Hydrocarbons, C5-rich

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Adequate information is available on the constituents to characterise the reproductive hazards of these streams after ingestion.

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

960 mg/m³

Species:

rat

Quality of whole database:

Adequate information is available on the constituents to characterise the reproductive hazards of these streams after inhalation.

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Adequate information is available on the constituents to characterise the reproductive hazards of these streams after skin contact.

Additional information

The available data onstream constituents benzene, cyclohexane and xylenes do not indicate reproductive toxicity of a severity that would warrant classification. However, n-hexane causes specific adverse effects on testes and thus is suspected to have effects on fertility, and toluene is classified as Rep Cat 2 (H361d) according to the CLP Regulation. Therefore, unless n-hexane or toluene are present, Aliphatics and Cyclics C5 and Higher streams are not considered to be reproductive toxicants and no classification or labelling is warranted.

n-Hexane (Classification: Category 2, H361):

Testicular atrophy in male rats is seen after repeated dose oral or inhalation exposure to generally high doses of n-hexane which also produce peripheral neuropathy and other systemic effects.

Toluene (Classification: Category 2, H361d):

There is no evidence that toluene produces malformation in animals or humans. There is some evidence of developmental toxicity (lower body weight at birth and delayed vaginal opening) at toluene exposure concentrations ≥ 1000 ppm, concentrations which are associated with slight maternal toxicity. The NOAEC for developmental and maternal effects is 600 ppm (2261mg/m³) (Thiel and Chahoud, 1997).

Isoprene:

There is no robust study that assesses the reproductive toxicity of isoprene.  However, considering the results of a guideline screening study for the reproduction/developmental toxicity of 1,3-butadiene as being directly relevant to isoprene (2-methyl-1,3-butadiene), the lack of effect of at an exposure concentration of 6000 ppm (13,276 mg/m3) and the fact that isoprene is a mutagenic carcinogen precludes the need for any additional testing.

Short description of key information:
It is recognised that there is a data gap for a multi-generation study (REACH reference 8.7.3). The applicant submits that this study does not need to be conducted as Aliphatics and Cyclics C5 and Higher streams contain at least 0.1% benzene which are known to be mutagenic and carcinogenic. The specific reproduction toxicity data on streams within this category are limited to a single 4 week general toxicity and reproduction/developmental toxicity screening study (OECD 422) by inhalation exposure to rats with Pyrolysis C5 (CAS 68476-55-1). This study showed no evidence of reproduction toxicity at the highest concentration tested (1012 ppm). Data on the fertility of specific constituents present in some streams indicate that only n-hexane possesses specific effects which warrant labelling. Therefore for streams that contain n-hexane at concentrations greater than or equal to 3%, classification is required for effects on fertility.

Justification for selection of Effect on fertility via oral route:
n-Hexane, present in some streams, has been shown to adversely affect fertility. However controls to protect against the carcinogenicity of benzene (present in all streams at 0.1% and above) will mitigate such risks to reproduction.

Justification for selection of Effect on fertility via inhalation route:
n-Hexane, present in some streams, has been shown to adversely affect fertility. However controls to protect against the carcinogenicity of benzene (present in all streams at 0.1% and above) will mitigate such risks to reproduction.

Justification for selection of Effect on fertility via dermal route:
n-Hexane, present in some streams, has been shown to adversely affect fertility. However controls to protect against the carcinogenicity of benzene (present in all streams at 0.1% and above) will mitigate such risks to reproduction.

Effects on developmental toxicity

Description of key information

It is recognised that there is a data gap for a developmental toxicity study (REACH reference 8.7.2). The applicant submits that this study does not need to be conducted as Aliphatics and Cyclics C5 and Higher streams contain at least 0.1% benzene which are known to be mutagenic and carcinogenic. The specific developmental toxicity data on streams within this category are limited to a single 4 week general toxicity and reproduction/developmental toxicity screening study (OECD 422) by inhalation exposure to rats on Pyrolysis C5 (CAS 68476-55-1). This study showed no evidence of developmental toxicity at the highest concentration tested (1012 ppm). Data on the developmental toxicity of specific constituents present in some streams indicate that only toluene is recognised as possessing specific effects which warrant labelling. Therefore for streams that contain toluene at concentrations greater than or equal to 3%, classification is required for developmental toxicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Adequate information is available on the constituents to characterise the developmental hazards of these streams after ingestion.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

32 mg/m³

Species:

rat

Quality of whole database:

Adequate information is available on the constituents to characterise the developmental hazards of these streams after inhalation.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Adequate information is available on the component substances to characterise the developmental hazards of these streams after skin contact

Additional information

The available data on the specific constituents benzene, cyclohexane and xylenes do not reveal developmental toxicity of a severity that would warrant classification. However, data on toluene indicate evidence of developmental toxicity at exposures of ≥ 1000 ppm. Therefore, unless toluene is present, Aliphatics and Cyclics C5 and Higher streams are considered not to be reproductive toxicants and no classification or labelling is warranted.

Toluene (Classification: Category 2, H361d):

There is no evidence that toluene produces malformation in animals or humans. There is some evidence of developmental toxicity (lower body weight at birth and delayed vaginal opening) at toluene exposure concentrations ≥ 1000 ppm, concentrations which are associated with slight maternal toxicity. The NOAEC for developmental and maternal effects is 600 ppm (2261mg/m³) (Thiel and Chahoud, 1997).

Benzene:

The pre-natal developmental toxicity (or teratogenic) potential of benzene inhaled at doses ranging from 1 to 500 ppm by pregnant Sprague-Dawley rats on gestation days 6-15 has been investigated in two studies (Coate et al, 1984; Kuna and Kapp, 1981). No maternal toxicity was observed at 100ppm (Coate et al, 1984) but maternal body weight and bodyweight gain were decreased at 50 and 500 ppm (Kuna and Kapp, 1981). Reduced foetal weight was seen at 100 ppm (Coate et al, 1984) and at 50 and 500 ppm (Kuna and Kapp). Reduced crown rump lengths and associated delay in ossification of extremities and sternebrae were seen in the same foetuses.

Overall, the NOAEC for teratogenicity in the rat was 500 ppm (1600 mg/m³), the NOAEC for maternal and developmental toxicity was 10 ppm (32 mg/m³).

Isoprene:

The relevant study for developmental toxicity was conducted by the NTP (National Toxicology Program, 1989) using the inhalation route of exposure. In this study, female Swiss CD-1 mice were exposed to 0, 280, 1400 or 7000 ppm (i.e. 0, 780, 3900 or 19,503 mg/m3) isoprene for 6 hours/day, 7 days/week on gestational days 6-17. 

Exposure to 7000 ppm isoprene significantly reduced maternal weight gain and uterine weight. Developmental toxicity was evident as a reduction in foetal body weight observed at 280 and 1400 ppm. Increased incidences of variations (i.e. supernumerary ribs) observed in the exposed groups, were considered a secondary non-specific consequence of maternal toxicity. Therefore, 1400 ppm (3900 mg/m3) was the NOAEC for maternal toxicity in mice. A NOAEC for developmental toxicity was not determined in this study because a reduction in foetal bodyweight was observed at the lowest exposure concentration tested, at 280 ppm (780 mg/m3). 

In the same study, female Sprague-Dawley rats were exposed to 0, 280, 1400 or 7000 ppm (i.e. 0, 780, 3900 or 19,503 mg/m3) isoprene for 6 hours/day, 7 days/week on gestational days 6-19. There was no adverse effect on the dam or offspring at any dose level and there was no increase in malformations or variations and therefore 7000 ppm (19,503 mg/m3) was the NOAEC for both maternal and developmental toxicity.

No classification is warranted under CLP since consideration of existing data indicates a lack of reproductive effects and, in relation to developmental toxicity, there was no increase in malformations or variations which were not associated with maternal toxicity.

Justification for selection of Effect on developmental toxicity: via oral route:
Toluene, present in some streams, has been shown to adversely affect the foetus. However controls to protect against the carcinogenicity of benzene (present in all streams at 0.1% and above) will mitigate such risks to foetal development.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Toluene, present in some streams, has been shown to adversely affect the foetus. However controls to protect against the carcinogenicity of benzene (present in all streams at 0.1% and above) will mitigate such risks to foetal development.

Justification for selection of Effect on developmental toxicity: via dermal route:
Toluene, present in some streams, has been shown to adversely affect the foetus. However controls to protect against the carcinogenicity of benzene (present in all streams at 0.1% and above) will mitigate such risks to foetal development.

Justification for classification or non-classification

The need for 2-generation reproduction toxicity and full developmental toxicity studies for Aliphatics and Cyclics C5 and Higher streams is waived as they are classified as mutagenic and carcinogenic. There are sufficient data available on constituents to conclude that streams within this class that contain less than 3% toluene or n-hexane are not reproductive toxicants and do not require a label for this endpoint. Aliphatic and Cyclic C5 and Higher streams which contain ≥ 3% toluene should be classified Category 2, H361d according to Reg (EC) 1272/2008. Streams that contain ≥ 5% toluene are classified Category 2, H361 according to Reg (EC) 1272/2008.