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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was GLP compliant and was conducted generally according to OECD 414 guidelines.
Justification for type of information:
HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
Petroleum substances of the OtherGO category are UVCB substances grouped within established production boundaries based on phys-chem properties and hydrocarbon type (a full justification for this grouping is given in the category justification document attached to the category object and to Section 13 of this dossier); substances within the OtherGO category have qualitatively similar properties. The prediction for read-across of hazard information on relevant human health endpoints in the category will be based on what is considered to be the worst-case substance.

The registered substances of the OtherGO category comprise complex combinations of hydrocarbon constituents. Based on boiling point distribution, the hydrocarbons present will be predominantly in the range of C11-C25 (boiling in the range of 205-400 0C) and can be broadly characterized into distinct hydrocarbon classes, namely aliphatics and aromatics. As described in more detail in the document attached below (“PAH hypothesis Nov 2018”), there are sufficient data showing that the aliphatic constituents of petroleum substances are not developmental toxicants, do not affect fertility, and do not produce reproductive organ toxicity (references to these data are included in Section 2 of the attached document). For aromatic molecules, data indicate that mainly 3-7 ring polycyclic aromatic compounds (PACs) may be associated with reproductive toxicity. These data include high boiling petroleum products with a relatively high level of PACs which do show potential for reproductive toxicity, whereas effects are absent in similar products without PACs.

It is therefore hypothesised that the reproductive toxicity of OtherGO will be related to the types and levels of aromatics present, and will generally follow a pattern of increasing severity with increased percentage of 3 – 7 ring PACs. Any trend for the developmental toxicity of gas oils would thus be hypothetically described in terms of increasing aromatic content and number of fused aromatic rings. For OtherGO specifically, the content of PACs relate to the refining stream from which the substances are produced – which can be a carcinogenic or non-carcinogenic feedstock. The first is already classified carcinogenic 1B, whereas the non-carcinogenic feedstock does not have high levels of 3+-ring PACs, and for these it is hypothesised that there is low potential for adverse effects in developmental reproductive toxicity tests from exposure to OtherGOs.

In conclusion, there is a hypothetical case to suggest that any developmental reproductive effects observed in petroleum substances are associated with 3 – 7 ring PACs, and there is in-vitro and in-vivo toxicity data to support this hypothesis. However, there is no comprehensive investigation of fertility and the implications of interaction with the AhR receptor, which is thought to be a critical step in the underlying mechanism of action for these effects. Currently, Concawe has several research efforts ongoing to further support these hypotheses for reproductive toxicity; results will be published in peer reviewed scientific journals and will be submitted in future dossier updates as they come available.

CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL)
Crude oil (Petroleum, CAS 8002-05-9) is a complex combination of hydrocarbons, a so called UVCB (unknown variable composition, complex reaction products, biological materials) extracted in its natural state from the ground. It consists predominantly of aliphatic, alicyclic and aromatic hydrocarbons. It is used as a feedstock for petroleum refining operations, which separate and convert it into UVCB fractions (petroleum streams) as shown in the diagram in the attached document. Gas Oils (SRGO, OtherGO and VHGO) are one of these streams and are consistently distilled between the lighter stream (lower boiling pt) of Kerosine and the heavier stream (higher boiling pt) of Fuel Oil (all gas oils have an approximate carbon range of C9-C30 with SRGO at the lighter- and VHGO at the heavier end). Therefore only the hydrocarbon constituents present in crude oil that come off at this specific boiling point range will be present in OtherGO with some overlap between neighbouring streams. They will share some common molecule types, which can give us some indication to the (reproductive) toxicity potential of OtherGO substances when this information is available for these related streams.

For this end point (rodent developmental toxicity) read-across to CAS No. 64741-43-1, a member of the Straight Run Gas Oils (SRGO) is proposed. As noted above SRGO are closely related to OtherGO, sharing many similar molecules and can provide us with useful information on potential toxicity. Information for this endpoint will be supported with information on rodent developmental toxicity from within the Other Go category, including the following:
• Rat OECD 422 (screening studies for reproductive and repeat dose toxicity) for all 3 Other Go category members
• The embryonic stem cell test (EST) and a number of other in-vitro tests to assess the prenatal developmental toxicity hazard (such as the zebra fish embryo test and various receptor binding assays) will be conducted for all CAS numbers. The EST test has been validated by ESAC (2002) [1] and is recommended as part of an integrated strategy [2] to address developmental toxicity. The test can be used as a predictive test and/or part of the ‘weight of evidence’ for addressing the endpoint of developmental toxicity in REACH [3].
• A Rat OECD 443 (Extended One Generation Reproductive Study) with CAS number 64742-79-6

Information for this read-across to the SRGO category will be supported with the following information:
• OECD 422 (screening studies for reproductive and repeat dose toxicity) for some SRGO category members. This will allow comparison of toxicity endpoints across the categories
• The EST as mentioned above will again allow a comparison across the categories.
• CatApp data which is aiming to develop a framework to support chemical-biological grouping and read-across of PS. In addition, initial data coming out of Cat-App provide further support that grouping of substances may indeed be dependent on their refining history and the percentage of PAH.
• Analytical data, for comparison across categories.

It should be noted that the in vivo work mentioned above is part of Concawe’s overall Human Health strategy, and is still to be initiated. In the first instance Concawe would like to explore building a robust argument for read-across using this data (when it is available), before initiating additional animal studies. However, Concawe accept that if this is not possible then a testing proposal for a rodent developmental toxicity study will be required.
See Category Justification Document for more detailed information.

[1] https://eurl-ecvam.jrc.ec.europa.eu/about-ecvam/archive-publications/publication//Embryotoxicity_statements.PDF
[2] Document of the subgroup ‘reproductive and developmental toxicity’ ECVAM-JRC
[3] https://echa.europa.eu/documents/10162/23047722/ir_csa_r7a_r76_reprotox_draft_en.pdf/e4ab36a5-e3d4-456c-b1d3-d9efcba31001

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
64741-43-1
Cas Number:
64741-43-1
IUPAC Name:
64741-43-1
Constituent 2
Reference substance name:
Straight-run petroleum gas oil,
IUPAC Name:
Straight-run petroleum gas oil,
Test material form:
other: low viscosity liquid hydrocarbon
Details on test material:
Sample F193
Straight Run Gas Oil
CAS 64741-43-1
Appearance: brown to black-coloured liquid; slightly cracked or burnt to asphaltic odour
Details of this material from MSDS:
Flash point: 150 °F
Boiling range: 320 - 800 °F
Autoignition T: 505 °F
Flammable limits: 0.7-6 % volume in air
Specific gravity: 0.89 - 0.95
Viscosity at 100°F: 200-2000 SUS
Reid Vapour pressure at 100°F: 0.1 psia
Vapour specific gravity: 10.0

Test animals

Species:
rat
Strain:
other: Crl:CD BR VAF/Plus

Administration / exposure

Route of administration:
dermal
Vehicle:
acetone
Duration of treatment / exposure:
Days 0 through 19 of gestation
Frequency of treatment:
Daily
Duration of test:
Days 0 through 20 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 250, or 500 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
25 dams per dose
Control animals:
yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Effect levels (fetuses)

Remarks on result:
other: see Details on embyotoxic/teratogenic effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The maternal LOAEL was 50 mg/kg/day, based on dermal effects. There was no maternal NOAEL. The developmental LOAEL was 250 mg/kg/day, based on pup body weight and malformations. The developmental NOAEL was 50 mg/kg/day.
Executive summary:

In a developmental toxicity study, straight-run petroleum gas oil (F-193) in acetone was dermally administered to 25 presumed pregnant rats/dose at dose levels of 0, 50, 250, or 500 mg/kg bw/day from days 0 through 19 of gestation.

 

Skin reactions (erythmea, oedema, atonia, and desquamation) occurred in all treatment groups. There was a significant reduction in body weight and feed consumption in the 250 - and 500 -mg/kg/day groups.  There was also a significant reduction in average litter size and live foetuses, increased resorptions in these groups.  The maternal LOAEL was 50 mg/kg/day, based on dermal effects. There was no maternal NOAEL. 

There was a significant decrease in pup body weight and increase in external, visceral, and skeletal malformations in the mid- and high-dose groups. The developmental LOAEL was 250 mg/kg/day, based on pup body weight and malformations The developmental NOAEL was 50 mg/kg/day.

 

This study received a Klimisch score of one and is classified as reliable without restrictions because it was GLP compliant and was generally conducted according to OECD 414 guidelines.