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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

There is no toxicological data available to assess the carcinogenic potential of the target substance ammonium-S-lactate. As ammonium-S-lactate dissociates into ammonium ions (NH4+) and lactate in aqueous and/or physiological conditions, the carcinogenic potential can be assessed by a read-across approach considering information from studies with dissociable compounds consisting of ammonium ions and lactate. For more details on the read-across justification, please refer to IUCLID section 13.

Based on the available data from the source substances calcium lactate, ammonium chloride and ammonium sulphate, the target substance ammonium-S-lactate can be considered as non-carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

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Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
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
Vehicle:
unchanged (no vehicle)
Clinical signs:
no effects observed
Description (incidence and severity):
There were no treatment-related abnormalities in condition or behaviour.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
In the chronic studies mortality rate was not affected by treatment with NH4Cl. The overall mortality rate at termination of the 30-month study was 62, 40 and 52% for males, and 69, 68 and 64% for females of the control, the 1% and 2.1% NH4Cl group, respectively.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the 30-month study, mean body weights were decreased in males and females of the 2.1% NH4Cl group. Body weights were also statistically significantly decreased in females of the 1% NH4Cl group at various stages of the 30-month study.The overall differences with the controls were between 4 and 10%.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no consistent differences in food intake among the groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
In the 2.1% NH4Cl group, water intake was ca. 20% increased in males at all stages but not in females. Water consumption was not noticeably affected by 1% NH4Cl treatment.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There were no consistent or treatment-related effects on red blood cell variables, clotting potential or total and differential white blood cell counts in any of the groups. Plasma chloride levels were increased with 2.1% NH4Cl, and occasionally in females fed 1% NH4Cl. The feeding of NH4Cl was accompanied by a dose-related decrease in base excess, associated with lower blood pH and bicarbonate concentration.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Alkaline phosphatase activity was increased in males fed 2.1% NH4Cl during the first few months.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Urinary pH was consistently decreased in rats fed 1 and 2.1% NH4Cl. The 2.1% NH4Cl diet induced increased titratable acidity and ammonia excretion. Net acid excretion with NH4Cl was also affected at the low-dose level. During the 4-day collection period in week 53, it was shown, that 2.1% NH4Cl significantly raised the urinary output of calcium from 1 to 2% and 4 to 7% of the total calcium intake, and the urinary output of phosphorus from 25 to 31% of the phosphorus intake. The volume of the urine collected during 24 h (food and water available), was generally increased in rats fed 2.1% NH4Cl. In females, this finding was no longer apparent in the later stages of the study, which may have been due to the high values obtained in the control group. The urinary density did not show consistent differences but tended to be decreased in males. Calcium and phosphate excretion showed dose-related increases in rats fed 1 and 2.1% NH4Cl and urinary urea excretion was increased with NH4Cl.
Brownish discoloration of the urine and haematuria of the urinary sediment were occasionally increased in rats fed NH4Cl, but there were no consistent or dose-related differences in incidence or severity of hematuria among these groups.
From 18 months (week 78 and 129), the incidence of granular casts in the urinary sediment was increased with 2.1% NH4Cl in both sexes. The occurrence of crystals was not affected in any group.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The relative weight of the kidneys (relative to body weight) was increased in rats of both sexes fed 2.1% NH4Cl after 4- and 13-weeks, and remained relatively high with 2.1% NH4Cl at the subsequent stages. There were no consistent or treatment-related changes in the weights of the liver, spleen, ovaries, pituitary, thyroid, thymus or heart.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic examination at necropsy after 30 months did not reveal significant differences among the treatment groups and the controls.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Most histopathological changes observed were about equally distributed among the treatment groups and the controls and represented normal background pathology for rats of this strain and age. A number of treatment-related non-neoplastic changes was observed:
Adrenals: Dose-related increases in the incidence of zona glomerulosa hypertrophy occurred in all treatment groups in both sexes at the end of the 30-month study. The zona glomerulosa was distinctly wider than in controls; the cells in this area were enlarged and showed a finely vacuolar cytoplasm.
Kidneys: With 2.1% NH4Cl, the incidence of oncocytic tubules was significantly decreased after 30 months. The overall incidence of nephrosis was comparable among the groups throughout the studies, but after 30 months the incidence of severe nephrosis was decreased in males of the 2.1% NH4Cl group, while the qualification ‘very severe nephrosis’ did not occur in this group. Nephrosis or chronic progressive nephrosis is a common lesion in ageing male Wistar rats,
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
In females, relatively high incidences of (adeno)carcinomas were found in the mammary gland with 2.1% NH4Cl. Because these changes were not accompanied by preneoplastic alterations in the 18- and 30-month studies and because their incidences were within the historical control data range, these findings were not related to treatment.
Apart from this observation, there were no treatment-related changes in any specific tumour type among the groups. The total number of rats with tumours or the total incidence of tumours was not affected by the treatment.
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 006 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 204 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effects observed
Key result
Critical effects observed:
no
Conclusions:
In conclusion, in a combined chronic toxicity/carcinogenicity feeding study, rats were orally exposed to 0, 1 and 2.1% ammonium chloride (corresponding to 455 and 1006 mg/kg bw/day for males and 551 and 1204 mg/kg bw/day for females) via the diet for 30 months. Ammonium chloride treatment did not affect the tumor incidence. It was concluded, that most of the observed changes can be regarded as physiological adaptations. Based on the results from this study, ammonium chloride can be considered to be non-carcinogenic.
Executive summary:

In a combined chronic toxicity/carcinogenicity study (similar to OECD 453), ammonium chloride (≥99.5% purity) was administered to 50 Wistar rats/sex/dose at dose levels of 0% (plain diet), 1% (corresponding to 455 mg/kg bw for males and 551 mg/kg bw for females) and 2.1% (1006 mg/kg bw/day for males and 1204 mg/kg bw/day for females) via the diet for 30 months.

No compound related effects in mortality, clinical signs, food consumption, clinical chemistry or gross pathology were observed. There was a slight decrease in body weight gain in males and females treated with ammonium chloride compared to controls. Increases in the incidence of zona glomerulosa hypertrophy occurred in the treatment groups in both sexes. Treatment with ammonium chloride decreased urinary pH, base excess in blood and increased urinary net acid excretion. Relative kidney weight was increased at early stages of the study.

In females, relatively high incidences of (adeno)carcinomas were found in the mammary gland with 2.1% ammonium chloride. Since these lesions were not accompanied by preneoplastic alterations at earlier timepoints and their incidences were within the range of historical control data, they were not considered treatment-related.

Apart from these observations, ammonium chloride did neither affect type, incidence and multiplicity of tumours, nor time of tumour appearance and the ratio benign-malignant tumours when compared to controls. It was concluded that most of the observed changes can be regarded as physiological adaptations.

Based on the results from this study, ammonium chloride can be considered to be non-carcinogenic and the NOAEL is 1006 mg/kg bw/day for males and 1204 mg/kg bw/day for females.

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:
weight of evidence
Justification for type of information:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
GLP compliance:
not specified
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.
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.
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:
effects observed, non-treatment-related
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 (see IUCLID section 13).

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
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
Description (incidence and severity):
Regarding general conditions, no obvious findings were observed in any group.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
The survival rate of the control, 1.5% and 3.0% dose group were 88%, 78% and 76%, respectively, for males, and 76%, 80% and 80%, respectively, for females. No significant difference was not observed among the groups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test substance-related change in body weights was found.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test substance-related change in food intake was found.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no obvious macroscopic findings in any group, except for massive, nodular or focal lesions suggesting neoplastic change.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
As a non-neoplastic lesion, incidence of chronic nephropathy in the kidney was significantly increased in the male 1.5% group. A similar increase, although not statistically significant, was also observed in the 3.0% group. As for other lesions, such as altered hepatocellular foci and bile duct proliferation in the liver and retinal atrophy in the eye were noted in the control and treatment groups, with no significant inter-group difference in their incidences or severity.
No effects were seen on reproductive organs (testis, ovary/uterus).
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Neoplastic lesions such as C-cell adenomas/adenocarcinomas in the thyroids, fibroadenomas/adenomas/adenocarcinomasin the mammary glands, adenomas/adenocarcinomas in the pituitary glands, interstitial cell tumors in the testes and endometrial stromal polyps in the uteri were noted in all groups, but these are all known to occur spontaneously in this strain, and neither increases in their incidences nor specific types of lesions were observed in the test-substance-administered groups.
Other effects:
not examined
Details on results:
On the other hand, by
The incidence of chronic nephropathy was increased in the 1.5% and 3.0% males as compared to the control, and relation to the kidney weight changes did not seem to be negligible.
Relevance of carcinogenic effects / potential:
While several tumors were noted there were no significant inter-group differences in their incidence or histological types, all being spontaneous tumors described previously in the same strain (Maekawa et al., 1983: Spontaneous tumors in F344/DuCrj rats. Gann 74, 365–372). Although some neoplastic lesions, such as malignant pheochromocytoma in the adrenal gland and adenomas in the anterior pituitaries were observed in the 3.0% group in the chronic toxicity study, no induction of such tumors was evident in the carcinogenicity study.
Key result
Dose descriptor:
LOAEL
Effect level:
1.5 other: % in diet
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
1.5 other: in diet
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no adverse effects observed
Conclusions:
In conclusion, in a carcinogenicity feeding study, ammonium sulfate was administered to rats for 104 weeks. No evidence of long-term carcinogenic activity was found.
Executive summary:

In a carcinogenicity study, ammonium sulfate was administered to 50 Fischer 344/DuCrj rats/sex/dose in the diet at dose levels of 0, 1.5% (corresponding to 564 and 650 mg/kg bw/day in males and females, respectively) and 3.0% (corresponding to 1288 and 1371 mg/kg bw/day in males and females, respectively) for 104 weeks. There were no compound related effects in mortality, clinical signs, body weight, food consumption or gross pathology.

The incidence of chronic nephropathy was increased in the 1.5% and 3.0% males as compared to the control after 104 weeks. At the doses tested, there was no treatment related increase in tumor incidence when compared to controls.

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 attached read-across report (see 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, ammonium-S-lactate does not warrant classification for carcinogenicity in accordance with CLP Regulation 1272/2008.

Additional information

No data is available for the target substance ammonium-S-lactate itself to assess the carcinogenic potential. Dissociation of ammonium-S-lactate in aqueous and/or physiological conditions results in the formation of ammonium (NH4+) and lactate ions. Oral ingestion of ammonium-S-lactate by living organisms, most notably humans, will therefore result in systemic exposure to the dissociation products of ammonium-S-lactate and the toxicology can be understood accordingly. In line with the read-across approach, data from the suitable read-across partners calcium lactate, ammonium chloride and ammonium sulphate were used.

In a combined chronic toxicity/ carcinogenicity study, calcium lactate (>97% purity) was administered ad libitum to F344 rats in drinking-water at levels of 0, 2.5 or 5 % for two years (Maekawa et al., 1991). 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.

In addition, in a carcinogenicity study, ammonium sulphate was administered to 50 Fischer 344/DuCrj rats/sex/dose in the diet at dose levels of 0, 1.5% (corresponding to 564 and 650 mg/kg bw/day in males and females, respectively) and 3.0% (corresponding to 1288 and 1371 mg/kg bw/day in males and females, respectively) for 104 weeks. No evidence of long-term carcinogenic activity was found (Ota et al., 2006)

In another combined chronic toxicity/ carcinogenicity study in rats (Lina et al., 2006, ammonium chloride treatment via the diet at dose levels up to 2.1% (corresponding to 1006 mg/kg bw/day for males and 1204 mg/kg bw/day for females) caused incidences of (adeno)carcinomas in the mammary gland of animals in the 2.1% dose group, but as these lesions were not accompanied by preneoplastic alterations at earlier timepoints and their incidences were within the range of historical control data, they were not considered treatment-related. Apart from these observations, ammonium chloride did neither affect type, incidence and multiplicity of tumours, nor time of tumour appearance and the ratio benign-malignant tumours when compared to controls.

Overall, the studies performed with the read-across partners do not suggest any substance-related carcinogenic potential.

Based on the available data, the target substance ammonium-S-lactate is not considered to be carcinogenic.