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Key value for chemical safety assessment

Effects on fertility

Description of key information

In accordance with Section 1 of REACH Annex XI, additional reproductive toxicity studies do not appear to be scientifically necessary, as two developmental/reproductive toxicity studies conducted under internationally agreed validation principles provided no indication that sufficiently refined lubricant base oils (IP 346< 3 wt%) have adverse reproductive effects. Further no adverse effects on reproductive organs have been noted in multiple dermal or inhalation repeat dose studies (28-day) or carcinogenesis bioassays.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
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
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

In a key reproduction/developmental screening study (WIL Research Laboratories, 1995), a sufficiently refined lubricant base oil (IP 346 < 3%) was administered by gavage at a dose of 1000 mg/kg (bw) to a group of 12 male and 12 female Sprague-Dawley rats. Rats designated F0 animals were dosed for a minimum of 14 days prior to mating. Dosing was continued after mating until a total dosing period of 30 days had elapsed for males and until day 4 of lactation for females (39 days). The animals were observed twice daily for appearance, behaviour, morbidity and mortality. Males and females were also observed during dosing and for one hour thereafter. Male F0 body weights were recorded weekly. Female F0 body weights were also recorded weekly until evidence of mating was observed and then on gestation days 0, 7, 14 and 20 and on lactation days 1 and 4. Food consumption was also recorded for F0 (both sexes). Animals were paired on a 1:1 basis. Positive evidence of mating was confirmed either by the presence of sperm in a vaginal smear or a vaginal plug. The day when evidence of mating was identified was termed Day 0 of gestation.

 

The following fertility indices were calculated: Female mating index; Male mating index; Female fertility index; and Male fertility index. All females were allowed to deliver their young naturally and rear them to post-natal day 4. Females were observed twice daily during the period of expected parturition for initiation and completion of parturition and for signs of dystocia. After parturition, litters were sexed and examined for evidence of gross malformations, numbers of stillborn and live pups. Litters were examined daily, and each pup received a detailed physical examination on days 1 and 4 of lactation. All abnormalities were recorded. The live litter size and viability index were calculated. All surviving pups were necropsied on post-natal day 4. A complete gross examination was made on all animals at necropsy. Selected organs of parental animals were weighed, and a wide range of tissues were fixed for subsequent histopathological examination.

 

There were no clinical findings and growth rates and food consumption values were normal. Fertility indices and mating indices for males and females were both 100%. At necropsy, there were no consistent findings, and the animals were considered to be normal. Organ weights and histopathology were considered normal. The NOAEL for this study was 1000 mg/kg/day.

In a key read-across reproductive toxicity study (Schreiner et al.1997) highly refined mineral oils (highly refined base oils) were tested in Sprague-Dawley rats. Highly refined base oils are similar in composition to other lubricant base oils, and hence similar effects would be expected.

Highly refined base oil was used as a vehicle control group in a key dermal application study reported by Schreiner et al. 1997 (Klimisch score = 1) to determine the potential reproductive effects of kerosene. The study employed a sham-treated control and a group in which white oil Squibb (340 SUS) mineral oil was administered at a dose of 1 ml/kg/day (approximately 1000 mg/kg/day). No animals died or were prematurely sacrificed and no clinical signs of toxicity were observed. Skin irritation among males varied from slight to moderate with increasing dose and was most severe in the high-dose group. Mild to moderate skin irritation was observed in females at the highest concentration. At terminal sacrifice, no findings were reported except for those on the skin. Microscopic changes were found in the skin of vehicle control and all kerosine-treated groups in the males. In females changes were only observed in the high-dose group animals. A mean dermal irritation score of 1.3 (maximum of 3) was observed. Body weights were unaffected by treatment. Reproductive/fertilitywas unaffected by treatment.No test-material-related microscopic changes were observed in the testes or epididymides of adult male rats or in the ovaries of adult female rats.

 

Squibb (340 SUS) mineral oil (a white mineral oil) caused no reproductive or developmental toxicity with 1 mL/kg/day (i.e., 1000 mg/kg/day) in an OECD 421 guideline study, but did cause mild to moderate skin irritation. Therefore, the reproductive/developmental NOAEL for this study is 1000 mg/kg/day and no LOAEL was determined.

Short description of key information:

Two key screening reproductive/developmental studies (OECD 421) were identified.  No reproductive or developmental effects were observed in Sprague-Dawley rats.

Justification for selection of Effect on fertility via oral route:

Only oral reproductive toxicity study.

Justification for selection of Effect on fertility via dermal route:

Only dermal reproductive toxicity study available

Effects on developmental toxicity

Description of key information

For sufficiently refined other lubricant base oils (IP 346 < 3%), one key developmental study (OECD 414) was identified.  The study was conducted dermally with Sprague-Dawley rats.  A maternal LOAEL was not reported but can be referenced to be 125 mg/kg/day based on skin irritation.  A developmental/teratogenic NOAEL was not reported; however, it can be inferred that this value is 2000 mg/kg/day.

There are no developmental toxicity studies of insufficiently refined other lubricant base oils (IP 346 ≥ 3%).  However, a read-across developmental study (OECD 414), on a UDAE was identified. Heavy paraffinic distillate furfural extract (UDAE) produced maternal, reproductive, and foetal toxicity in Sprague-Dawley rats when applied dermally.  Maternal toxicity was exhibited as vaginal discharge (dose-related), body weight decrease, reduction in thymus weight and increase in liver weight (125 mg/kg/day and higher) and aberrant haematology and serum chemistry (125 and/or 500 mg/kg/day). Evidence of potential reproductive effects was shown by an increased number of dams with resorptions and intrauterine death.  DAE was developmentally toxic regardless of exposure duration as indicated by increased resorptions and decreased foetal body weights.  Furthermore, when exposures were increased to 1000 mg/kg/day and given only during gestation days 10 through 12, cleft palate and ossification delays were observed.  Cleft palate was considered to indicate a potential teratogenic effect of UDAE.

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
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information
Sufficiently Refined Other Lubricant Base Oils (IP 346 < 3%) One key developmental study (Mobil Environmental and Health Science Laboratory, 1987) on sufficiently refined other lubricant base oils was identified. In this study, 100 SUS solvent refined base oil was administered to female Sprague Dawley rats dermally. There were five dose groups. Groups 2 through 4 (10 dams/group in Groups 2 and 3; 15 dams/group in Group 4) were administered 125, 500, 2000 mg/kg/day using a 1 cc syringe (calibrated in 0.01 cc). Dams were clipped on the dorsal surface, and the test material was dispensed evenly over the test site. Animals were fitted with Elizabethan-style collars. The control group (Group 1; 15 dams/group) was clipped and collared in a similar fashion. For the control group, the dorsal skin of each rat was stroked with the tip of a 1 cc syringe, but no test material was applied. A fifth dose group (5 dams/group) was used, in which dams were applied the base oil on gestation day 0-17 at a dose level of 2000 mg/kg/day. A base oil fortified with [1-14C]octacosane was administered on gestation day 18.

Dermal application of the lubricant base oil to pregnant rats during gestation produced slight dermal irritation at all dose levels. At these dosages, the lubricant base oil produced erythema and flaking of the skin at the site of application in a dose-dependent manner. One animal in the 500 mg/kg/day dose group had dermal oedema. There were no other signs of maternal toxicity. Serum components were not adversely affected by the test material. According to the Group 5 results, the test material metabolites were able to pass across the placenta, but did not bioaccumulate in the foetuses. Maternal LOAEL was 125 mg/kg/day based on skin irritation. There was no evidence of teratogenicity. There were no treatment-related changes observed during the external, skeletal, or visceral evaluations. Mean foetal weight and crown-rump lengths were comparable across all dose groups. Developmental/teratogenic NOAEL was 2000 mg/kg/day.

Insufficiently Refined Other Lubricant Base Oils (IP 346 3%)
There are no developmental toxicity studies of lubricant base oils with IP 346 3%. However, there is a read-across developmental toxicity study (Klimisch score=1, Mobile Environmental Health Science Laboratory, 1989) of an untreated distillate aromatic extract [UDAE] (heavy paraffinic vacuum distillate) which was used to assess the developmental toxicity of insufficiently refined other lubricant base oils.

Read-across from UDAE is based on the fact that UDAEs are generated by the solvent extraction of aromatic components in the refining process to generate LBO. In that sense, UDAEs contain extremely high content of polycyclic aromatic compounds (PACs) compared to the LBO. Untreated distillate aromatic extracts represent a worst case read for other lubricating base oils with IP346 ≥ 3wt% as these insufficiently refined oils may contain significant amounts of polycyclic aromatic hydrocarbons. 

In this study UDAE (CAS No. 64742-04-7), 318, was tested in a dermal study during gestation days 0 to 19 for developmental effects and maternal toxicity in the Sprague-Dawley rat.

 

Nine groups of pregnant rats were divided in three groups: prenatal, postnatal and bioavailability groups. These groups are further described below. Bioavailability group procedures and results are described separately.

 

Prenatal groups: the undiluted test sample was applied without occlusion to the shaved skin of pregnant rats at doses of 8, 30, and 125 mg/kg/day on gestation days 0-19 (15/group). An additional group received the same treatment at 500 mg/kg/day on gestation days 0 through 16. Initially, administration of the test sample to the 500 mg/kg/day group was also scheduled for gestation days 0 through 19, however treatment was discontinued after gestation day 16 because a high incidence of resorption was suspected (as indicated by a red vaginal discharge observed among rats in this group). Another prenatal group received the same treatment at 1000 mg/kg/day only on gestation days 10 through 12, an interval at which the developing foetus is sensitive to teratogenic insult. A group of sham treated rats served as control. Prenatal groups were sacrificed on gestation day 20.

 

The postnatal group was exposed under the same conditions as the prenatal group. Postnatal animals (10/group) were dosed at 0 or 125 mg/kg/day on gestation days 0 through 19. Postnatal groups were allowed to deliver their offspring naturally. Pups were observed on post partum day 0 for external malformations and variations and then together with their dams, sacrificed on post partum day 4.

 

End points examined in adults included clinical signs (all groups except bioavailability group) body weight (all groups), food consumption (all groups except bioavailability group), haematology and serum chemistry (only prenatal groups), liver and thymus weights (all groups except bioavailability group), and uterine and net body weights (all groups except bioavailability group). Foetal toxicity examinations included: resorption incidences, anomalous development (gross, skeletal and visceral abnormalities) and body weight.

 

Results - Prenatal Group

 

Prenatal groups were sacrificed on gestation day 20. All mothers were necropsied and grossly examined. Uterus and ovaries were excised and examined grossly. Numbers of corporea lutea per ovary of each pregnant animal were counted. Ovaries of non-pregnant animals were grossly examined and then discarded. Number and location of implantations, early and late resorptions and live and dead foetuses were recorded.

 

Maternal toxicity: Red vaginal discharge was observed in a number of pregnant animals in all DAE-exposed groups. Although authors mentioned this as being dose related, no statistics are provided.

 

In general animals exposed at 125 and 500 mg/kg consumed less food; at this dose level significant reduction in body weight gain, net body weight gain, and gravid uterine weight occurred throughout gestation. Body weight gain was also decreased at dose level of 1000 mg/kg/day. Of the haematology parameters evaluated, platelet and white blood cell counts were significantly affected in a dose related manner. Effects on 14 of 22 analyzed serum components were noted at the 125 or/and 500 mg/kg/day dose levels.

 

Thymus weights were significantly reduced and liver weights increased at doses in excess of 30 mg/kg/day. 

 

Reproductive effects: Implantation was not adversely affected by treatment. The number of dams with no viable offspring was increased at dose levels from 125 mg/kg/day. Litter size was significantly lower and resorptions were significantly increased compared to controls at 125 mg/kg/day and higher.

 

Foetal toxicity and development: At 30 mg/kg/day, although not statistically-significant, a twofold increase over controls in the number of resorptions was observed, which the authors considered as of biological relevance. Treatment at 125 mg/kg/day and at higher doses resulted in decreased mean foetal body weights. A statistically significant increase in the incidence of incompletely ossified skull bones in foetuses exposed in utero to 125 mg/kg/day was observed. 

 

When the period of exposure was restricted to gestation days 10 through 12 and the dose increased to 1000 mg/kg, defects in costal cartilage development were significantly increased. Two of 114 foetuses evaluated were oedematous and had cleft palates. The cleft palate finding was considered by the authors to be biologically significant and evidence of a teratogenic effect, basis very low historical control incidences at theirs and other laboratories.

 

Results - Postnatal Group

 

In the postnatal group (10/group), three females were found to be not pregnant, five females reabsorbed their entire litters and one dam had only two pups, which she subsequently cannibalized. The postpartum analysis of the single viable litter of this group was not meaningful.

 

Results - Bioavailability Group

 

The bioavailability group included 3 females which were dosed with14C-carbazole- and3H benzo[a]-pyrene [BaP] - labelled DAE at 1000/kg/day on gestation days 10 through 12 and were treated under the same conditions as the previous two groups. Animals were housed in metabolic cages until sacrifice; urine and faeces were collected.

 

Bioavailability group animals were sacrificed on gestation day 13. Maternal tissues collected for radioactivity measurements were: blood, thymus, liver, small intestine, large intestine, kidneys, stomach and ovaries. Placentas, embryos, amniotic fluid and yolk sacs were pooled for each dam before analysis of radioactivity.

 

Bioavailability analyses revealed that dermal absorption of both radiolabelled substrates occurred.14C-Carbazole was more extensively absorbed than 3H-BaP over a 72-hour period (20% and 4% of the original dose respectively after three applications). After 72 hours, about 2% of 14C-Carbazole and 3H-BaP (2.1% and 1.8% respectively) was found in the maternal tissues, primarily in blood, large and small intestines. By comparison, less than 0.01% of each surrogate was detected in the embryo, indicating that 3H-benzo[a]-pyrene and 14C-Carbazole do not selectively accumulate in the embryo under conditions of this study. 

 

The authors concluded that under study conditions UDAE produced maternal, reproductive and foetal toxicity. Maternal toxicity was exhibited as vaginal discharge (dose-related), body weight decrease, reduction in thymus weight and increase in liver weight (125 mg/kg/day and higher) and aberrant haematology and serum chemistry (125 and/or 500 mg/kg/day). Evidence of potential reproductive effects was shown by an increased number of dams with resorptions and intrauterine death. DAE was developmentally toxic regardless of exposure duration as indicated by increased resorptions and decreased foetal body weights. Furthermore, when exposures were increased to 1000 mg/kg/day and given only during gestation days 10 through 12, cleft palate and ossification delays were observed. Cleft palate was considered to indicate a potential teratogenic effect of DAE.

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

One of Two dermal developmental toxicity studies

Justification for classification or non-classification

A key screening reproductive/developmental toxicity study on sufficiently refined other lubricant base oils showed no effects on reproductive parameters. Sufficiently refined other lubricant base oils do not meet the EU criteria for reproductive toxicity and are not classified under Annex VI of EU CLP Regulation (EC No. 1272/2008).

Developmental toxicity studies conducted using sufficiently refined other lubricant base oils (IP 346 < 3%) did not reveal any treatment-related teratogenic effects. Sufficiently refined other lubricant base oils do not meet the EU criteria for developmental toxicity and are not classified.

There are no developmental toxicity data for insufficiently refined lubricant base oils, but for classification purposes their hazards are assumed to be similar to those of untreated distillate aromatic extracts[UDAE] . In a read-across developmental study UDAE produced maternal, reproductive, and foetal toxicity in Sprague-Dawley rats. Consequently, insufficiently refined other lubricant base oils (IP 346 3%) are classified as Repr. 2 (H361d: Suspected of damaging the unborn child) under Annex VI of EU CLP Regulation (EC No. 1272/2008).