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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Strontium

A sub-chronic study was conducted with strontium chloride hexahydrate using groups of 10 male and 10 female Wistar rats. The rats were given the test substance via diet at dose levels of 0, 75, 300, 1200 or 4800 ppm (0, 7.5, 30, 120, or 480 mg/kg/day, respectively) for a duration of 90 days. The following parameters were investigated: clinical signs/mortality, body weight, food consumption/food efficiency, haematology, clinical chemistry, urinalysis, organ weights, and histopathology. Additional 10 males were included as satellite animals for the determination of the strontium levels in blood, bone and muscle, which were examined in weeks 0, 4, 8 and 12.

In a range-finding experiment, rats with an initial body weight of 130-170 g were divided into 5 groups each consisting of 3 females and 3 males, receiving 0, 3, 30, 300 and 3000 ppm strontium chloride hexahydrate in the diets respectively during two weeks. The animals were weighed at the beginning of the experiment and after 1 and 2 weeks. Food intake was recorded during the experimental period and was measured per cage (two rats) and expressed as the average intake per day per rat. Food conversion was calculated, blood samples were taken at the end of the experiment and haematological investigation was restricted to haemoglobin, haematocrit and the number of erythrocytes and leucocytes. The mean cell volume, mean cell haemoglobin concentration, and mean cell haemoglobin were calculated. At the end of the 2 weeks X-ray photographs were made of all animals. Strontium concentration was measured in blood, bone and muscle. Liver and kidneys were weighed and examined histopathologically by preparing paraffin sections (5 µm) stained with hematoxylin and eosin. Behaviour, growth, food intake and food efficiency were not affected in the range-finding experiment. Haematological investigation revealed only a slight elevation of the total number of erythrocytes in males and females and a slight increase of the white cell count in the males at the highest dose level. No differences were found in liver and kidney weights and histopathological examination revealed no abnormalities. Strontium in blood and muscle were only noted at the highest dose level whereas from 300 ppm onwards increased concentrations were found in bone.

In the main study, growth, behaviour, food intake and food efficiency were not affected by the treatment. Apart from a slight increase in the ALP activity in the highest dose group, no differences in clinical chemistry were noted. Levels of Ca, Mg and P in blood were similar for all animals and the Ca/P ratio was unaffected. Significant increase of the relative thyroid weights was found for the males at the 1200 ppm (control group: 0.0054 %; treatment group: 0.0072 %; P < 0.01) and 4800 ppm dose levels (control group: 0.0054 %; treatment group: 0.0068 %; P < 0.001). Although, no reasoning for this finding was be given, it was regarded as treatment-related. Relative pituitary weights of the females at 300 ppm dose level (control group: 0.0074 %; treatment group: 0.0062 %; P < 0.05) and at 4800 ppm dose level (control group: 0.0074 %; treatment group: 0.0056 %; P < 0.01) were significantly decreased, but not in the 1200 ppm group. Due to the lack of a dose-response relationship, this finding is not considered biologically relevant. Glycogen depletion of the liver was noted in the highest dose group. However, this was may be caused by stress, starvation or diurnal rhythm and not by treatment with the test substance. Increased strontium concentrations in blood and muscle were solely measured in animals at 4800 ppm. The strontium content in bone was increased at all dose levels with a plateau on week 4 and onwards (steady state). No treatment-related changes were observed in the X-ray photographs or during microscopical examination. Slight changes in the liver (glycogen depletion) and thyroid (activation). Thus, up to the highest dose of 4800 ppm no rachitic changes occurred.

The NOAEL (males) of 300 ppm strontium chloride hexahydrate (equivalent to 30 mg/kg/day, nominal) was derived, based on the significant increase of the relative thyroid weights, found for the males at the 1200 ppm and 4800 ppm dose levels. The substance NOAEL corresponds to NOAEL (males) of 9.9 mg strontium/kg/day (nominal).

Neodecanoate

 Repeated dose toxicity, oral:

Seven male and seven female rats were exposed to 0; 10; 30; 100, or 300 mg/kg/day propanoic acid, 2,2-dimethyl- (CAS# 75-98-9) by oral gavage for 28 consecutive days (Shell Research Ltd., 1990). No treatment related changes were observed in body weight, food intake, haematology, or histopathology. The only clinical signs seen in this study were a shaking of heads, sneezing, dark nasal discharge, immediately after dosing 100 and 300 mg/kg/day. This behaviour could result from a mild irritant effect of the volatile acidic test compound. Slight increase of alkaline phosphatise, cholesterol and bilirubin levels at the 100 and 300 mg/kg/day dose levels, and slight increase of alkaline phosphatise and cholesterol levels in the plasma of females at the 30 mg/kg/day dose level. Increase in kidney and liver weight was observed in the 300 mg/kg/day group. None of these changes correlated with histopathological effects. These findings were considered adaptive changes and not indicative of a treatment-related adverse effect. The no observed adverse effect level (NOAEL) in this study was 300 mg/kg.

 

Five male and five female rats were exposed to 0; 10; 55; or 300 mg/kg/day fatty acids, C9-C13 neo (CAS# 68938-07-8) by oral gavage for 28 consecutive days (Shell Internationale Petroleum Maatschappij, 1994). There were no mortalities. Increased salivation was observed after dosing in rats receiving 300 mg/kg. No treatment related changes were observed in body weight, food consumption, haematology, or clinical chemistry. In males receiving 300 mg/kg, kidney weight increased and necropsy revealed an abnormal appearance of the kidney. A dose-related hyaline droplet was noted in males at all treatment levels. The findings in the kidney of the treated males are species and sex specific and not considered relevant to humans. The NOAEL in this study was 300 mg/kg.

 

Dermal

In a repeated-dose dermal study, neodecanoic acid was applied repeatedly (once daily for 10 applications with a rest period on days 5 and 6) to the skin of rabbits at doses of 0.5 or 2.5 ml/kg (400 or 2280 mg/kg/day).  All animals survived the exposure.  Wheezing was noted in one animal at the 0.5 ml dose level.  Animals at the lower dose level generally showed an overall body weight gain while those at the high level showed terminal weight losses.  The low level animals generally showed slight erythema and moderate atonia and desquamation following the first or fourth application and during the remainder of the study.  At the high level, moderate erythema and moderate or marked atonia and desquamation were present in all animals.  In addition, slight edema was present following the fifth application and slight fissures or cracks were observed in several animals following the last seven applications.  The exposed skin also became hypersensitive to the touch.  There were no indications of systemic toxicity attributed to exposure.

 

A repeated dose dermal toxicity study was conducted for propanoic acid, 2,2-dimethyl- (CAS# 75-98-9) in male rabbits (Hazelton Laboratories Inc., 1964). Test material in isopropyl alcohol solution was repeatedly applied to the shaved intact skin of albino rabbits 5 days/week for two weeks (for a total of 10 applications) at doses of 30 or 300 mg/kg/day. Slight to moderate irritation at the low dose and moderate to marked irritation at the high dose was observed. Slight or moderate erythema, atonia, and desquamation were seen at the low dose. At the high dose, skin irritation consisted of moderate erythema, slight to marked edema, moderate or marked atonia and desquamation. Some dermal necrosis at the site of application was seen in three rabbits and persisted throughout the study. Control animals that received only the solvent (isopropyl alcohol) showed slight irritation. There were no signs of systemic toxicity attributable to dermal absorption of propanoic acid, 2,2-dimethyl-. The NOAEL for systemic toxicity in this study was 300 mg/kg.

 

Carboxylic acid, C6-8 neo (CAS# 95823-36-2) was applied at 55.4 mg/kg and 553.7 mg/kg to the shaved intact skin of rabbits for 10 applications (Hazleton Laboratories, Inc., 1964). No treatment related effects were observed on behaviour of clinical signs during the in-life phase of the study. Gross pathology of the animals in all dose groups did not reveal any abnormalities. Repeated application of carboxylic acid C6-8 neo did produce marked skin irritation with some dermal necrosis at the site of application in the high dose group. Since no systemic effects were observed in this study, the NOAEL for systemic effects following subchronic dermal application of carboxylic acid, C6-8 neo was 553.7 mg/kg.

 

Members of the Neo acid C5 to C28 Category have a low order of toxicity under conditions of repeat exposure by oral and dermal routes. In addition, they display a consistent degree of subchronic toxicity by either oral or dermal route of exposure. No classification for repeated dose toxicity is indicated according to the classification, labelling, and packaging (CLP) regulation (EC) No 1272/2008.

 

Strontium neodecanoate

Since no repeated dose toxicity study is available specifically for strontium neodecanoate, information on the individual moieties strontium and neodecanoate will be used for the hazard assessment and when applicable for the risk characterisation of strontium neodecanoate.Since no adverse effects were observed in studies conducted with strontium and neodecanoate, in all probability strontium neodecanoate has also no potential to induce adverse effects after repeated exposure.

 

For the purpose of hazard assessment of strontium neodecanoate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of neodecanoic acid in strontium neodecanoate, the NOAEL of 75 mg/kg bw/day for the reproductive toxicity will be used.In case of strontium the NOAEL of 9.9 mg Sr/kg bw/day for the repeated dose toxicity will be used.

Justification for classification or non-classification

In relevant and reliable repeated dose toxicity studies for both moieties of strontium neodecanoate, there were no toxicological findings reported. Thus, according to the criteria of REGULATION (EC) No 1272/2008 and its subsequent adaptions, strontium neodecanoate does neither have to be classified and has no obligatory labelling requirement for repeated oral toxicity nor for specific target organ toxicity after repeated exposure (STOT RE).

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