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Description of key information

Repeat dose studies on two C5 non-cyclics streams and two major components of these streams have been considered. There is evidence of specific target organ toxicity in several studies. A finding common to several of the studies is kidney changes characteristic of hyaline droplet nephropathy in male rats. This male rat-specific effect is considered not to be relevant to humans.
Although C5 non-cyclics streams may contain low levels of benzene and/or toluene, the maximum levels present are below those which would warrant classification for specific target organ systemic toxicity after repeated exposure.

Key value for chemical safety assessment

Additional information

Repeated dose studies have been conducted by the inhalation route on two of the UVCB C5 non-cyclic category streams (CAS 68476-55-1 Pyrolysis C5 and CAS 68602-79-9 Hydrotreated C5). In addition data are available for the marker substance isoprene and potential major components 1,3 pentadiene and 2-methyl-2 butene .

UVCB Stream data

The Pyrolysis C5 stream (CAS No.68476-55-1) has been tested in a 28-day repeated dose study in rats at concentrations of 0, 98, 302 or 1012 ppm (HLS, 2004a). No general systemic effects were observed during the routine clinical examination in motor activity. Histopathological changes (minimal centrilobular hepatocyte hypertrophy) were seen at 1012 ppm in both sexes. In male rats only higher kidney weights and renal cortical tubules with hyaline droplets were apparent in all treatment groups. The kidney effects observed in male rats is a well studied phenomenon known as hyaline droplet nephropathy. This phenomenon has been extensively evaluated and is a male rat-specific phenomenon and is considered not adverse or relevant for human risk assessment. It can be concluded that the NOAEC is 302 ppm.

The Hydrotreated C5 stream (CAS No.68602-79-9) has been tested in a 28-day repeated dose study in rats at concentrations of 0, 939, 3145 or 8059 ppm (HLS, 2004b). Other than lethargy and increased salivation observed at 8502 ppm, no other treatment-related clinical signs were noted. There were no treatment related changes were observed in body weight, motor activity or in the functional observational battery.In both sexes at 8502 ppm and females at 3033 ppm, atrophy and some ‘disorganisation’ of the olfactory epithelium of nasal turbinates were noted. Basophilic cortical tubules were increased in incidence and severity in the kidneys of all male exposure groups and females at 3033 and 8502 ppm. Male rats in all treatment groups had renal cortical tubules with hyaline droplets and, as for Pyrolysis C5, this nephropathy is not considered relevant for human risk assessment.In the liver of males at 8502 ppm there was minimal centrilobular hepatocyte hypertrophy and slightly higher liver weights than controls.It was concluded that the NOAEC was 992 ppm.

Marker and component substance data

Data for the marker substances benzene (Classification: DSD -Toxic T, R48/23/24/25; CLP - STOT-RE Category 1, H372) and toluene (Classification: DSD - Harmful Xn, R48/20; CLP - STOT-RE Category 2, H373) which are known to cause target organ toxicity are not considered in this instance since levels will not exceed the thresholds for classification according to DPD and CLP.

The marker substance isoprene is not classified for repeat dose toxicity under DSD. In brief, there is a clear species difference in response to exposure to isoprene, with mice being more sensitive than rats.In rats findings were essentially limited to splenic fibrosis and interstitial cell hyperplasia of the testis.In contrast, in mice non-neoplastic toxicities include spinal cord degeneration, partial rear limb paralysis, testicular atrophy, olfactory epithelial degeneration, forestomach epithelial hyperplasia and macrocytic anaemia (NTP, 1994; Placke et al., 1996). The overall repeat dose NOAEC for rats is 220 ppm (613 mg/m3) based on splenic fibrosis in males in a two-year study (NTP, 1999). The overall repeat dose LOAEC in mice is 70 ppm (195 mg/m3) based on increased incidence of spinal cord degeneration after 26 weeks exposure and 26 weeks recovery period, with no NOAEC identified in the Melnick et al (1994) study. However, it is of note that this effect was not reproduced in the chronic oncogenicity study, which also showed a clear NOAEC at 10 ppm (Placke et al, 1996).

The potentially major component, 2 -methyl-2 -butene, is not currently classified under DSD but, considering self-classification, does not warrant classification for repeat dose toxicity under DSD or a STOT-RE classification under CLP. Similarly, 1,3-pentadiene does not warrant classification. In a combined repeat oral dose and reproductive/developmental toxicity screening study with 1,3-pentadiene in rats (EBSI, 1992a) effects were limited to a transient decrease in food consumption in the high dose (1000 mg/kg day) females.No other treatment-related effects were observed in parents or their offspring.The NOAEL for repeat dose toxicity was 100 mg/kg/day.

Reference

Melnick RL et al (1994). Isoprene, an endogenous hydrocarbon and industrial chemical, induces multiple organ neoplasia in rodents after 26 weeks of inhalation exposure. Cancer Res., Vol. 54, pp. 5333-5339.

Justification for classification or non-classification

Representative C5 non-cyclics streams and the major components demonstrate functional disturbance or morphological change which has toxicological significance only at doses in excess of the levels which warrant classification under DPD or CLP.

Most streams within this category contain less than 1% benzene and less than 10% toluene and therefore do not require a classification for this endpoint under DPD or CLP. Streams containing greater than 1% benzene are classified for H373.