Manganese neodecanoate

Endpoint summary

Description of key information

No repeated dose toxicity study with manganese neodecanoate is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties manganese and neodecanoate.

In relevant and reliable oral repeated dose toxicity studies as well as supporting studies for both moieties of manganese neodecanoate, there were no toxicological findings reported.

However, due to adverse effects observed in long-term inhalation studies and considering the read-across principles for manganese neodecanoate based on the toxicological assessment of the individual moieties, it is therefore proposed to also read-across the classification of Specific target organ toxicity-repeated exposure, category 2 based on neurological effects (H373- brain, inhalation) of manganese sulphate.

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:

adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Manganese, oral data(information taken from IEH, 2004)

The effects of 13 weeks of dietary administration of manganese sulphate to F344/N rats (at 1600, 3130, 6250, 12500 or 25 000 ppm) and B6C3F1 mice (3130, 6250, 12 500, 25 000 or 50 000 ppm) have been reported by NTP (1993). In rats, inclusion levels equated to overall doses of 110 to 1700 mg/kg bw/day in males and 115 to 2000 mg/kg/day in females. Treatment was generally well tolerated in the rats although some reduction in weight gain (up to 11%) occurred in females at 6250 ppm or above. No clearly treatment-related changes in haematology or histopathology were noted. However, liver weight (absolute and relative to body weight) was reduced in males and females given 25 000 ppm, as was lung weight in treated female groups. In mice, achieved doses ranged from 330 to 7400 mg/kg bw/day in males and 390 to 6900 mg/kg/day in females. Although food intake was essentially unaffected, growth performance was impaired in all treated male groups, particularly at 50 000 ppm (65% reduction). Female mice at the highest level showed a 36% reduction in weight gain. Other effects in mice were limited to the 50 000 ppm group, where reduced liver weight was noted in males and changes suggestive of microcytic anaemia (i.e., reduced haematocrit, haemoglobin and mean erythrocytic volume) were noted for both sexes. At this level 3/10 males also showed epithelial hyperplasia and hyperkeratosis of the forestomach.

 

In addition to assessing the carcinogenicity of manganese sulphate, a 2-year study by the NTP provided detailed information on a range of non-neurological endpoints following long-term dietary exposure (NTP, 1993). In the study, F344/N rats and B6C3F1 mice were fed diets containing manganese sulphate at 1500, 5000 or 15 000 ppm for 2 years. Achieved dosages were, for rats, 60, 200 or 615 mg/kg bw/day in males and 70, 230 or 715 mg/kg/day in females and, for mice, 160, 540 or 1800 mg/kg/day in males and 200, 700 or 2250 mg/kg/day in females. Endpoints considered included survival, general signs of toxicity, growth performance, clinical pathology, metal content of some tissues, and pathology. In rats, reduced survival, associated with increased severity of nephropathy and renal failure, was noted in males given 15 000 ppm from week 93. Males of this group also showed a slightly (5%) lower body weight until week 80, after which the difference between treated and control animals increased to approximately 10%. Other treated rats were not thus affected, and the food intakes of all groups were similar. Hepatic iron levels were reduced at 9 and 15 months for rats given 5000 ppm or above, while renal copper levels were increased in males at 9 months and females at 9- and 15-months. Secondary to the increased nephropathy in high dose males, increased incidences of mineralisation of blood vessels and glandular stomach, parathyroid hyperplasia, and fibrous osteodystrophy were noted. A somewhat different picture was seen in the mice. Overall, despite similar food intakes, body weights were reduced by 6, 9 and 13% in female mice given 1500, 5000 or 15 000 ppm, respectively; males were not thus affected. Haematology and clinical chemistry were unaffected, although hepatic iron levels were lower at 9 and 15 months in females and at 15 months in males given 5000 or 15 000 ppm. Non-neoplastic effects of treatment were restricted to increased incidences of thyroid follicular dilatation and hyperplasia, in mice given 15 000 ppm, and of focal epithelial hyperplasia, in males given 15 000 ppm and all groups of treated females.

 

Manganese, inhalation data(information taken from SCOEL, 2011)

Because of the heterogeneity of the data (different types of industry, different manganese compounds and particle sizes, different study designs and different neurofunctional measurements), and the inherent limitations of every individual study,it is not possible to identify one single critical study that would be the best basis for setting the IOELVs.Some studies identified a LOAEL, other a NOAEL. Some studies relied on the respirable fraction; other on the inhalable or “total” (thoracic) fraction. A global approach using the most methodologically-sound studies, as used in the IEH Criteria document (2004) and a number of additional good quality studies published since this review was therefore considered to be the most robust and reliable approach. The studies by Roelset al. (1992), Gibbset al.(1999) Myerset al.2003b, Younget al. 2005, Bast-Pettersenet al.(2004) and Ellingsenet al.(2008) as well as Lucchiniet al.1999 in HC (2008) which showed adverse neurological effects and identified a point-of-departure (POD) in the dose-effect/response relationship may offer a basis for recommending an IOELV.

Thus, a reasonablerespirable IOELVof0.05 mg/m³can be recommended, and a reasonableinhalable IOELVof0.2 mg/m³is also recommended. While recommending these values, SCOEL recognises that the overall systemic absorption of coarser particles (> respirable) is probably substantially lower than for the respirable fraction. Thus, SCOEL recommends both a respirable and an inhalable IOELV which would need to be observed conjointly.

 

 

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.

 

Manganese neodecanoate

Since no repeated dose toxicity study is available specifically for manganese neodecanoate, information on the individual moieties manganese and neodecanoate will be used for the hazard assessment and when applicable for the risk characterisation of manganese neodecanoate. For the purpose of hazard assessment of manganese 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 manganese neodecanoate, the NOAEL of 75 mg Neo/kg bw/day for the reproductive toxicity will be used. In case of manganese the NOAEL of 65 mg Mn/kg bw/day obtained in a repeated dose toxicity study will be used.

Justification for classification or non-classification

In relevant and reliable repeated dose toxicity studies as well as supporting studies for both moieties of manganese neodecanoate, there were no toxicological findings reported in oral toxicity studies. However, due to adverse effects observed in long-term inhalation studies and considering the read-across principles for manganese neodecanoate based on the toxicological assessment of the individual moieties, it is therefore proposed to also read-across the classification of Specific target organ toxicity-repeated exposure, category 2 based on neurological effects (H373- brain, inhalation) of manganese sulphate to manganese neodecanoate.