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Description of key information

The limited repeat dose toxicity data on specific streams identified for this category (oral toxicity studies for CAS 68477-54-3 [Low Dicyclopentadiene Resin Oil] and CAS 48478-10-4 [Dicyclopentadiene/Codimer Concentrate] provided no evidence of significant target organ toxicity. However, there are substantial data on the repeated dose toxicity of a number of specific components benzene, toluene, styrene and ethylbenzene present in some streams which demonstrate significant target organ toxicity.  Classification witll be required for streams that contain concentrations greater than or equal to 1% (benzene) or 10% (toluene).

Key value for chemical safety assessment

Additional information

Repeated dose toxicity data on Resin Oils and Cyclic Diene streams is limited oral OECD guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) studies on two streams - CAS 68477-54-3 [Low Dicyclopentadiene Resin Oil] and CAS 48478-10-4 [Dicyclopentadiene/Codimer Concentrate].

CAS 68477-54-3 [Low Dicyclopentadiene Resin Oil]: Oral doses of 0, 35, 125, or 375 mg/kg/day were administered once daily for 29 or 30 days. At 375 mg/kg/day clinical signs of toxicity, lower body weight and food consumption and histopathological changes were observed. In addition, effects on body weight, clinical signs and food consumption were observed in males at 125 mg/kg/day. The NOAEL for systemic toxicity was 35 mg/kg/day in male and 125 mg/kg/day in female rats.

CAS 48478-10-4 [Dicyclopentadiene/Codimer Concentrate]: Oral gavage doses of 0, 5, 25, or 100 mg/kg/day were administered once daily for 29 or 30 days. The only toxicologically significant treatment-related effects were histopathological changes in the thyroid (follicular cell hypertrophy) at 25 and 100 mg/kg/day in both males and females. The NOAEL for systemic toxicity was 5 mg/kg/day in male and female rats.

The available data on the specific components dicyclopentadiene, 1,3–butadiene, naphthalene, isoprene and xylenes do not reveal any specific target organ toxicity of a severity that would warrant classification. Therefore no classification or labelling is warranted for streams that only contain these components.

3a,4,7,7a-tetrahydro-4,7-methanoindene (DCPD, dicyclopentadiene) is not classified for repeat dose toxicity under Annex I DSD or under CLP). While some effects were seen in repeat dose studies, these are believed to be due to chronic irritation of the lungs and gastrointestinal tract with secondary stress-related effects rather specific target organ toxicity. DCPD is irritating; therefore it is biologically plausible that the mortality is mostly attributable to respiratory and gastric irritation effects rather than systemic effects. Liver effects seen in the rat oral study were not considered sufficient to warrant classification. Repeated exposure inhalation studies in rodents show mortality at levels that would be predicted by their LC50s, and appears related to respiratory irritation/portal-of-entry effects. The original Bushy Run 90-day study showed mortality in the mice at 276 mg/m3. The LC50 in mice is about half that of rats, which might be expected for a respiratory irritant (higher ventilation rate in the mouse).

Other specific components which have been identified as present in some streams are benzene, toluene, styrene and ethylbenzene. These are identified as producing serious target organ toxicity following repeated oral, dermal or inhalation exposures in animals and man:

Benzene (Classification: EU -Toxic T, R48/23/24/25; GHS/CLP - STOT-RE Category 1, H372): After repeated dose exposure via oral or inhalation routes, benzene causes adverse effects on the haematopoietic system of animals and man. The oral LOAEL was 25 mg/kg bw/day for male and female mice (NTP, 1986) and the inhalation LOAEC for haematotoxicity in mice is 10 ppm (32 mg/m3) (Ward et al, 1985). For human a NOAEC of 3.5 ppm (11.2 mg/m3) is obtained based on the 95% LCL for the threshold level of neutrophils, the most sensitive endpoint reported by Schnatter et al, (2010).

Toluene (Classification: EU - Harmful Xn, R48/20; GHS/CLP - STOT-RE Category 2, H373): Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neuropsychological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments. The NOAEC for subchronic oral toxicity in rats is 625 mg/kg/day based on neuropathology (Huff, 1990). The NOAEC for inhalation toxicity in the rat is 300 ppm (1131 mg/m3) based on effects on body weight, mortality and adverse local effects (nasal erosion) (Gibson and Hardisty, 1983). The NOAEC for neuropsychological effects, auditory dysfunction and disturbances of colour vision in humans is 26 ppm (98 mg/m3) (Seeber et al, 2004); Schaper et al, 2003, 2004).

Styrene (Not currently classified): Inhalation studies in animals have reported damage to the nasal olfactory epithelium in rats and mice, liver damage in mice, eye irritation in rats and guinea pigs, ototoxicity in rats and impaired nerve conduction velocity. The EU transitional RAR has identified a NOAEC of 50 ppm in humans based on color vision discrimination effects in occupationally exposed workers.

Ethylbenzene (Not currently classified): No repeated dose toxicity studies in humans have been identified. The EU transitional RAR (EU, 2008a) concluded "Repeat-dose or prolonged exposure to ethylbenzene specifically affected the nervous system, but did not induce overt toxicity of any other organ system." The auditory system is the most sensitive to the toxic effects of ethylbenzene after inhalation exposure (Gagnaire et al, 2007) while the liver is the most sensitive following oral exposure (Mellert et al, 2006). The LOAEL for ototoxicity was 200 ppm (868 mg/m3) and the NOAEL for hepatotoxicity was 75 mg/kg/day in a 13 week oral gavage study in rats.

Reference

EU (2008a). Draft Risk Assessment Report for Ethylbenzene. http://echa.europa.eu/doc/trd_substances/ethylbenzene/rar/trd_rar_germany_ethylbenzene.pdf

Justification for classification or non-classification

There are sufficient data available to conclude that streams within this class which contain less than 1% benzene and less than 10% toluene do not require classification for this endpoint.

Streams which contain ≥1% but less than 10% benzene should be classified as Harmful Xn R48/20/21/22 according to Dir 1999/45/EC and Cat 2, H373 according to Reg (EC) 1272/2008; streams containing ≥10% benzene should be classified as Toxic, R48/23/24/25 according to Dir 1999/45/EC and Cat 1, H372 according to Reg (EC) 1272/2008.

Streams which contain ≥10% toluene should be classified as Xn, labelled R48/20 according to Dir 1999/45/EC and Cat 2, H373 according to Reg (EC) 1272/2008.