Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Two studies investigating carcinogenic effects of the test substance are available. In the key study (Hiasa et al., 1990), the NOAEL for systemic effects was 1210 and 1160 mg/kg bw/day for males and females, respectively, based on increased drinking water consumption in both sexes and higher mortality in males. No neoplastic effects were observed up to the highest concentration. In addition no formation of bladder stones and possibly associated tumors was reported. In a second very old disregarded study (Fitzhugh and Nelson, 1946) bladder tumors occurred in high dose groups. These tumors were associated with physical irritation from bladder stones which occurred at those doses. The NOAEL was found to be 750 mg/kg bw/day. This very old study was judged as disregarded study due to limitations in documentation, especially lack of information on purity.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 160 mg/kg bw/day
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In the key study (Hiasa et al., 1990) male and female Fischer 344 rats were administered 0, 1.25 or 2.5 % diethylene glycol in drinking water for two years after pretreatment with N-ethyl-N-hydroxyethylnitrosamine for tumor initiation. The intake of the test material was 0, 1210 or 2630 mg/kg bw/day for males and 0, 1160 or 2550 mg/kg bw/day for females.

At the high dose level drinking water consumption was clearly increased (females 17 %, males 25 %), and 19/50 males died compared to 13/50 in the control group. The serum lactate dehydrogenase activity was increased and serum urea was decreased in males, the creatine phosphokinase activity and the weights of the lung were increased in both sexes, but these changes were not reported to be clearly significant. In the urine no changes could be detected, but it was not mentioned if oxalate was measured. No bladder stones were reported. The incidences of tumors in all organs did not significantly differ between the three groups.In conclusion, this experiment did not provide evidence for a carcinogenic or kidney tumor promotion potential.

The systemic and carcinogenetic NOAEL was 1210 and 1160 mg/kg bw/day for males and females, respectively, based on increased drinking water consumption in both sexes and higher mortality in males.

 

In a second study, Fitzhugh and Nelson (1946) conducted a 2-year feeding study using male Osborne-Mendel rats. Doses of 0, 750, 1500 and 3000 mg/kg bw/day were used. Bladder stones composed of calcium oxalate occurred in all except one rat on the 3000 mg/kg bw/day group, and in a lesser number in those on the lower concentration. Bladder tumors occurred in about half of the rats on the 3000 and 1500 mg/kg bw/day groups, and in none of those on the 750 mg/kg bw/day group of diethylene glycol. In untreated controls there were no stones or tumors in the urinary tracts. The tumors of the bladder were both papillary and intramural. The former were generally benign, while some of the intramurally located tumors showed varying degrees of malignancy. These tumors were associated with irritation from bladder stones which occurred at those doses. Tumor formation is most likely due to secondary effects of the bladder stones and potentially linked to impurities. The NOAEL was found to be 750 mg/kg bw/day.

This study was evaluated to be not reliable as only basic information are available. More specifically no information about purity of the substance is given, which is in particular of high importance as possible impurities might strongly influence the formation of bladder stones (see below).

 

Summary and conclusion

The key study (Hiasa et al., 1990) clearly showed the absence of any neoplastic effects up to very high doses, which are above the recommended limit dose of 1000 mg/kg bw/day. Only systemic effects were reported. In addition no formation of bladder stones was shown.

In the second study formation of bladder stones was shown which were attributed to the formation of bladder tumors due to secondary irritating effects.

Bladder cancer formation resulting from chronic irritaion of the bladder epethelium caused by the presence of urinary calculi has been identified as a threshold effect which is also time-related due to irritation that stimulates cell division and epethelial hyperplasia. The formation of bladder stones is most likely attributed to the purity of the substance as shown in a SCCP opinion (see below, next paragraph). As no information on purity of the substance was given in this old study it was disregared.

Also, Cohen (1995, 1998) proposed that this mechanism of bladder cancer formation may be less important to humans. with any irinary crystals formed causing severe pain and leading to consultation with urologist and removal of the crystals.

In data from a SCCP Opinion the issue of bladder stone formation was further investigated. Diethylene glycol containing only 0.031 % of ethylene glycol was fed to weanlings, 2 month old, and 1 year old rats for up to 2 years at levels of 4.0 and 2.0 % in a laboratory chow. Although the weanling rats developed more bladder stones than the other groups, the difference was insignificant. The yearling rats developed their bladder stones somewhat earlier. The highest stone formation was 8 in 20 (40%) rats at the 4% dosage level. None was found in the rats fed the 2 % level. The results indicate that diethylene glycol substantially free of ethylene glycol does not cause bladder stones, suggesting that it is not metabolized to any great degree to ethylene glycol as the substance is well known to cause bladder stones (HSDB on diethylene glycol. Hazardous Substances Data Bank).

In addition data from repeated dose studies are available investigating also the formation off bladder stones (see IUCLID section 7.5). Gaunt et al.(1975) reported a 225-day oral feeding study. Male and female rats were given concentrations of 0.085, 0.17, 0.4 and 2.0 % (= 64, 128, 300, 1500 mg/kg bw/day). Dietary concentrations of 0.4 and 2.0 % resulted in oxalate crystalluria and mild defects in renal function as measured by concentration tests. The elevated levels of oxalic acid in urine in this study were considered to be a biomarker and do not indicate toxicity. Mild defects of renal function at 0.4 % diethylene glycol were therefore considered to define the NOAEL as 128 mg/kg bw/day. Generally, it should be noted, that the data on repeated dose toxicity of diethylene glycol are comparatively old and it cannot be excluded that the presence of ethylene glycol as impurity in the DEG may have influenced the results. Thus, while calcium oxalate crystals were found in the rat bladder in a 225 day experiment at 128 mg/kg bw/day, bladder stones were not observed at more than 1000 mg/kg bw/day in another study with diethylene glycol containing only 0.031% ethylene glycol.

In summary, with respect to available data from carcinogenicity, mutagenicity (please also refer to discussion on mutagenicity, chapter 5.7.3) as well as repeated dose toxicity studies indication is given that bladder stones might be formed mainly due to different impurities. Bladder stones might then induce the formation of bladder tumors as a secondary physical and chronic irritating effect seen with laboratory animals. As these effects cannot be linked to the pure diethylene glycol a classification for carcinogenicity is not justified based on the available data set and might be a secondary effect due to physical irritation cause by bladder stones.

This argumentation is in line with the conclusion on carcinogenicity reported in the Chemical hazard assessment report on DEG (NICNAS, 2009) where it is stated that that DEG did not induce bladder tumours in rats unless a foreign body or lesion was present, such as an oxalate-containing bladder stone or a surgery-induced bladder lesion (Weil et al. 1965 and 1967). These authors concluded that the bladder tumours seen were due to mechanical irritation by oxalate-containing bladder stones rather than the carcinogenic response to DEG. In more recent studies such as Ito et al. (1988), Masui (1988) and Hiasa et al. (1990* and 1991*), DEG did not demonstrate any evidence of carcinogenic effects after oral administration. Several studies in mice also showed that DEG is not carcinogenic after dermal application.

(For NICNAS report, 2009, please also refer to IUCLID Chapter 13).

In a recently conducted literature search (August 2014), no further relevant information on carcinogenicity were identified (please refer to IUCLID section 12).

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified for carcinogenicity under Regulation (EC) No 1272/2008.