Dilactide

Carcinogenicity

Description of key information

A 2 year drinking water study in rats with calcium lactate is available (Maekawa, 1991). The calcium salt of lactic acid (calcium lactate) did not induce any dose-related increase in the incidences of tumours in any organ or tissue. The finding is supported by a 5 and 13 m study with lactic acid in rabbits (Shubik 1957 as cited in Anderson, 1998). Lactic acid (and also calcium lactate) is an acceptable read-across partner for dilactide as dilactide is rapidly converted by hydrolysis into lactic acid under aqueous conditions.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

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 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

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

Description (incidence and severity):

No specific dose-related changes were observed in any of the biochemical parameters.

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 details and justification of read-across please refer to the read-across report attached to IUCLID section 13.

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 on degradation products, dilactide does not warrant classification for carcinogenicity.

Additional information

The tested substance 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. Lactic acid (and also Calcium lactate) is an acceptable read-across partner for dilactide as lactide is rapidly converted by hydrolysis into lactic acid under aqueous conditions.

Calcium lactate did not induce any tumours in a 2 years carcinogenicity study (Maekawa, 1991). Moreover, in a 16 months study in rabbits, lactic acid did not induce any tumours. These results can be seen as available supporting information for the carcinogenicity evaluation of dilactide.