Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Screening for reproductive / developmental toxicity


In accordance with column 2 of REACH Annex VIII, information requirement 8.7.1 (a screening study for reproductive/ developmental toxicity) does not need to be conducted as a pre-natal developmental toxicity study is available on the substance (as required under REACH Annex IX, 8.7.2).


In addition, the substance is considered to be carcinogenic, mutagenic and toxic to reproduction (category 1B) and the appropriate risk management measures are implemented.


 


Extended one-generation reproductive toxicity


According to column 2 of REACH Annex IX, section 8.7, a reproductive toxicity study does not need to be conducted if the substance is known to have an adverse effect on fertility, meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage fertility (H360F), and the available data are adequate to support a robust risk assessment. Since the substance is reasonably known to be toxic for reproduction category 1B, and specifically may damage fertility (H360F), and bearing in mind the exposure assessment indicates no risk (due to the operational controls and risk management measures that are implemented), further testing for reproductive toxicity is neither considered necessary nor considered to be an expedient or responsible use of animals.


Additionally, column 2 of REACH Annex IX further stipulates that additional reproductive toxicity studies do not need to be conducted if the substance is known to be a genotoxic carcinogen and/or a known germ cell mutagen and appropriate risk management measures are implemented. Since the substance is reasonably known to be carcinogenic and mutagenic (category 1B), and since appropriate risk management measures are implemented, this further substantiates the lack of need for additional testing.


 


Please refer to the document ‘Consideration of the long term toxicity of Distillates (shale oil)’, as included in section 13, for further information.

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with column 2 of REACH Annex VIII, information requirement 8.7.1 (a screening study for reproductive/ developmental toxicity) does not need to be conducted as a pre-natal developmental toxicity study is available on the substance (as required under REACH Annex IX, 8.7.2).
In addition, the substance is considered to be carcinogenic, mutagenic and toxic to reproduction (category 1B) and the appropriate risk management measures are implemented.
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Study period:
to be confirmed
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented
the study does not need to be conducted because the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented
no further testing on fertility is necessary because the substance is known to have an adverse effect on fertility, meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage fertility (H360F), and the available data are adequate to support a robust risk assessment and classification and labelling
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to column 2 of REACH Annex IX, section 8.7, a reproductive toxicity study does not need to be conducted if the substance is known to have an adverse effect on fertility, meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage fertility (H360F), and the available data are adequate to support a robust risk assessment. Since the substance is reasonably known to be toxic for reproduction category 1B, and specifically may damage fertility (H360F), and bearing in mind the exposure assessment indicates no risk (due to the operational controls and risk management measures that are implemented), further testing for reproductive toxicity is neither considered necessary nor considered to be an expedient or responsible use of animals.
Additionally, column 2 of REACH Annex IX further stipulates that additional reproductive toxicity studies do not need to be conducted if the substance is known to be a genotoxic carcinogen and/or a known germ cell mutagen and appropriate risk management measures are implemented. Since the substance is reasonably known to be carcinogenic and mutagenic (category 1B), and since appropriate risk management measures are implemented, this further substantiates the lack of need for additional testing.
Please refer to the attached document '1904651.UK0 - 7899 Consideration of the long term toxicity of Distillates (shale oil)' for further information.
Principles of method if other than guideline:
Shale oil, a UVCB (Unknown or Variable composition, Complex reaction products or Biological materials) substance mainly consisting of hydrocarbons, is produced by VKG Oil and marketed in three shale oil fractions: a Light, Middle and Heavy fraction.
Given the supply levels of these fractions, the performance of a repeated-dose sub-chronic oral (90-day) and an extended one-generation reproductive toxicity study (EOGRTS) for each shale oil fraction, is triggered. Nevertheless, VKG Oil proposed to test only the Heavy shale oil fraction and apply the endpoints to all three shale oil fractions.
ECHA studied this proposal and issued a Draft decision on the testing proposal for each fraction, not accepting that the Heavy fraction results would represent a worst-case result for the Light and Middle fractions.
From the responses, it is evident that although ECHA’s concerns are at first glance reasonable, scientific evidence gives confidence in the proposed read-across.
More specifically, the Heavy fraction can be considered to offer worst-case results to the Light and Middle fraction when tested for repeated-dose toxicity (90-day oral study). Furthermore, the Heavy fraction can be considered as worst case when tested for reproductive toxicity (EOGRTS).

In order to allay the concerns regarding human health safety, VKG Oil makes a new proposal, according to which no further animal testing is performed, and VKG Oil adopts a conservative classification and labelling regarding human health effects:

Risk assessment is performed based on the most toxicologically relevant component, benzo(a)pyrene. Classification and DNELs can be derived based on calculation from the OEL recognised at European level. Even at 12% , the presence of PAHs are still the only component that need to be taken into consideration in the derivation of DNELs, because comparison of existing reference doses and exposure limits show that for PAHs are 10,000 lower than next lowest reference dose i.e. extrapolating the OEL for each oil fraction from the PAH content still results in the lowers OEL, than if were done based on the content of the remaining materials. See the attached document: "Shale oil: comments on ECHA’s Draft decision".
Reproductive effects observed:
not specified
Additional information

Risk assessment is performed based on the most toxicologically relevant component, benzo(a)pyrene. Classification and DNELs can be derived based on calculation from the OEL recognised at European level. Even at 1% , the presence of PAHs are still the only component that need to be taken into consideration in the derivation of DNELs, because comparison of existing reference doses and exposure limits show that for PAHs are 10000 lower than next lowest reference dose i.e. extrapolating the OEL for each oil fraction from the PAH content still results in the lowers OEL, than if were done based on the content of the remaining materials. See the attached document: "Shale oil: comments on ECHA’s Draft decision". 

See the attached document: "Shale oil: comments on ECHA’s Draft decision".

Effects on developmental toxicity

Description of key information

Developmental toxicity (rat)


Under the conditions of the study the No Observed Adverse Effect Level (NOAEL) for maternal toxicity was 250 mg/kg bw/day. The NOAEL for embryofoetal development was 50 mg/kg bw/day and the NOAEL for teratogenic effects was 100 mg/kg bw/day, the highest dose level tested.


Developmental toxicity (rabbit)


According to column 2 of REACH Annex X, information requirement 8.7.2, a study does not need to be conducted if the substance is known to cause developmental toxicity meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage the unborn child (H360D), and the available data are adequate to support a robust risk assessment. Since the registered substance is reasonably known to be toxic for reproduction category 1B, and specifically may damage the unborn child (H360D), and bearing in mind the exposure assessment indicates no risk (due to the operational controls and risk management measures that are implemented), further testing for developmental toxicity is neither considered necessary nor considered to be an expedient or responsible use of animals.


Additionally, column 2 of REACH Annex X further stipulates that additional reproductive toxicity studies do not need to be conducted if the substance is known to be a genotoxic carcinogen and/or a known germ cell mutagen and appropriate risk management measures are implemented. Since the registered substance is reasonably known to be carcinogenic and mutagenic (category 1B), and since appropriate risk management measures are implemented, this further substantiates the lack of need for additional testing.


 


Please refer to the document ‘Consideration of the long term toxicity of Distillates (shale oil)’, as included in section 13, for further information.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available study was conducted under GLP conditions and in accordance with internationally recognised guideline OECD 414. It was therefore assigned a reliability score of 1 in line with the criteria outlined in Klimisch et al. (1997). A further OECD 414 is required to confirm there is no greater sensitivitiy in a second species, along with an OECD 416 study to investigate reproductive effects.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental toxicity (rat)


The developmental toxicity of the test material was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guidelines OECD 414 and EU Method B.31.


During the study, the test material was administered by oral gavage to groups of mated female Wistar rats at dose levels of 0 (corn oil vehicle control), 50, 100 and 250 mg/kg bw/day. The females received treatment from day 6 to day 19 post coitum. During the treatment period the females were observed for mortality and morbidity as well as for any adverse clinical signs. Body weights and food consumption were recorded. On day 20 post coitum the females were sacrificed, subjected to necropsy and the foetuses removed by caesarean section. Post mortem examination included a gross macroscopic examination of all internal organs with emphasis on the uterus, uterine contents, position of foetuses in the uterus and the number of corpora lutea were counted and recorded.


Foetuses were removed from the uterus, sexed, weighed individually, examined for gross external abnormalities and then sacrificed. Half of the litter was subjected to skeletal examination while the other half was subjected to visceral examination.


Treatment caused salivation at 50 and 250 mg/kg bw/day, mainly at 250 mg/kg bw/day in a dose-dependent manner. Slightly lower food consumption and lower body-weight gain were observed in all test material-treated groups. These values did not deviate by more than 11, 8 and 13 % from the control group for food consumption and by more than 5, 5 and 6 % for body weight, at 50, 100 and 250 mg/kg bw/day.


In the observations deriving from the hysterectomies, test material-related embryofoetal toxicity was observed at 250 mg/kg bw/day with an increase in post-implantation losses.


Treatment led to a decrease in mean foetal body weight in all test material-treated groups. These values did not deviate by more than 6 % at 50 mg/kg bw/day and 14 % at 100 and 250 mg/kg bw/day. At the external examination, no findings were recorded.


The skeletal examination of the foetuses did not reveal any toxicologically relevant alterations. The slight delay in ossification in some litters at 100 and 250 mg/kg bw/day compared to the control group can be considered a variation without pathological meaning and secondary to lower foetal body weight.


The visceral examination revealed the following: at 250 mg/kg bw/day there were five litters with one foetus each with abnormalities: three foetuses with diaphragmatic hernia, one foetus with asymmetric nasal septum and one foetus with oval-shaped eyes; at 100 mg/kg bw/day one foetus had abnormality with dilation of cerebral aqueduct; at 50 mg/kg bw/day one foetus had abnormalities, such as severe dilation of cerebral ventricles, no recognisable ocular structures and asymmetry of nasal structures. Finally, two litters from the control group showed abnormalities, i.e. one foetus with oval shaped lens and one foetus with interrupted ureter and renal pelvis severely dilated.


The diaphragmatic hernia could be considered related to the test material as it was only observed at 250 mg/kg bw/day. There was no evidence of a compound-related effect in the number of occurrences in the remaining abnormalities found in the test material-treated groups.


Furthermore, there was an increase in the incidence of common variations, such as left-sided umbilical artery and bilateral azygos vein, in the test material-treated groups. Other common variations, mainly involving urogenital morphology (dilated renal pelvis, and dilated and/or convoluted ureter, malpositioned kidney, malpositioned cranial testis) in addition to other findings (additional small lobe and dark-area in the liver) were recorded in all groups including the control group. These alterations should be regarded as spontaneous variations with limited pathological relevance.


Therefore, based on the results of this study, the top dose tested of 250 mg/kg bw/day is considered the No Observed Adverse Effect Level (NOAEL) for maternal toxicity. Although there were decreases in food consumption and body weight at 250 mg/kg bw/day, the decreases in body weight gain were not greater than 5 - 6 %.


With respect to the effects on embryofoetal development, 50 mg/kg bw/day is considered to be the NOAEL based on the lower foetal body weight (14 %) at 100 and 250 mg/kg bw/day and the increase in the post-implantation losses at 250 mg/kg bw/day.


Regarding the potential for teratogenic effects, 100 mg/kg bw/day is considered to be the NOAEL based on the diaphragmatic hernia recorded at 250 mg/kg bw/day.


 


 


Developmental toxicity (rabbit)


According to column 2 of REACH Annex X, information requirement 8.7.2, a study does not need to be conducted if the substance is known to cause developmental toxicity meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage the unborn child (H360D), and the available data are adequate to support a robust risk assessment. Since the registered substance is reasonably known to be toxic for reproduction category 1B, and specifically may damage the unborn child (H360D), and bearing in mind the exposure assessment indicates no risk (due to the operational controls and risk management measures that are implemented), further testing for developmental toxicity is neither considered necessary nor considered to be an expedient or responsible use of animals.


Additionally, column 2 of REACH Annex X further stipulates that additional reproductive toxicity studies do not need to be conducted if the substance is known to be a genotoxic carcinogen and/or a known germ cell mutagen and appropriate risk management measures are implemented. Since the registered substance is reasonably known to be carcinogenic and mutagenic (category 1B), and since appropriate risk management measures are implemented, this further substantiates the lack of need for additional testing.


 


Please refer to the document ‘Consideration of the long term toxicity of Distillates (shale oil)’, as included in section 13, for further information.

Justification for classification or non-classification

The substance is classified as toxic for reproduction (category 1B FD) in consideration of the presence of polyaromatic hydrocarbons (PAHs) analysed in the substance at a level greater than the generic cut-off limits for classification for reproductive toxicity. PAHs are widely acknowledged to possess CMR properties. The harmonised classification of the PAH substance benzo[a]pyrene is applied to this substance as it has been established that this substance is considered to be representative of the PAHs contained within the registered substance. Furthermore, the hazard of benzo[a]pyrene is well established in light of the wealth of toxicological data that are available on the substance.


Please refer to the document ‘Consideration of the long term toxicity of Distillates (shale oil)’, as included in section 13, for further information.