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Carcinogenicity

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Description of key information

There are no reliable studies available for the assessment of the carcinogenicity endpoint with the target substance, ethyl (S)-lactate. Therefore, available data from an oral carcinogenicity study conducted with a suitable read-across partner, calcium lactate was used to assess the carcinogenicity of the target substance. In addition, the conclusion of the OECD SIDS report, 2004 on the carcinogenic potential of ethanol is provided, stating that occupational exposure to ethanol and the use of ethanol in consumer products does not pose a carcinogenic hazard.

Based on the available data, no classification for carcinogenicity is warranted for the target substance ethyl (S)-lactate.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
For justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Species:
rabbit
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
No tumors were reported after 5 or 16 months, respectively details not provided.
Conclusions:
Based on the results, lactic acid is considered as not carcinogenic.
Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
In females, the mortality rate in the 5% group was slightly higher than those in the other two groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Compared with the controls, a 13% decrease in body-weight gain was observed in male and female rats of the high-dose group. The toxicological relevance was not further discussed.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Throughout the administration period, daily water consumption was almost constant in all groups of both sexes.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No specific dose-related changes were observed in any of the haematological parameters.
Clinical biochemistry findings:
no effects observed
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Females in the 5% group exhibited slightly but significantly higher kidney weights compared with controls. Histologically, however, there was no difference in the severity of chronic nephropathy between different groups.
A significant dose-dependent increase was observed in the relative brain weights of both male and female rats although no histological change was detected which may result from the decrease in body weight gains.

Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
A number of non-neoplastic lesions (e.g. myocardial fibrosis, bile-duct proliferation, hepatic microgranulomas and chronic nephropathy) were observed in all groups, with no difference in their incidences and/or degrees.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
A slight increase in calcium deposition in the papilla compared to controls was observed in females of the 5% dose group. This type of lesion was histologically different from nephrocalcinosis and might depend on the increase in urinary calcium levels.
It is known that these lesions occur spontaneously in old F344 rats (Goodman et al., (1979): "Neoplastic and nonneoplastic lesions in aging F344 rats.", Toxicology and Applied Pharmacology 48, 237-248.). The data show that no clear toxic lesions specifically caused by long-term administration of calcium lactate, except for the slight calcium deposition in the renal papilla, were detected in any organ. The type of lesion observed in the kidney of female rats in the 5% group was histologically different from the so-called nephrocalcinosis, which is characterized by an intraluminal deposition of calcium observed mainly in the cortico-medullary region. The pathogenesis of this lesion is unclear and might depend on the increase in the urinary calcium level; this parameter was not determined in this study.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Tumours were found in many organs and/or tissues in all groups including the controls. In males from all groups, tumours of the testis were the most frequent, followed by those of the adrenal gland, thyroid gland, pituitary gland, haematopoietic organs, mammary gland, lung and pancreas. In females, the commonest tumours were those of the uterus, pituitary gland, haematopoietic organs, mammary gland, thyroid gland, adrenal gland and pancreas. Tumours were also detected in other organs/tissues from rats of all groups, but at lower incidences. Histologically, all the tumours observed in this experiment were similar to those known to occur spontaneously in F344 rats, as reported in previous studies (Goodman et al.,1979; Maekawa et al.,1983; Maita et al.,1987; Solleveld et al.,1984). None of the experimental groups showed a significant increase in the incidence of any specific tumours compared with the corresponding control value (chi-square and/or Fisher's test), and also no positive trend was noted in the occurrence of any tumour (trend analysis test; Pete et al., 1980). It was therefore concluded that calcium lactate had no carcinogenic activity in F344 rats when it was given continuously in the drinking-water for 2 years.
Other effects:
not specified
Key result
Dose descriptor:
NOAEC
Effect level:
50 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no calcium lactate-related carcinogenic activity observed
Key result
Critical effects observed:
no
Conclusions:
It was concluded that calcium lactate had neither toxic nor carcinogenic activity in F344 rats when it was given continuously in the drinking water for 2 years.
Executive summary:

In a carcinogenicity study Calcium lactate (> 97 % purity) was administered ad libitum to 50 F344 rats per sex per dose in drinking-water at levels of 0, 2.5 or 5 % for two years. Calcium lactate is the calcium salt of lactic acid, which is a major and essential species in mammalian primary metabolism and a ubiquitous ingredient in all kinds of food.

No clear toxic lesion was specifically caused by long-term administration of Calcium lactate. No significant dose-related increase in the incidences of tumours in any organ or tissue was found. The results indicate that calcium lactate had neither toxic nor carcinogenic activity in F344 rats.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Conclusions:
Based on the available information it was concluded in the OECD SIDS report on ethanol, that with some confidence occupational exposure to ethanol and the use of ethanol in consumer products does not pose a carcinogenic hazard.
Executive summary:

In the literature many laboratory carcinogenicity studies in animals exist using ethanol as the test substance. However, these are almost universally carried out to improve the understanding of the risks associated with the consumption of alcoholic beverages. Characteristically, these are carried out by the oral route and at high doses, well in excess of 1000 mg//kg bw/day, which means they are inadequately designed and provide too little data to characterise the carcinogenic potential of ethanol at doses relevant to occupational exposure and use of consumer products containing the substance.

In a carcinogenicity study conducted by the National Toxicology program conducted according to GLP, mice were exposed to ethanol in drinking water at the relatively high doses of 2.5 and 5.0% for 2 years, which resulted in average daily consumptions of ca. 100 and 180 mg ethanol for males and 80 and 155 mg ethanol for females. It showed only equivocal evidence of carcinogenic activity of in males based on increased incidences of hepatocellular neoplasms. However, there was no evidence of carcinogenic activity of ethanol in female mice exposed to either concentration (NTP, 2004). There remains no robust evidence of carcinogenicity in laboratory animals at doses other than those associated with consumption of alcoholic beverages. This is consistent with the findings of IARC who concluded that there is inadequate evidence for the carcinogenicity of ethanol in experimental animals (IARC, 1988).

Regarding studies in human the OECD SIDS report stated:” that although no epidemiological studies are available for ethanol per se, there are a large number of studies (retrospective cohort, prospective cohort and case-control studies) on the effects of alcoholic beverages, which contain ethanol and water as the two main components. These epidemiological studies clearly indicate that drinking alcoholic beverages is causally related to cancers of the oral cavity, pharynx (excluding the nasopharynx), larynx and oesophagus. The effect appears to be independent of beverage type. The aetiology is likely to proceed via a mechanism whereby frequent exposure to high local concentrations of liquid ethanol and its metabolites leads to persistent irritation, and eventually hyperplasia and finally tumor formation. (Greim H., 1999). For the oral cavity, pharynx, larynx and oesophagus, alcoholic beverage consumption in excess of 10-40 g ethanol per day is necessary before there is a convincing increase in the relative risk of cancer (Greim H., 1999; UK Dept of Health, 1995). Such a mechanism would not therefore be relevant to occupational exposure. Drinking alcoholic beverages is also likely to be causally linked to liver cancer. The liver is the primary site of metabolism and sees high concentrations of ethanol and its metabolites. Tumor formation is normally associated with cirrhosis, which is in turn normally seen only following chronic alcohol abuse in excess of 80 g ethanol per day (Greim H., 1999; UK Dept of Health, 1995). Such a scenario is not relevant to occupational exposure to ethanol. Drinking alcoholic beverages is also possibly causally linked to cancer of the breast and large bowel. Should the causal link with breast cancer be proven, the mechanism is believed to be via disturbance of the hormonal system. There is little or no indication of a causal relation with cancer of the stomach, pancreas, lung, urinary bladder, kidney, ovary, prostate, lymphatic or haematopoietic system. There is no convincing evidence that the carcinogenic effects of alcoholic beverages in humans occurs as a result of the mutagenic effect of ethanol, acetaldehyde or other beverage constituents (UK Dept of Health, 1995). The International Agency for Research on Cancer has classified alcoholic beverages (but not ethanol) as Group 1 - carcinogenic to humans (IARC, 1988). The International Life Sciences Institute (ILSI, 1999) has published an extensive review of the health issues relating to alcohol consumption. They concluded that ethanol is not a carcinogen by standard laboratory tests. Such tests are the normal measure for the assessment of industrial chemicals and any chemical that would be expected to present a carcinogenic hazard to workers or consumers during normal handling and use would be expected to show a positive result in one or more of such tests.”

The results of the genotoxicity in vitro test battery (OECD 471, OECD 473 and OECD 490) showed, that ethyl (S)-lactate do no induce genetic toxicity and these results can be seen as indicative for non-carcinogenic potential.

Ethyl (S)-lactate is rapidly hydrolysed into lactic acid and ethanol in vivo and thus it is justified that the assessment of the carcinogenicity can be based on information for lactic acid and ethanol.

Regarding lactic acid it can be stated that lactic acid is a major and essential species in mammalian primary metabolism and a ubiquitous ingredient in all kinds of food and thus carcinogenicity is not a relevant end point for such a substance, since there is no way of lowering exposure below minimum required levels or normal (or even abnormal) internal levels.

That lactic acid do not pose any carcinogenic potential was supported by the results of a long-term toxicity, carcinogenicity study in F344 rats treated with calcium lactate. Calcium lactate is a salt of lactic acid and immediately dissociates in aqueous environments into lactic acid and the Ca2+.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available data from the read-across partners, the target substance ethyl (S)-lactate does not warrant classification for carcinogenicity in accordance with CLP Regulation 1272/2008.

Additional information

The results of the genotoxicity in vitro test battery (OECD 471, OECD 473 and OECD 490) showed, that ethyl (S)-lactate do no induce genetic toxicity and these results can be seen as indicative for a non-carcinogenic potential.

Ethyl (S)-lactate is rapidly hydrolysed into lactic acid and ethanol in vivo and thus it is justified that the assessment of the carcinogenicity can be based on information for the source substances lactic acid and ethanol.

Regarding lactic acid it can be stated that lactic acid is a major and essential species in mammalian primary metabolism and a ubiquitous ingredient in all kinds of food and thus carcinogenicity is not a relevant end point for such a substance, since there is no way of lowering exposure below minimum required levels or normal (or even abnormal) internal levels.

That lactic acid do not pose any carcinogenic potential was supported by the results of a long-term toxicity, carcinogenicity study in F344 rats treated with calcium lactate. Calcium lactate is a salt of lactic acid and immediately dissociates in aqueous environments into lactic acid and the Ca2+. Calcium lactate was given ad libitum in the drinking-water at levels of 0, 2.5 or 5% to groups of 50 male and 50 female rats for two years. No clear toxic lesion was specifically caused by long-term administration of calcium lactate. No significant dose-related increase was found in the incidences of tumours in any organ or tissue. The results indicated that calcium lactate had neither toxic nor carcinogenic activity in F344 rats. Regarding ethanol it can be stated that there is no compelling evidence to warrant a classification of ethanol for cancer in the context of the relevant classification and labelling regulations for chemical substances.

Based on the available data from the read-across partners, the target substance ethyl (S)-lactate does not warrant classification for carcinogenicity in accordance with CLP Regulation 1272/2008.