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Toxicological information

Carcinogenicity

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Description of key information

Not carcinogenic. A 2 year drinking water study in rat is available. Lactic acid did not induce any dose-related increase

in the incidences of tumours in any organ or tissue. A supporting study mentioned in the review of Andersen (1998) about rabbits gives same results. Exposition of female rabbits to Lactic Acid over 13 months did not induce tumors.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Review
Reference:
Composition 0
Principles of method if other than guideline:
Female rabbits (number not specified) were dosed orally with 0.1 - 0.2 g/kg Lactic Acid in 100-150 mL water twice daily for 5 months, and five female rabbits were dosed orally with 0.1-0.7 g/kg Lactic Acid in 50-100 mL water twice daily for 16 months (13 months actual treatment) (Shubik and Hartwell, 1957).
Test material information:
Composition 1
Species:
rabbit
Route of administration:
oral: drinking water
Duration of treatment / exposure:
5-13 months
Frequency of treatment:
Twice daily
Remarks:
Doses / Concentrations:
0.1-0.2 g/kg bw (5 months), and 0.1-0.7 g/kg bw (13 months)
Basis:

Control animals:
not specified
Details on results:
Result (carcinogenicity): negative

No tumors were reported after 5 or 16 months, respectively. No Details are provided.

Conclusions:
Not carcinogenic.
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Reference:
Composition 0
Principles of method if other than guideline:
2 year exposure to substance in drinking water.
Test material information:
Composition 1
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Male and female 5-wk-old specific-pathogen-free (SPF) Fischer (F344) rats were purchased from Charles River Japan Inc. (Kanagawa, Japan) They were mamtained on the basal diet (CRF-1, Onental Yeast Inc., Tokyo, Japan) and tap-water until they were 6wk old (i.e. when the study starled).
Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Details on exposure:
Ad libitum exposure to drinking water containing 2.5 or 5% calcium lactate. Daily water intake was recorded, and daily calcium lactate intake was calculated from this. High dose males were exposed to a grand total of 625.4 g calcium lactate, and low dose males to a grand total of 329.4 g calcium lactate. For females, these numbers were 412.1 g and 237.7 g, respectively.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily, ad lib.
Post exposure period:
9 weeks
Remarks:
Doses / Concentrations:
2.5% calcium lactate in drinking water
Basis:
nominal in water
Remarks:
Doses / Concentrations:
5% calcium lactate in drinking water
Basis:
nominal in water
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: Autopsy on rats that died during study and those killed at the end. Examinations macro- and microscopically for presence of non-neoplastic and neoplastic lesions.
Observations and examinations performed and frequency:
Rats were randomly allocated to three groups, each consistmg of 50 males and 50 females. They were housed three (or four) males or five females to a plastic cage and kept m an air-conditioned room ( 2 4 ± P C , 55 ± 5% relative humidity) Calcium lactate was dissolved in distilled water at Ievels of 0 (control) or 2.5% or 5%.. These doses were selected after a 13-wk subchronic toxicity study done prior to the present study
(Matsushima et al, 1989) Rats were given these solutions ad lib as their drinking-water. The calcium lactate solutions were replaced with freshly prepared solutions three times a week, on which occasions the amount of solutions consumed was measured in order to calculate the intake of calcium lactate. Administration of the compound ended after 104 wk, and the rats were then given distilled water for a recovery penod of 9wk. At week 3, all surviving animals were killed and autopsied Haematological and biochemical examinations were also conducted in these rats
Throughout the experiment, rats in all groups were given the basal diet ad lib. They were observed daily and chlinical signs and deaths were recorded. Body weights were measured once a week for the first 13 wk of the study, and every 4 wk thereafter.
Sacrifice and pathology:
An autopsy was immediately performed on rats that died (or were killed when moribund) during the study and those killed at the end of the study. The animals were then examined macro- and microscopically for the presence of non-neoplastic and neoplastic lesions All organs and/or tissues were routinely fixed in 10% buffered formalin, sectioned and stained with haematoxyim and eosin.
Statistics:
Statistical analyses were performed using Fisher's exact probabiliy test and/or the chi-square test, and also the age-adjusted statistical test recommended by Peto et al. (1980).
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Result (carcinogenicity): negative
Relevance of carcinogenic effects / potential:
Since lactic acid is a major metabolic species, and a ubiquitous food ingredient, carcinogenicity is an irrelevant end point.
Conclusions:
It was concluded that calcium lactate had neither toxic nor carcinogenic activiity in F344 rats when it was given continuously in the drinking-water for 2 yr.
Executive summary:

The long-term toxicity carcinogenicity of calcium lactate, a food additive, was examined in F344 rats Calcium lactate was given ad lib 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.

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
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:
read-across source
Related information:
Composition 1
Principles of method if other than guideline:
2 year exposure to substance in drinking water.
Test material information:
Composition 1
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Male and female 5-wk-old specific-pathogen-free (SPF) Fischer (F344) rats were purchased from Charles River Japan Inc. (Kanagawa, Japan) They were mamtained on the basal diet (CRF-1, Onental Yeast Inc., Tokyo, Japan) and tap-water until they were 6wk old (i.e. when the study starled).
Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Details on exposure:
Ad libitum exposure to drinking water containing 2.5 or 5% calcium lactate. Daily water intake was recorded, and daily calcium lactate intake was calculated from this. High dose males were exposed to a grand total of 625.4 g calcium lactate, and low dose males to a grand total of 329.4 g calcium lactate. For females, these numbers were 412.1 g and 237.7 g, respectively.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily, ad lib.
Post exposure period:
9 weeks
Remarks:
Doses / Concentrations:
2.5% calcium lactate in drinking water
Basis:
nominal in water
Remarks:
Doses / Concentrations:
5% calcium lactate in drinking water
Basis:
nominal in water
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: Autopsy on rats that died during study and those killed at the end. Examinations macro- and microscopically for presence of non-neoplastic and neoplastic lesions.
Observations and examinations performed and frequency:
Rats were randomly allocated to three groups, each consistmg of 50 males and 50 females. They were housed three (or four) males or five females to a plastic cage and kept m an air-conditioned ammal room ( 2 4 ± P C , 55 ± 5% relative humidity) Calcium lactate was dissolved in distilled water_at Ievels_of_0_£control)r"2 5 or 5%.. These doses were selected after a 13-wk subchronic toxicity study done pnor to the present study v«i
CC: -fcr^r
589
/"-i (Matsushima et al, 1989) Rats were given these •^
solutions ad lib as their dnnking-water The calcium lactate solutions were replaced with freshly prepared solutions three times a week, on which occasions the amount of solutions consumed was measured m order to calculate the intake of calcium lactate Administration of the compound ended after 104 wk, and the rats were then given distilled water for a recovery penod of 9wk. At wkl!3, all surviving animals were killed and autopsied Haematological and biochemical exammations were also camed out m these rats
Throughout the expenment, rats in all groups were given the basal diet ad lib. They were observed daily and chnical signs and deaths were recorded. Body weights were measured once a week for the first 13 wk of the study, and every 4 wk thereafter
Sacrifice and pathology:
An autopsy was immediatelyperformed on rats that died (or were killed when moribund) during the study and those killed at the end of the study The animals were then examined macro- and microscopically for the presence of non-neoplastic and neoplastic lesions All organs and/or tissues were routinely fixed m 10% buffered formahn, sectioned and stained with haematoxylm and eosin.
Statistics:
Statistical analyse swere performed using Fisher's exact probabihty test and/or the chi-square test, and also the age-adjusted statistical test recommended by Peto et al. (1980).
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Result (carcinogenicity): negative
Relevance of carcinogenic effects / potential:
Since lactic acid is a major metabolic species, and a ubiquitous food ingredient, carcinogenicity is an irrelevant end point.
Conclusions:
It was concluded that lactate had neither toxic nor carcinogenic activity in F344 rats when it was given continuously in the drinking-water for 2 yr.
Executive summary:

The long-term toxicity carcinogenicity of lactate was examined in F344 rats. Lactate was given ad libidum 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 lactate. No significant dose-related increase was found in the incidences of tumours in any organ or tissue. The results indicated that 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.

Additional information

Lactic acid is a major and essential species in mammalian primary metabolism and a ubiquitous ingredient in all kinds of food. 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.

Justification for classification or non-classification