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Description of key information

Reliable studies are available for inhalation, which revealed a NOAEC 612 mg/m3 (= 125 ppm). In addition other subchronic inhalation studies revealed an NOAEC of 100 ppm (= 490 mg/m3). In oral subchronic studies a NOAEL of 154 mg/kg bw/d have been obtained. However, the documentation of this study is limited.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
154 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
612 mg/m³

Additional information

Data on this endpoint are presented in Section 4.1.2.6 of the EU RAR (2001; page 57ff).

 

The following overall NOAEL/NOAECs were recommended in the EU RAR (2001) for risk assessment procedures:

 

Oral administration:

NOAEL 154 mg/kg bw/d 6 months rat, oral, gavage (and shows an increased kidney weights at 462 and 769 mg/kg bw/d).

Applicant comment: In a 28d study no effect were observed in male rats up to a concentration of 535.8 mg/kg bw/d, given in diet.

 

Inhalative administration:

NOAEC 100 ppm (equivalent to 490 mg/m3); LOAEL 500 ppm and mild toxicity at 1200 ppm in Fischer 344 rats.

Applicant comment: Recently performed NTP studies revealed a comparable NOAEC of 62.5 ppm (= 306.25 mg/m3).

 

Dermal administration:

For dermal repeated applications the cumene caused moderate skin irritation and a development of a thin layer of devitalized tissue which resulted in exfoliation and dermatitis. Applicant comment: No NOAEL were given in EU RAR

 

ORAL EXPOSURE

In a 28d subacute study male rats were exposed via diet to concentrations of 22.8, 224.8 and 535.8 mg/kg bw/d. No effects were observed on body weight, gross lesion and organ body weight ratios. Therefore, the NOAEL is >=535.8 mg/kg bw/d. In addition, one older study without detailed description is presented as supporting study. Rats (10 per group) were exposed via gavage to cumene at 0, 154, 462 and 769 mg/kg bw/d once per day, 5 days/week during 6 months (Wolf et al. 1956; cited in EU RAR 2001). A NOAEL of 154 mg/kg bw/d and a LOAEL of 462 mg/kg bw/d were established, based on effects on kidney weight.

 

DERMAL EXPOSURE

For the dermal route there is no key study for repeated dose toxicity available. One older study without detailed description is mentioned in EU RAR.

Repeated application of cumene upon skin of white rabbits caused moderate irritation (definite erythema) and a development of a thin layer of devitalized tissue, which resulted in exfoliation (Wolf et al. 1956, cited in EU RAR).

However, as inhalation is the most important exposure route and for this exposure recent NTP studies in rats and mice are available, there is no need to investigate the dermal route of exposure by conducting a new experimental study.

In addition EU RAR reported the result of a study performed with a mixture containing 30 % cumene. This substance was applied at a level of 2 ml/kg bw/day, 5 days/week for 28 days to the backs of white rabbits caused skin oedema, fissuring and moderate to severe erythema (Procter & Gamble 1985, cited in EU RAR). Macroscopically and microscopic investigation revealed dermatitis and other cellular dermal effects. However, as a mixture was tested the result is considered to be of low relevance for the assessment of cumene.

 

INHALATION EXPOSURE

Besides the studies cited in EU RAR, the recently performed NTP studies were selected as key studies for this endpoint (see robust study summaries in IUCLID section 4.5.3). In these studies performed according to OECD Guideline effects of cumene exposure via inhalation were investigated in rats (Fisher 344) and mice (B6C3F1) .

 

Groups of 10 male and 10 female mice were exposed to cumene vapor at concentrations of 0, 62.5, 125, 250, 500, or 1,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. Eight females from the 1,000 ppm group died during week 1 of the study. Mean body weights of males exposed to 500 or 1,000 ppm were significantly less than those of the chamber controls. Liver weights of mice exposed to 500 or 1,000 ppm were significantly increased. For relative liver weight an increase was observed at 125 ppm. The weight of the cauda epididymis and the spermatid count were significantly decreased in 1,000 ppm males.

 

Groups of 10 male and 10 female rats were exposed to cumene vapor at concentrations of 0, 62.5, 125, 250, 500, or 1,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All rats survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Kidney weights of males exposed to 125 ppm or greater and liver weights females exposed to 1,000 ppm were significantly greater than those of the chamber controls. There were significant differences between exposed to 250 ppm and control females in the relative length of time spent in the estrous stages. The amount of alpha2u-globulin in the right kidneys was significantly increased in male rats exposed to 125 ppm or greater. The incidences of medullary granular casts in males exposed to 250 ppm or greater were significantly increased. The severities of renal tubule cortex hyaline droplet accumulation and regeneration increased with increasing exposure concentration in male rats.

In these studies a NOAEC of 125 ppm could be derived for rats based on effects on kidney weight. For mice the same NOAEC was determined based on relative increase in liver weight.

The findings from the NTP studies are supported by serveral other subchronic studies, which are reported in detail in the EUA RAR.

One subchronic study with rats reported a NOAEL of 100 ppm, for Fischer 344 rats exposed via inhalation for 91 days (Cushman et al. 1995; cited in EU RAR). In another longterm study serveral other species like rats, guinea pigs, monkeys and dogs were exposed 6 weeks at 8h per day and continuously for 90d (Jenkins et al. 1970; cited in EU RAR). However, the only reported effect was reduction of body weight gain.

With rats also a subacute (5d) inhalation study is available (Gulf Oil Corporation 1985a; cited in EU RAR)..

In addition, rats and rabbits have been exposed over 130 -160 days and revealed effects on body weight gain and congestion of some organs at 500 ppm for rats, while rabbits were unaffected at 1300 ppm (Fabre et al. 1955, cited in EU RAR).

In the EU RAR also another 28d stuyd with rats is presented (Branch and Ribelin1985, cited in EU RAR).

Besides the findings in animals the EU RAR listed also some findings in humans. In the use of cumene as a solvent involving exposure over a period of 1 to 2 years, it was found that no toxic injury resulted from daily exposures to those concentrations of vapour that could be readily tolerated.

For most persons, the vapours became painful to the eyes and upper respiratory passages in the concentration range of 300 to 400 ppm although some persons readily tolerated concentrations considerably in excess of 400 ppm (Dow Chemical Company 1948, cited in EU RAR).

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

Based on the current findings there is no indication of a specific target organ with relevance to human health. Effects found in the kidney of male rats are caused by alpha-2-u globulin. This mode of action is not relevant for humans.