Fuels, diesel, co-processed with hydrocarbons derived from thermally cracked waste plastics

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study planned (based on read-across)

Study period:

Subject to approval following ECHA/MSCA review of this testing proposal

Justification for type of information:

***The following testing proposal has been prepared by Concawe and includes (but is not limited to) the source substances for EC 951-495-3***
TESTING PROPOSAL ON VERTEBRATE ANIMALS

[Please provide information for all of the points below. The information should be specific to the endpoint for which testing is proposed. Note that for testing proposals addressing testing on vertebrate animals under the REACH Regulation this document will be published on the ECHA website along with the third-party consultation on the testing proposal(s).]

NON-CONFIDENTIAL NAME OF SUBSTANCE:

These tests are proposed to be conducted on three members of the VHGO category, (one robust study has already been identified on EC 269-822-7/CAS 68334-30-5 Fuels, diesel) with the results then read-across to other category members. Brief justification is given below, with additional support for the category given in the category justification document (attached to the category object and to Section 13 of the dossier) and in the document "VHGO strategy Oct 2019" attached below in the "attached justification" field.

Repeat dose toxicity (90-day OECD 411 study) with the following registered substances;
- EC 265-059-9/CAS 64741-58-8 Gas oils (petroleum), light vacuum
- EC 270-673-5/CAS 68476-31-3 Fuel oil, no. 4
- EC 265-078-2/CAS 64741-77-1 Distillates (petroleum), light hydrocracked

Repeat dose toxicity (90-day OECD 408 study) with the following registered substances;
- EC 265-059-9/CAS 64741-58-8 Gas oils (petroleum), light vacuum

In addition, it is anticipated that these results will allow read-across to the to the following CAS numbers:
- EC 270-671-4/CAS 68476-30-2 Fuel oil, no. 2
- EC 270-676-1/CAS 68476-34-6 Fuels, diesel, no. 2
- EC 265-049-4/CAS 64741-49-7 Condensates (petroleum), vacuum tower
- EC 265-190-1/CAS 64742-87-6 Gas oils (petroleum), hydrodesulfurized light vacuum
- EC 295-407-5/CAS 92045-24-4 Gas oils (petroleum), hydrotreated light vacuum

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION

[please address all points below]:

- Available GLP studies

Vacuum gas oils, hydrocracked gas oils and distillate fuels (VHGOs) are part of the larger group of petroleum substances defined as Gas Oils which are consistently distilled between the lighter stream (lower boiling pt) of Kerosine and the heavier stream (higher boiling pt) of Fuel Oil.

VHGO’s are complex petroleum substances (they are considered UVCB’s) and the hydrocarbons present are predominantly in the range of C9-C30 and can be broadly characterized into a number of distinct hydrocarbon classes, namely Aliphatics, consisting of paraffinics (n-alkanes), iso-paraffinics (branched alkanes), naphthenics (cycloalkanes), and Aromatics, consisting of mono-aromatics, di-aromatics and poly-aromatics. The category consists of 9 registered substances.

For compliance with all other regulatory regimes, petroleum substances (PS) have been tested via the dermal and/or inhalation route as this is the route of human exposure; this is also an objective of REACH which states that tests should be done by the ‘most appropriate route of administration, having regard to the likely route of human exposure’. This has allowed successful risk management of these substances and avoids the uncertainty of route-to route extrapolation which is required if the oral route is used.
There are several existing repeated dose studies via all three routes of exposure, with the majority of testing conducted by the dermal route (expected to be the most relevant to human exposure). Of these, the following are considered the most relevant:
- Dermal 90-day: Current Key Study on EC /CAS 6474149-7 (1989 NOAEL 30 mg/kg/day)
- Dermal 90-day: Modern study on EC 269-822-7/CAS 68334-30-5 (2012 NOAEL 600 mg/kg/day)
- Inhalation 90-day: Current Key Study on EC 269-822-7/CAS 68334-30-5 (1984 Systemic NOAEC > 1710 mg/m3
- Oral 90-day: out of category read-across on EC 232-366-4/CAS 8008-20-6 (2000 NOAEL 750 mg/kg/day)
- Oral Chronic study: out of category read-across on EC 232-455-8/CAS 8042-47-5 (2004 NOAEL > 1200 mg/kg/day)
The two studies listed as out of category read-across are intended as supporting studies; these two categories do not contain significant quantities of PAH constituents that are expected to drive toxicity in the VHGO category. They help to demonstrate that the remaining pools of constituents are unlikely to cause significant concern for human health.
It is considered appropriate to improve the quality of VHGO category database and to help justify read-across used in other endpoints by conducting three 90-day dermal toxicity tests and one 90-day oral toxicity test on substances within the VHGO category.

Concawe intend to take a holistic approach to the risk assessment and management process of Petroleum Substances and this involves a program to support grouping and read across with a targeted testing strategy. The tests proposed for this category are part of that strategy. The CAS numbers listed above have been selected from the VHGO category because they represent samples containing a high percentage of poly-aromatic hydrocarbons (PAH) with more than 3 cyclic rings (considered to be the constituent pool driving toxicity) and other constituent pools to cover the chemical space in the category. Based on evidence in the literature, previous, and on-going, investigative work, Concawe have a working hypothesis that systemic and reproductive toxicity observed with some petroleum streams is associated with the presence of >3-ring PAHs. Initial results coming from one of these multi-year research projects, which aims to underpin the reprotox testing hypothesis using a battery of in-vitro assays, provides further support for this hypothesis[1].

As part of this testing proposal Concawe have developed a testing strategy for petroleum substances which has been applied to the VHGO category – this testing proposal should not be considered in isolation.

For more information see “overall comments” below.

- Available non-GLP studies

There are existing studies that can help to provide supporting information for this endpoint, but additional information is required to provide robust category data.

- Historical human data

No relevant human health data are available.

- (Q)SAR

There are no QSAR’s which are adequate to fully evaluate the 90-day endpoint nor a UVCB substance.

- In vitro methods

Currently, no available alternatives to animal testing are considered adequate to be used on their own for regulatory purposes for detecting toxicity after repeated exposure[2].

- Weight of evidence

There is insufficient data at this point to build a weight of evidence argument to address the repeated dose endpoint for this CAS number. The information from these studies will be part of the data which will support grouping and read across, this data will be used in weight of evidence arguments for remaining VHGOs in this category.

- Grouping and read-across

There are 9 registered CAS numbers in the Vacuum Gas Oils, Hydrocracked Gas Oils & Distillate Fuels (VHGO) category. It is the intention that the 90-day data from these studies will be applied to the remaining VHGO category members therefore reducing the need for animal tests. Together with detailed analytical data and in vitro data from ongoing Concawe programs including the Cat-App project, these studies will be used to demonstrate chemical-biological similarity, and underpin read-across of data applicable to registrations of substances covering the CAS numbers in this category.

For more information on Cat-App and other ongoing initiatives to further support grouping of petroleum substances and read across assessments, see “general comment” below.

- Substance-tailored exposure driven testing [if applicable]

Not applicable

- Approaches in addition to above [if applicable]


• There is a large existing data base of repeat dose dermal and inhalation studies for Petroleum Substances which is used for risk assessment. However, the value of some of this existing database has been questioned on the basis of lesser requirements for test substance identity at the time the testing was conducted. If the data from these dermal studies shows a similar pattern of toxicity (or absence of toxicity) then this will support the value of this existing data for hazard identification.

- Other reasons [if applicable]

Not applicable

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VII TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:

Adaptation options as defined in Annexes VII to X were not applicable for this category and this endpoint. Regarding the column 2 rules for adaption, the data base was fully evaluated according to ‘Guidance on information requirements and Chemical Safety Assessment Chapter R.7a: Endpoint specific guidance’.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:

- Overall comment and further information

With the aim to minimize -and avoid unnecessary- animal testing (on all 192 petroleum substances) while not underestimating the potential human health risks, a testing approach and overall informed tiered testing strategy is proposed holistically across the entire portfolio of petroleum substances. Targeted CAS numbers will be subject to in-vivo testing covering all Concawe petroleum categories following a scientifically supported grouping and read across approach. These 90-day studies are an important part of that strategy.

This single testing proposal should not be viewed in isolation, it should be considered as part of Concawes overall testing proposal, following the overall Concawe testing strategy for petroleum substances and the VHGO category, more detailed information on the proposed testing for this category is referred to the document "VHGO strategy Oct 2019" attached below in the "attached justification" field.

For more information on the way Concawe is aiming to reduce animal testing for the hazard evaluation of petroleum products under REACH, please contact [e-mail] and see for example www.concawe.eu/cat-app, amongst other ongoing efforts to further underpin grouping, read across and testing hypotheses.

[1] Kamelia et al 2017. Prenatal developmental toxicity testing of petroleum substances: Application of the mouse embryonic stem cell test (EST) to compare in vitro potencies with potencies observed in vivo. Toxicol In Vitro. 2017 Oct;44:303-312.

[2] Chapter R.7a: Endpoint specific guidance Version 4.1 – July 2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Test material

Test material information

Constituent 1

Reference substance name:

Gas oils (petroleum), light vacuum

EC Number:

265-059-9

EC Name:

Gas oils (petroleum), light vacuum

Cas Number:

64741-58-8

IUPAC Name:

Gas oils (petroleum), light vacuum

Specific details on test material used for the study:

Test material is an example of one of the substances expected to be used in the planned studies.

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The species of rat is commonly used in repeated dose testing.