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Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening tests (OECD 422) were conducted with oral (gavage) exposure to rats of 6 UVCB streams that represent the compositional space of LOA Category L Resin Oils and Cyclic Dienes category. The substances tested that represent the category boundary were:

 

• L-02 – Naphtha (petroleum), steam-cracked, C8-11 aromatic hydrocarbon and cycloalkadiene fraction (CAS N/A; EC 701-462-2)


• L-03 – Extract residues (coal), light oil alk., acid ext., indene fraction (CAS 101316-62-5; 309-867-2)


• L-04 – Alkenes, C9-11, C10-rich (CAS 68526-56-7; EC 271-213-6)


• L-05 – Distillates (petroleum), steam-cracked, C8-12 fraction (CAS 68477-54-3; EC 270-737-2)


• L-09 Equivalent – Naphtha (petroleum), light steam-cracked, debenzenized, C8-16-cycloalkadiene conc. (CAS 68478-10-4; EC 270-790-1)*


• L-11 Equivalent – Solvent naphtha (coal) (CAS 65996-79-4; EC 266-013-0)**

 

* The testing material described here as “L-09 Equivalent” was reported in the study with descriptors as listed here - Naphtha (petroleum), light steam-cracked, debenzenized, C8-16-cycloalkadiene conc. (CAS 68478-10-4; EC 270-790-1) – but as the composition was not fully described in the report, it has been described here as an equivalent stream. Statistical analysis of the composition has demonstrated that it groups with L-09 and other similar streams.

 

** The testing material described here as “L-11 Equivalent” was reported in the study with the CAS number 68477-54-3 (“Distillates (petroleum), steam-cracked, C8-12 fraction”). This CAS number was given the code L-05 in the initial metabolomics studies performed by LOA, and in subsequent analyses. However, statistical analysis of the composition of this testing material compared with the compositions of other testing materials used in studies performed using Category L UVCB streams have demonstrated that this stream analytically resembles the stream L-11. For this reason, we have described it here as L-11 Equivalent, to ensure that compositions are adequately evaluated rather than descriptors. Further information on this is available in the LOA testing strategy attached in Section 13.2.

 

There were no effects on reproductive performance in any of the substances tested that was not accompanied by significant parental toxicity. Discussed in greater detail in “Additional Information”.

 

The parental NOAEL, reproductive toxicity NOAEL and Developmental toxicity NOAEL data are summarised in the table:

 

Substance/Dose	NOAEL mg/kg/day	Comment
L-02: Naphtha (petroleum), steam-cracked, C8-11 aromatic hydrocarbon and cycloalkadiene fraction (CAS 68516-20-1) 0, 60, 200, 600 mg/kg/day	Parental NOAEL at least 600	No parental NOAEL could be established in the absence of α2u globulin nephropathy.
	Reproductive NOAEL600	Based on oestrous cycle irregularity
	Developmental NOAEL600	Based on pup mortality and lower pup body weights
L-03: Extract residues (coal), light oil alk., acid ext., indene fraction (CAS 101316-62-5; 309-867-2) 0, 30, 100, 300 mg/kg/day	Parental NOAEL300	No parental NOAEL could be established in the absence of α2u globulin nephropathy.
	Reproductive NOAEL300	No reproductive NOAEL could be established in the absence of any adverse effects
	Developmental NOAEL100	Based on lower pup body weights
L-04: Alkenes, C9-11, C10-rich (CAS 68526-56-7) 0, 25, 70, 200/140 mg/kg/day	Parental NOAEL70	Based on reduced food consumption and reduced body weight gain, piloerection and hunched posture at the top dose
	Reproductive NOAEL70	Based on estrous cycle and a reduced number of implantation sites
	Developmental NOAEL25	Based on mortality and cumulative survival index
L5: Distillates (petroleum), steam-cracked, C8-12 fraction (CAS 68477-54-3; EC 270-737-2) 0, 60, 200, 600 mg/kg/day	Parental NOAEL600	No parental NOAEL could be established in the absence of α2u globulin nephropathy.
	Reproductive NOAEL600	No reproductive NOAEL could be established in the absence of any adverse effects
	Developmental NOAEL200	Based on the lower pup body weights
L-09: Naphtha (petroleum), light steam-cracked, debenzenized, C8-16-cycloalkadiene conc. 0, 5 25, 100 mg/kg/day	Parental NOAEL5	Based upon potentially adverse follicular cell hypertrophy in the thyroid gland
	Reproductive NOAEL100	No reproductive NOAEL could be established in the absence of any adverse effects
	Developmental NOAEL100	No developmental NOAEL could be established in the absence of any adverse effects
L-11: Solvent naphtha (coal) (CAS 65996-79-4; EC 266-013-0) 0, 35 125, 375 mg/kg/day	Parental NOAEL125	Based upon potentially adverse follicular cell hypertrophy in the thyroid gland
	Reproductive NOAEL375	No reproductive NOAEL could be established in the absence of any adverse effects
	Developmental NOAEL125	Based on lower pup body weights

 

Additional information

Reproductive data are available from OECD 422 combined repeated-dose/reproduction/developmental toxicity studies for 6 UVCB streams within Category L, which comprise all of the compositional space for the category. In two of the streams tested, estrous cycles were perturbed by administration of the test item, and this was considered adverse. Both of the streams in which estrous cycle effects were described as adverse - Alkenes C9-11 C10-rich and Naphtha (petroleum), steam-cracked, C8-11 aromatic hydrocarbon and cycloalkadiene fraction – are notable for containing 75% and 20% DCPD respectively. For Alkenes C9-11 C10-rich, this occurred at concentrations in which severe parental systemic toxicity was also noted, and this may have contributed to this effect. In Alkenes C9-11 C10-rich, the number of implantation sites was adversely decreased.

 

Existing data from reproductive toxicity studies on DCPD did not examine the estrous cycle, so the direct contribution of DCPD cannot be determined. Naphtha (petroleum), steam-cracked, C8-11 aromatic hydrocarbon and cycloalkadiene fraction also contains a number of other aromatic constituents, notably styrene, ethylbenzene and the three isomers of xylene. However, reproductive screening data from these have not indicated an issue with estrous cycling. No other toxicologically relevant effects on the reproductive system were detected in these screening studies.

 

Further extended one-generation toxicity studies are proposed for Category L UVCB streams according to the testing strategy set out in Section 13.2.

Effects on developmental toxicity

Description of key information

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening tests (OECD 422) were conducted with oral (gavage) exposure to rats of 6 UVCB streams that represent the compositional space of LOA Category L Resin Oils and Cyclic Dienes category. The substances tested that represent the category boundary were:

 

• L-02 – Naphtha (petroleum), steam-cracked, C8-11 aromatic hydrocarbon and cycloalkadiene fraction (CAS N/A; EC 701-462-2)


• L-03 – Extract residues (coal), light oil alk., acid ext., indene fraction (CAS 101316-62-5; 309-867-2)


• L-04 – Alkenes, C9-11, C10-rich (CAS 68526-56-7; EC 271-213-6)


• L-05 – Distillates (petroleum), steam-cracked, C8-12 fraction (CAS 68477-54-3; EC 270-737-2)


• L-09 Equivalent – Naphtha (petroleum), light steam-cracked, debenzenized, C8-16-cycloalkadiene conc. (CAS 68478-10-4; EC 270-790-1)*


• L-11 Equivalent – Solvent naphtha (coal) (CAS 65996-79-4; EC 266-013-0)**

 

* The testing material described here as “L-09 Equivalent” was reported in the study with descriptors as listed here - Naphtha (petroleum), light steam-cracked, debenzenized, C8-16-cycloalkadiene conc. (CAS 68478-10-4; EC 270-790-1) – but as the composition was not fully described in the report, it has been described here as an equivalent stream. Statistical analysis of the composition has demonstrated that it groups with L-09 and other similar streams.

 

** The testing material described here as “L-11 Equivalent” was reported in the study with the CAS number 68477-54-3 (“Distillates (petroleum), steam-cracked, C8-12 fraction”). This CAS number was given the code L-05 in the initial metabolomics studies performed by LOA, and in subsequent analyses. However, statistical analysis of the composition of this testing material compared with the compositions of other testing materials used in studies performed using Category L UVCB streams have demonstrated that this stream analytically resembles the stream L-11. For this reason, we have described it here as L-11 Equivalent, to ensure that compositions are adequately evaluated rather than descriptors. Further information on this is available in the LOA testing strategy attached in Section 13.2.

 

There were no effects on reproductive performance in any of the substances tested that was not accompanied by significant parental toxicity. Discussed in greater detail in “Additional Information”.

 

The parental NOAEL, reproductive toxicity NOAEL and Developmental toxicity NOAEL data are summarised in the table:

 

Substance/Dose	NOAEL mg/kg/day	Comment
L-02: Naphtha (petroleum), steam-cracked, C8-11 aromatic hydrocarbon and cycloalkadiene fraction (CAS 68516-20-1) 0, 60, 200, 600 mg/kg/day	Parental NOAEL at least 600	No parental NOAEL could be established in the absence of α2u globulin nephropathy.
	Reproductive NOAEL600	Based on oestrous cycle irregularity
	Developmental NOAEL600	Based on pup mortality and lower pup body weights
L-03: Extract residues (coal), light oil alk., acid ext., indene fraction (CAS 101316-62-5; 309-867-2) 0, 30, 100, 300 mg/kg/day	Parental NOAEL300	No parental NOAEL could be established in the absence of α2u globulin nephropathy.
	Reproductive NOAEL300	No reproductive NOAEL could be established in the absence of any adverse effects
	Developmental NOAEL100	Based on lower pup body weights
L-04: Alkenes, C9-11, C10-rich (CAS 68526-56-7) 0, 25, 70, 200/140 mg/kg/day	Parental NOAEL70	Based on reduced food consumption and reduced body weight gain, piloerection and hunched posture at the top dose
	Reproductive NOAEL70	Based on estrous cycle and a reduced number of implantation sites
	Developmental NOAEL25	Based on mortality and cumulative survival index
L5: Distillates (petroleum), steam-cracked, C8-12 fraction (CAS 68477-54-3; EC 270-737-2) 0, 60, 200, 600 mg/kg/day	Parental NOAEL600	No parental NOAEL could be established in the absence of α2u globulin nephropathy.
	Reproductive NOAEL600	No reproductive NOAEL could be established in the absence of any adverse effects
	Developmental NOAEL200	Based on the lower pup body weights
L-09: Naphtha (petroleum), light steam-cracked, debenzenized, C8-16-cycloalkadiene conc. 0, 5 25, 100 mg/kg/day	Parental NOAEL5	Based upon potentially adverse follicular cell hypertrophy in the thyroid gland
	Reproductive NOAEL100	No reproductive NOAEL could be established in the absence of any adverse effects
	Developmental NOAEL100	No developmental NOAEL could be established in the absence of any adverse effects
L-11: Solvent naphtha (coal) (CAS 65996-79-4; EC 266-013-0) 0, 35 125, 375 mg/kg/day	Parental NOAEL125	Based upon potentially adverse follicular cell hypertrophy in the thyroid gland
	Reproductive NOAEL375	No reproductive NOAEL could be established in the absence of any adverse effects
	Developmental NOAEL125	Based on lower pup body weights

 

Additional information

Data are available for 6 UVCB streams that comprise the category compositional space, and for specific constituents which are found in the category and which have classifications relevant to developmental toxicity, such as toluene.

 

In the developmental screening component of the OECD 422 studies, adverse decreases in pup weights were seen in studies that represent streams in all compositions at the top dose in each study. In each case though, parental toxicity was described including centrilobular hepatocyte hypertrophy in the liver and significantly decreased overall body weight.

 

For Alkenes, C9-11, C10-rich (high in DCPD), the decrease in pup weight was apparent from the mid-dose, which was 70 mg/kg bw/day. However, this test material was associated with more severe parental toxicity throughout all dose groups, and this is reflected in its DCPD content. In recent OECD 414 studies with DCPD conducted at Charles River Laboratories in 2022, all maternal animals in the top dose group of 100 mg/kg bw/day died prior to the scheduled necropsy due either to severe body weight loss (which may have been the result of lower food consumption). Other effects described as adverse in this study resulted from four litters being either found dead, not being found at all or being sacrificed in extremis. These included a reduction in the viability, cumulative survival and mortality indices which while severe enough to warrant being described as adverse, were not observed in a dose-dependent manner. It is likely that these also resulted from the overall condition of the parental animals. Decreased lower live birth, cumulative survival and viability indices were also decreased for the top dose-group for Naphtha (petroleum), steam-cracked, C8-11 aromatic hydrocarbon and cycloalkadiene fraction, which lists Styrene (21%) and DCPD (20%) as its principle constituents. Styrene has also been associated with decreased pup weights in developmental studies, however this has been attributed also to parental toxicity in studies where this has occurred.

Justification for classification or non-classification

Data available the streams CAS 68477-54-3 (Low Dicyclopentadiene Resin Oil), CAS 68478-10-4 (Dicyclopentadiene/Codimer Concentrate) and on constituent substances indicate that streams within this class that contain less than 5% (EU/DPD) or 3% (GHS/CLP) toluene are not reproductive toxicants and do not require a label for this endpoint.

Resin Oils and Cyclic Dienes streams which contain ≥ 3% toluene should be classified "Suspected of damaging the unborn child" Category 2, H361d according to Reg (EC) 1272/2008.