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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

chronic toxicity: oral
Type of information:
other: Data sharing dispute
Adequacy of study:
key study
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: No standard test guideline followed. No test concentrations noted or measured, only pH values.

Data source

Reference Type:
Systemic and local effects of long-term exposure to alkaline drinking water in rats
Merne M.E.T., Syrjänen KJ, Syrjänen SM
Bibliographic source:
Int. J. Exp. Path. 82, 231-219

Materials and methods

Principles of method if other than guideline:
To assess the systemic (organ) and local (oral mucosal) effects of alkalinity, drinking water supplemented with Ca(OH)2 or NaOH to adjust pH to 11.2 or 12 was administered to rats (n=36) for 52 weeks.
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium hydroxide
EC Number:
EC Name:
Sodium hydroxide
Cas Number:
Molecular formula:
sodium hydroxide

Test animals

Details on test animals or test system and environmental conditions:
- Age at study initiation: in groups 1, 2 and 3, the experiment was started when the rats were 12 weeks old, and in grouops 4 and 5 at the age of 6 weeks
- Housing: rats were housed in solid-polycarbonate bottom metal wire cages with alderwood bedding in groups of three.
- Diet (e.g. ad libitum): the animals were provided with standard laboratory animal feed (SDS, RM3, Essex, UK).
- Water (e.g. ad libitum): water was always available ad libitum. The water given to the rats in the study groups was modified to meet the criteria of the study design

- Temperature (°C): 20-22°C
- Humidity (%): (relative), 45-55%
- Photoperiod (hrs dark / hrs light): 12-h light and 12-h dark cycle

Administration / exposure

Route of administration:
oral: drinking water
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
the duration of the experiment in all groups was one year (52 weeks)
No. of animals per sex per dose:
group 1 (control, pH 7): 6 females, 6 males
group 2 (Ca(OH)2, pH 11.2): 6 females, 6 males
group 3 (NaOH, pH 11.2) : 6 females, 6 males
group 4 (Ca(OH)2, pH 12): 3 females, 3 males
group 5 (NaOH, pH 12): 3 females, 3 males
Control animals:
yes, concurrent vehicle


Sacrifice and pathology:
After completion of the study, the rats were killed using carbon dioxide, and necropsy samples were taken from the oral buccal mucosa, palate, tongue, oesophagus, stomach, intestines, liver, and kidney. in groups 4 and 5, additional samples were obtained from the salivary glands (parotis, submandibularis, sublingualis), masseter muscle, thyroid, hypothalamus, and overay or testes. The samples were fixed in 10% neutral formalin, embedded in paraffin, cut into 5-µm sections, and stained with haema
toxylin and eosin for routine light microscopic evaluation. All biopsy samples were examined by a board-certified pathologist (KS), blinded for all other data.
Other examinations:
All animals were weighed at the completion of the experiment
Kruskall-Wallis test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: All animals survived the experiment and remained in good condition until the end of the experiment. However, female rats, especially in Group 2 but also in Group 4 and 5, had dull-appearing and thin fur in patches at the end of the experiment. Some light-brownish discoloration of the oral mucosa was seen in Group 2 rats.

BODY WEIGHT AND WEIGHT GAIN: The mean weight of the rats in the experimental groups was lower (1-29%) than that of control animals. The lowest bodyweight was observed in rats receiving Ca(OH)2 and in those with exposure starting at low age (6 weeks). Thus, the weights of the rats in experimental groups differed statistically significantly from the controls in the following groups: female rats of group 2, female rats of Group 4, female and male rats of group 5

FOOD EFFICIENCY: food intake was equal in the study and control rats

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): water intake was monitored intermittently in all groups, showing no differences between groups.

NON-NEOPLASTIC: No histological changes attributable to alkaline exposure occurred in the oral mucosa or other tissues studied. Alkaline exposure did not affect cell proliferation in the oral epithelium, as shown by the equal expression did not affect cell proliferation in the oral epithelium, as shown by the equal expression of PCNA in groups. The up-regulation of HSP70 protein expression in the oral mucosa of rats exposed to alkaline water, especially Ca(OH)2 treated rats, may indicate a protective response. Intercellular adhesion molecule-1 (ICAM-1) positivity was lost in6/12 rats treated with Ca(OH)2 with pH 11.2, and loss of CD44 expression was seen in 3/6 rats in both study groups exposed to alkaline water with pH 12.

Effect levels

Remarks on result:
other: no details reported

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The results suggest that the oral mucosa in rats is resistant to the effects of highly alkaline drinking water. The observed effects on growth can be explained by NaOH neutralising the acid in the stomach which decreases the digestion and the absorption of the food. Oral studies with high concentrations of the substance are corrosive or irritating, while at low concentrations the hydroxide will be neutralised in the stomach by gastric juice, which has a very low pH. Furthermore it should be realised that oral exposure to NaOH is negligible under normal handling and use conditions. Weight of animals before testing is not described.

Applicant's summary and conclusion