm/spermatid parameters in males, a NOAEL of greater than or equal to 125 mg/kg body weight/day (the highest dose evaluated) was obtained for effects of coker light gas oil on the male and female reproductive system. 

 

A two-generation reproductive toxicity study does not need to be conducted if the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented. Accordingly, as cracked gas oils are classified as Category 1B carcinogens (H350) according to EU CLP Regulation (EC No. 1272/2008), further investigations of effects on fertility are not proposed.

Short description of key information:

No data are available on the potential impact of cracked gas oils on fertility following repeated vapour inhalation or oral exposure. Non-guideline studies were located that examined the potential impact of cracked gas oils on reproductive function following dermal exposure.  Results from reproductive screening tests indicate that at least female reproduction capacity was not affected by treatment beginning 7 days prior to mating, even when maternal toxicity was observed.  In addition, following dermal administration of Beaumont coker light gas oil for 5 days/week over 13 weeks, the NOAEL for cracked gas oils on reproductive organ weights and histology in male and female rats, and on sperm/spermatid parameters in males, is greater than or equal to 125 mg/kg/day.  

Effects on developmental toxicity

Description of key information

No data are available on the potential impact of cracked gas oils on developmental toxicity following repeated inhalation exposure. One study was identified using oral exposure. The study design was unconventional and is not considered to be a reliable basis for assessing developmental toxicity.

In studies investigating the developmental toxicity of cracked gas oil streams after dermal exposure in the rat, 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 were 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 and decreased maternal body weight are possible significant confounding factors in the interpretation these studies 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 foetuses. Destruction of the barrier function of the skin may also affect absorption of the test sample across the skin, giving unrepresentative systemic exposures. However, evaluating the weight of evidence suggests a supported NOAEL of 50 mg/kg bw/day for developmental toxicity following dermal exposure.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Additional information

In a key GLP compliant study (Klimisch score = 2, UBTL 1994a), groups of female Sprague- Dawley rats received 0 (sham control), 1, 50 or 250 mg/kg body weight/day of light coker gas oil. Treatment of the females commenced one week prior to mating with untreated males. Pregnant females were then assigned to the test (n = 12/dose level) and control groups (n = 15) and treatment continued until gestation day 20. Pup parameters were assessed at the time of delivery and on lactational day 4.

 

None of the dams died during the course of the study. Slight to moderate erythema, oedema and eschar were present at the treatment site in the low- and mid- dose groups, with more severe responses (including slight to severe erythema, ulceration in one animal) recorded in the 250 mg/kg body weight/day group. Mean body weight was decreased by approximately 10% (significant) in high- dose animals throughout gestation, with a comparable (significant) reduction in weight gain on during gestational days 0 to 4. Maternal body weight at lactational day 4, and weight gain during the period lactational day 0 to 4 were also significantly decreased in postnatal dams from the 250 mg/kg body weight/day group. The only effect noted in the offspring was a significant decrease in mean pup weight at birth (- 7%) and at lactational day 4 (‑14%) in the high- dose litters. Based on these results, the authors of the study determined a NOAEL of 50 mg/kg body weight/day for effects of light coker gas oil on foetal/pup development (reduced body weight of live pups/ litter) after administration to pregnant rats on gestational days 0 to 20. Skin irritation was observed at the test site in all maternal treated animals, and a confounding effect on foetuses cannot be excluded.

 

In a reproductive/developmental screening study (UBTL, 1994b; Klimisch score = 2), light coker gas oil was applied neat to clipped dorsal skin (area unspecified) at dose levels of 0 (sham control), 1, 250 or 1000 mg/kg body weight/day, commencing 1 week prior to mating and continuing through the mating period. Although it was intended that the animals would be treated from gestational day 0 until gestational day 20, extreme irritation was present at the test site in the 1000 mg/kg body weight group, which failed to mate and was sacrificed on gestational day 5. Similarly, treatment of the mid- dose group was halted between gestational days 8 and 11, again due to extreme dermal irritation, but the dams were allowed to deliver their litters. Irritation of the test site was present in all groups, and ranged from slight to moderate erythema, oedema and slight eschar for animals receiving 1 mg/kg body weight/day up to slight to extreme erythema, oedema and eschar with discharge and fissuring in the 250 and 1000 mg/kg/day groups. Maternal body weight, food consumption, and reproductive/developmental parameters were affected in the mid- dose group. A NOAEL of 1 mg/kg body weight for both maternal and developmental toxicity of light coker gas oil was identified.

 

In another GLP- compliant non- guideline study (UBTL, 1994c), the developmental toxicity of light cycle oil (F- 213) was evaluated in pregnant Sprague- Dawley rats following dermal application at dose levels of 0 (sham control), 50, 333 or 1000 mg/kg body weight/day. There was a dose- dependent increase in the severity of erythema, oedema and eschar. There were no treatment- related deaths. Clinical signs included vaginal discharge (possibly indicative of resorptions) on gestational days 1 to 7 in 8 of 12 dams receiving 333 mg/kg body weight/day (treated throughout gestation), and 3 of 12 dams from the high- dose group (treated through gestational day 4, 5, or 6 only). Maternal body weight was reduced in the 333 mg/kg/day group during pregnancy, with terminal body weight at gestational day 20 decreased by 28% (significant). Food intake in these animals was also significantly reduced by 15- 20% during early to mid- pregnancy (up to gestational day 12). Gestational length was increased significantly in the mid- dose group, with resorptions found in the uterus of one dam at necropsy on lactational day 4. Effects on maternal parameters were unremarkable in the 50 mg/kg body weight/day group.

 

Pup body weight at birth was 14% lower than controls (significant) in the mid- dose (333 mg/kg/day) litters with a 25% reduction (significant) apparent at lactational day 4. The number of live births (- 15%) and pup survival (- 31%) at lactational day 4 were both significantly different from the controls. Litter characteristics for the 50 mg/kg body weight/day group were comparable to those of the controls. A NOAEL of 50 mg/kg body weight/day was identified for both maternal toxicity (reduced body weight, vaginal discharge possibly indicative of resorption) and foetal toxicity (significantly reduced body weight, decreased live litter size, decreased pup survival).

 

In a developmental toxicity study (Mobil, 1988; Klimisch score =2), presumed pregnant females were administered light catalytic cracked distillate to the shorn dorsal skin at doses of 25, 50, 125, 250, or 500 mg/kg/day on gestational days 0 to 19. Another group received 1000 mg/kg/day on either gestational days 0 to 6 or gestational days 6 to 15. Erythema and flaking of the skin were observed in all groups exposed to light catalytic cracked distillate. Eschar, fissuring, scabbing and scar formation was observed in all but the 25 mg/kg/day group. Skin irritation was particularly severe in the 500 and 1000 mg/kg/day groups. At doses higher than 25 mg/kg/day there was a decrease in body weight and body weight gain compared to the controls and this was accompanied by a reduction in food consumption. There were no treatment- related findings at necropsy. Foetal body weights were reduced only in the 500 and 1000 mg/kg groups and statistical significance was achieved only in the latter group. A developmental NOAEL of 250 mg/kg/day was established.

 

Coker Light Gas Oil (CLGO) was applied daily to the shorn dorsal skin of groups of ten presumed- pregnant female rats (aged approximately 7 weeks; Mobil, 1989; Klimisch score = 1). Animals were administered doses of 15 or 60 mg/kg/day from gestational day 0 to 19, 250 mg/kg/day from gestational day 0 to 15 (discontinued due to dermal irritation), or 500 mg/kg/day on gestational days 10 to 12. The only clinical signs that were considered to be substance- related are those of skin irritation, which ranged from moderate to severe. Erythema, flaking, scabbing and thickening of the skin was observed in all groups exposed to CLGO. In those animals exposed to CLGO for more than 16 days fissuring, eschar and necrosis of the skin was also observed.

 

Growth rates were normal except for those of the 250 and 500 mg/kg day groups whose body weights were significantly less than controls at day 20 of gestation. There were no treatment related effects on female reproduction or developmental parameters. The maternal LOAEL was 15 mg/kg/day based on skin irritation and the foetal NOAEL was 500 mg/kg/day due to the lack of effects on the offspring; note the 500 mg/kg/day dose group was only treated for a few days.

 

Pregnant SD rats were treated with light coker gas oil at doses of 0 (acetone), 50, 100 or 250 mg/kg body weight/day on GD 0- 19 (50 and 100 mg/kg) or 6- 11 ( 250 mg/kg) (Argus, 1993). There were no maternal deaths during the study. Skin reactions (grade 1 or 2) were observed in all dose groups (including the controls) and included erythema, oedema, atonia and desquamation. Vocalisation occurred at an unspecified period in 1, 15, and 16 rats in the 50, 100 and 250 mg/kg/day dosage groups and was considered test substance- related by the study authors (recorded also in a pilot study).

 

Maternal body weight gains were reduced in the 100 and the 250 mg/kg body weight/day animals. Foetal malformations included individual incidences of a depressed eye bulge, variations in ossification of the ribs, sternebrae and pelvis, a threadlike tail tip and dilation of the pelvis of the right kidney of one rat in the 50 mg/kg /day group (from a total of 184 evaluated foetuses); dilation of the pelvis of one kidney and an unspecified reversible developmental delay in 4/189 foetuses evaluated from the 100 mg/kg/day group; and situs inversus of the heart and stomach (one animal each from 180 evaluated) in the 250 mg/kg day group. The study authors determined a maternal NOAEL of less than 50 mg/kg body weight/day (based on dermal irritation in all treated groups and reduced body weight gains and/or food consumption in the two higher dose groups), with a foetal NOAEL of at least 250 mg/kg body weight/day, based on no evidence of embryo- foetal effects at this level.

 

In a developmental toxicity study of unconventional design, 5 refinery streams were administered orally to groups of pregnant SD rats on GD 13 as a single dose of 2000 mg/kg body weight (Mobil, 1994). The samples included a light cycle oil (CAS# 64741- 59- 9) and a Beaumont coker light gas oil (CAS# 64741- 82- 8). There were 12 dams per treatment group with the exception of light cycle oil where only 4 animals were used due to the occurrence of severe clinical signs. Various clinical signs were observed in groups, including prostration, piloerection, decreased activity and red vaginal discharge (all especially marked with light cycle oil). Mean body weight change and net body weight gain were adversely affected for all treatments. Absolute and relative thymus weights were reduced by 36% and 38%, respectively, in females exposed to light cycle oil (considered to be biologically significant).

Foetal weights were decreased by approx. 15% in litters from dams exposed to light cycle oil. A statistically significant increase in malformation of the hind paw digits was observed in 11 foetuses from one dam exposed to Beaumont coker light gas oil. One foetus from a dam treated with light cycle oil exhibited digit anomalies on both hind- and forepaws. Despite the poor condition of the females and the extreme red vaginal discharge that was observed in the dams exposed to light cycle oil, foetal viability did not appear to be affected. Developmental effects included decreased foetal weights and foetal external anomalies in one foetus (anomalies in the digits of both fore and hind paws). Foetuses from dams exposed to light cycle oil weighed less than control foetuses. The foetal incidence of malformation was significantly increased in foetuses from females exposed to Beaumont coker light gas oil. However, the unconventional design of this oral developmental toxicity study makes it unsuited for further assessment, and the findings will not be considered further.

In the supporting study (WIL Research Laboratories, 2012, Klimisch score = 1) conducted according to OECD 414, Distillates (petroleum), light catalytic cracked (CAS 64741-59-9) was applied dermally to Sprague-Dawley rats at the concertation of 100, 450 and 750 mg/kg/ body weight /per day. Maternal toxicity was evident in the presence of developmental toxicity at 450 and 750 mg/kg/day. Mortality and moribundity were noted in the 750 mg/kg/day group, as 1 female was euthanized in extremis on gestation day 13 and 1 female was found dead on gestation day 16. All other females survived to the scheduled necropsy on gestation day 20. Test substance-related clinical findings (yellow and/or red material around the urogenital area, red vaginal discharge and/or body pale and cool to touch) were noted at the daily examinations and/or 1 to 2 hours following exposure in both the 450 and 750 mg/kg/day groups, and dermal observations consisting of very slight to moderate erythema, very slight to slight edema, and desquamation were noted in the 750 mg/kg/day group. No evidence of maternal toxicity was noted at 100 mg/kg/day. Therefore, a dosage level of 100 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity. Increased postimplantation loss with corresponding decreased mean numbers and litter proportions of viable fetuses, as well as lower mean fetal weights and reduced fetal skeletal ossification indicative of developmental delay were noted at 450 and 750 mg/kg/day. Therefore, a dosage level of 100 mg/kg/day was considered to be the NOAEL for embryo/fetal development. when distillates (petroleum), light catalytic cracked was administered by dermal application to bred Crl:CD(SD) rats.

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

Only oral study. Two materials tested. Unconventional design, involving a single oral dose on gestation day 13 only. Significant maternal toxicity observed.

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

One of seven developmental toxicity studies. In the studies there was evidence of significant maternal toxicity (skin irritation and decreased weight gain). Although there were some effects on foetal weight, these only occurred in the presence of maternal toxicity.

Toxicity to reproduction: other studies

Additional information

This endpoint is not a REACH requirement. No information identified.

Justification for classification or non-classification

Results of ‘screening’ studies available investigating reproductive capacity indicate that effects on female fertility are unlikely. Whilst the data do not provide definitive information for classification purposes, no classification for effects on fertility is proposed, since cracked gas oils are regulated as Category 1B carcinogens (H350) according to EU CLP Regulation (EC No. 1272/2008).

A number of developmental toxicity studies show effects (reduced pup weight and delayed development) on the developing foetus but only at dose levels which also cause significant maternal toxicity (moderate to severe dermal irritation and effects on body weight). No classification for effects on development is proposed however since there was no evidence of foetal effects in the absence of significant maternal toxicity.