Manganese neodecanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No toxicity data on adverse effects on sexual function and fertility with manganese neodecanoate are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties manganese and neodecanoate.

Manganese neodecanoate is not expected to show adverse effects on sexual function and fertility, since the two moieties manganese and neodecanoic acid have not shown adverse effects reproduction in relevant high quality animal experiments.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Manganese(information taken from IEH, 2004)

In an NTP 2-year feeding study on Fischer 344 rats and B6C3F1 mice, there were no changes in testes weight noted and no effects on the seminiferous vesicles with manganese sulphate fed in the diet at concentrations of up to 15 000 ppm. Histopathological examination performed on mammary gland, ovary, prostate gland, testes/epididymis, and uterus did not reveal any test item-related effects (NTP, 1993).

 

In a study only briefly described, Kar et al. (1972) treated rats with 8 mg manganese chloride (8 mg/kg bw) intraperitoneally, daily. Testicular manganese content was determined together with levels of amino acids after 30 and 60 days. Manganese content of the testes showed a 4- and 9-fold increase respectively and after 60 days there were increases in alanine, cysteine, leucine, proline, phenylalanine and glutamine, as compared to controls. The authors concluded that manganese showed evidence of an effect on metabolism in the testes much earlier than changes in histology.

Laskey et al. (1982) chronically treated Long-Evans rats with manganese (II,III) oxide Mn3O4 beginning on day 1 of gestation up to 224 days of age. The manganese was administered in low or high iron diets at concentrations of 350, 1050 and 3050 ppm. The highest manganese level with low iron was stopped after 40 days as there were 50% fatalities. The highest concentration with sufficient iron in the diet, showed some reduction in fertility and the higher doses showed some minimal effects on male reproductive development as measured by testes weight, sperm count and serum follicle stimulating hormone and testosterone. None of these effects was severe enough to alter functional reproduction.

Laskey et al. (1985) described a study in which Long-Evans rats were dosed orally from birth to 21 days with particulate manganese (II,III) oxide (Mn3O4) at doses of 0, 71 or 214 μg/kg bw/day. Assessments were made of hypothalamic, pituitary and testicular function by the measurement of endogenous and stimulated serum concentrations of the pituitary hormones, luteinising hormone and follicle stimulating hormone, and testosterone after 21 and 28 days. There were no significant dose or time-dependent changes in body or testes weight or in follicle stimulating hormone or luteinising hormone levels. There was a significant reduction in serum testosterone after 7 days of stimulation with human chorionic gonadotropin and the authors suggested that any effect is at the level of the testicular Leydig cell and there are no effects on the hypothalamus or pituitary. The hypothalamic manganese concentration seen in these animals is three times that seen in other studies where alterations in the dopaminergic systems have been reported.

In a further study, male Sprague-Dawley rats were fed manganese sulphate (1000 ppm) in drinking water for 12 weeks and territorial aggression, sexual behaviour and fertility were then investigated. There was a decrease in territorial aggression in the treated rats and some slight effects on sexual behaviour, elongation in the time to ejaculation and post-ejaculation. There were no changes in fertility but an increase was seen in the number of resorptions (Bataineh et al., 1998).

New-born CD-1 mice were chronically exposed to manganese oxide for 58, 73 or 90 days. The control diet contained 50 ppm manganese sulphate while the treated mice were exposed to a further 1050 ppm manganese as manganese (IV) oxide. The mice were tested for reactive locomotor activity and sexual development. While body, liver and kidney weights remained unchanged, the growth of the testes, seminal vesicles and preputial glands were retarded. The activity of the rats in a maze over a 2-hour period was significantly reduced at 73 days (Gray & Laskey, 1980).

Joardar and Sharma (1990) compared the cytogenetic and clastogenetic effects of cationic (manganese sulphate) and anionic (potassium permanganate) salts of manganese in male Swiss mice. The manganese sulphate concentrations used were 610, 205 and 102.5 mg/kg bw and potassium permanganate, 380, 130 and 65 mg/kg bw. These concentrations constituted 1/5, 1/15 and 1/30 of a previously experimentally derived LD50 although no details are given. Among the endpoints measured was sperm-head abnormality in five animals for each treatment, administered orally for 5 days then killed after 35 days; 500 sperm were assessed for each animal. There was a significant trend for increased sperm head abnormalities for both manganese sulphate and potassium permanganate.

Fertility was estimated in male Swiss mice exposed for 12 weeks to 1000, 2000, 4000 or 8000 mg/ℓ manganese chloride in drinking water (Elbetieha et al., 2001). Mice were then mated for 10 days with unexposed females, which were then killed after a further 10 days and the number of pregnant females, implantation sites, viable fetuses and resorptions recorded. Fertility was significantly reduced in males exposed to 8000 mg/ℓ although there were no changes in the other parameters. In a further experiment, female mice were exposed to the same concentrations of manganese chloride for 12 weeks and then mated with unexposed males for 10 days and killed after a further 10 days as before. Fertility was not reduced in any treatment group but the numbers of implantation sites and viable fetuses were significantly reduced in the highest dose group (8000 mg/ℓ).

 

Rabbits were treated with single intratracheal injection of manganese dioxide (250 mg/kg bw) and killed at 4 and 8 months for histological and biochemical analysis. After 8 months, groups of treated and untreated rabbits were also tested for fertility. After 4 months, there were signs of degeneration in about 30% of seminiferous tubules, while at 8 months there was extensive disruption of the tubules with marked degeneration of spermatocytes and spermatids. This was accompanied by infertility.

There were decreased levels of enzymes found in the testes of the treated rabbits — acid phosphatase

(27%), adenosine triphosphatase (38%), succinic dehydrogenase (78%). The authors suggested that manganese affected the energy metabolism in the testes leading to the destruction of sperm producing structures (Chandra et al., 1973b). In a further study by the same group (Imam & Chandra, 1975), male rabbits received daily intravenous injections of 3.5 mg manganese chloride /kg bw for 5, 10, 15 and 30 days before killing. The testes then underwent histological and histochemical analysis. Again, there was a decrease in succinic dehydrogenase and a decrease in glucose-6-phosphate dehydrogenase in the seminiferous tubules with increasing degeneration from day 5 onward.

Huang et al. (2001) showed that manganese nitrate inhibited sperm motility in vitro at a concentration of 500 ppm. However, there was no evidence of accompanying lipid peroxidation, measured by the production of malondialdehyde and indicative of free radical damage. The authors concluded that this effect on sperm motility at high concentration was not biologically or environmentally relevant.

 

A number of studies in rats, mice and rabbits suggest that manganese has an adverse effect on male reproductive organs and fertility.

However, the results from the best reported study, that of a 2-year study in rats and mice (NTP, 1993), indicated no change in testes weight or in the seminiferous tubules on exposure to manganese sulphate at concentrations up to 15 000 ppm.

 

Neodecanoate

In a modified three-generation reproductive toxicity study, male and female Sprague-Dawley rats were administered neodecanoic acid at 0, 100, 500 and 1500 ppm (approximately 0, 5, 25 and 75 mg/kg-bw/day, respectively) in the diet. No adverse effects were observed on survival, appearance, behaviour, body-weight gain and food consumption in the parental, F1 or F2 generations. The reproductive performance of the parents was not affected. No treatment-related gross or microscopic pathological findings were observed at any of the dietary levels.

 

No classification for reproductive toxicity is indicated according to the classification, labelling and packaging (CLP) regulation (EC) No 1272/2008.

 

Manganese neodecanoate

Information on the individual moieties manganese and neodecanoic acid 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/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.

Effects on developmental toxicity

Description of key information

No toxicity data on adverse effects on development of the offspring with manganese neodecanoate are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties manganese and neodecanoate. 

Manganese neodecanoate is not expected to impair development, since the two moieties manganese and neodecanoate have not shown adverse effects on developmental.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Manganese

In a prenatal developmental toxicity study manganese sulphate was administered to female rats in the diet at concentration of 24, 54, 154, 504, or 1004 mg manganese /kg dry diet for 8 weeks. After 8 weeks the animals were allowed to mate. On gestational day 21 the animals were sacrificed, the uterus removed and the number of foetuses, implantation sites and resorptions were determined. The foetuses were subject to skeletal staining and the concentrations of manganese, Fe, Cu and Zn were determined in both whole foetus and maternal liver. There was no impact on foetuses at any of the doses studied. There was also no impact on reproductive parameters at any dose level. It was also observed that increasing dietary concentrations of manganese caused a decrease in iron concentration in the foetus and in the maternal liver. The effect of manganese in diet on concentration of Cu and Zn in foetus and maternal liver was relatively modest.

 

In a study by Webster and Valois (1987) pregnant female mice were treated with a single intraperitoneal injection of 12.5, 25 or 50 mg manganese sulphate on day 8, 9 or 10 of pregnancy. On day 8, the highest dose was embryolethal and the other doses induced a low incidence of neural tube defects in the surviving foetuses. The 25 mg dose caused maternal toxicity, coinciding with peak blood concentrations of 1000 ng/mL for 30 minutes. Blood levels exceeded 100 ng/mL for 24 hours. When manganese was incubated with rat embryos for 48 hours, 25 and 50 ng/mL had no effect while there was no survival at 200 ng/mL. They also looked at postnatal brain manganese after a single dose of 54Mn and found that manganese entered the foetal and neonatal brain more easily than the adult brain.

 

Neodecanoate

In a modified three-generation reproductive toxicity study, male and female Sprague-Dawley rats were administered neodecanoic acid at 0, 100, 500 and 1500 ppm (approximately 0, 5, 25 and 75 mg/kg-bw/day, respectively) in the diet. No adverse effects were observed on survival, appearance, behaviour, body-weight gain and food consumption in the parental, F1 or F2 generations. The reproductive performance of the parents was not affected. No treatment-related gross or microscopic pathological findings were observed at any of the dietary levels.

 

In a prenatal developmental toxicity study, pregnant rats, n=22 per dose, were treated by oral gavage to 50, 250, 600 or 800 mg/kg/day Neoheptanoic acid during gestation days 6-15. On gestation day 21, the dams were euthanized and the pups were examined for signs of developmental toxicity. Under the conditions of the experimental methods, the test material produced maternal toxicity at dose levels of 600 and 800 mg/kg with maternal lethality at 800 mg/kg. The test material was severely embryotoxic at 800 mg/kg with less than 20% of embryos surviving. Offspring of the 800 mg/kg group had reduced body weight, reduced crown-rump distance, displayed variations signifying delayed development, and a significant percentage (25%) were malformed. In the 600 mg/kg group, there was an increase number of dams with 3 or more resorptions. Offspring of the 600 mg/kg group displayed significant incidences of major (hydrocephalus) and minor (knobby or angular ribs, extra lumbar vertebrae) malformations but showed few signs of delayed development and were not runted. There was no statistically significant evidence of maternal toxicity at dose levels of 50 or 250 mg/kg. There was a slight, but not statistically significant, increase in embryonic resorption noted for the 250 mg/kg group. There was no statistically significant evidence of developmental toxicity at doses for 50 or 250 mg/kg. The NOAEL for maternal toxicity is 600 mg/kg and the NOAEL for developmental toxicity is 250 mg/kg. 

 

No classification for reproductive or developmental toxicity is indicated according to the classification, labelling and packaging (CLP) regulation (EC) No 1272/2008.

 

Manganese neodecanoate

Information on the individual moieties manganese and neodecanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of manganese neodecanoate.For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.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/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 chronic repeated dose toxicity study will be used.

Justification for classification or non-classification

Manganese neodecanoate is not expected to impair fertility or development, since the two moieties manganese and neodecanoate have not shown adverse effects in reproduction or prenatal developmental toxicity studies. No classification for toxicity to reproduction is indicated according to the classification, labelling and packaging (CLP) regulation (EC) No 1272/2008.