Lithium 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 lithium neodecanoate are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties lithium and neodecanoate. Lithium neodecanoate is not expected to show adverse effects on sexual function and fertility, since the two moieties lithium 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

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

 

Lithium

Two-generation reproduction toxicity study in Rats by oral administration (Advinus, G7469, 2012)

A two-generation reproduction toxicity study in rats with lithium carbonate was performed according to OECD Guideline No. 416 (2001). The test item was dissolved in Milli-Q water and administered orally to Wistar rats at dose levels of 5, 15 and 45 mg/kg bw/day. Similarly, concurrent vehicle control group animals were administered Milli-Q water (vehicle) alone.

 

A stability and homogeneity study (Advinus Study No.: G7467) for lithium carbonate was carried out at concentrations of 0.1 and 100.0 mg/mL in Milli-Q water. The results indicated that the test item was homogeneous in the vehicle and stable for up to 8 days at both the concentration levels when stored at room temperature. The dose formulations were analyzed for test item concentrations on Day 1 and once in every 3 months during the treatment period. The results indicated that the mean concentrations were within the 10 % permissible variation against the nominal concentrations of 0.5, 1.5 and 4.5 mg/mL.

Each group consisted of 25 male and 25 female rats. Animals from all groups were observed for clinical signs, behaviour, physical abnormalities and changes in body weight, food and water consumption during various phases of the experiment. The oestrous cycle length and pattern was evaluated by vaginal smears examination for all females during 2 weeks prior to mating. After a minimum of 10 weeks of treatment, females were cohabitated with males in a 1:1 (one male to one female) ratio. The number, weight, survivability and mortality of pups were observed during the lactation period. Physical signs of postnatal development were observed daily until the criterion was met. Vaginal opening and preputial separation were also observed in pups selected for the F1-generation.

The animals were subjected to detailed necropsy at sacrifice and study plan specified organs were weighed. Andrological assessment like sperm motility was evaluated for all groups, whereas the sperm morphology, enumeration of homogenisation resistant testicular spermatids and caudaepididymal sperm counts were carried out only in control and high dose groups.

Histopathological examination of parents was initially carried out for the preserved organs including gross lesions from control and high dose group animals. Further, based on the microscopic changes observed in the high dose, liver, kidneys and adrenals from males and liver, kidneys and thyroid from females of P generation and liver, kidneys and thyroid from males, liver and kidneys from females of F1 generation were considered as target organs and were examined in lower dose groups. The reproductive organs of non-pregnant females were also examined in the low and mid dose groups.

The left testis was collected in modified Davidson’s fixative and one 4-5 µm thick section was prepared and stained with PAS and Haematoxylin for microscopic examination.

The post lactational ovaries were examined for qualitative depletion of primordial follicles. A quantitative evaluation of primordial and primary follicles was done in F1 females. Ovarian follicle count was carried out for the control and high dose groups and all the not littered females of F1 generation suspected of reduced fertility.

For F1 and F2 weanlings, histopathological examination of the organs of reproductive system and kidneys as potential primary target was carried out for the available one randomly selected pup/sex/litter in all the groups. All gross lesions were also examined for the pups with external abnormalities or clinical signs.

 

At 5 mg/kg bw/day had no effects on general health, body weights, food and water intake, oestrus cyclicity, preciotal time, gestation length, pups survivability, mating, fertility, fecundity or sperm parameters in both generations. There were no treatment-related changes with regard to any absolute or relative organ weights including reproductive organs and other gross or microscopic findings of parents, offspring or weanlings in both the generations.

 

At 15 mg/kg bw/day, treatment significantly increased the water intake periodically in males of both generations. There were no effects on general health, body weights, food intake, oestrous cyclicity, pre-coital time, gestation length, pups survivability, mating, fertility, and fecundity or sperm parameters in both the generations. There were no treatment-related changes in reproductive and other organ weights and gross findings of parents or weanlings in both the generations. Microscopically, slightly dilated tubules of kidneys were seen in both generation males and females, however they were considered to be an adaptation to the pharmacology of lithium carbonate (vasopressin-downregulation) and therefore not considered as a toxicological effect.

 

At 45 mg/kg bw/day, treatment-related findings included increased body weights and net body weight gains in males of P generation and increased water intake in both P and F1 generations in males. Apparently higher net body weight gains were observed in both P and F1 generations premating females. There were no treatment-related changes in reproductive organ weights and gross findings of parents or weanlings in both the generations. There were also no relevant treatment-related changes in oestrous cyclicity, pre-coital time, gestation length, pups survivability, mating, fertility, and fecundity or sperm parameters in both the generations when dose response and historical control ranges were taken into account. Post-mortem examination in P generation demonstrated a higher body weight in males, a significant increase in the absolute and relative liver weight in males and in the relative liver weight in females. Furthermore, a marginal increase in absolute and relative adrenal weight and an increase in absolute but not in relative weight of thyroid in males only was noted.

In F1 generation, the terminal body weight was not affected. A significant increase in the absolute and relative liver weight was observed in males only.

Microscopically, increased cytoplasmic rarefaction of hepatocytes in liver in males was observed, whereas in females, hepatocellular hypertrophy and focal basophilic hepatocytes were observed. Increased colloids in thyroid follicles of females were also observed. However, these changes were not present in the F1 parental rats. In F1 generation, the terminal body weight was not affected. A significant increase in the liver weight was observed in males. Microscopically, increased cytoplasmic rarefaction of hepatocytes in liver in males was observed. In females, focal basophilic hepatocytes were observed in the liver. Finally, pronounced and severely dilated tubules of kidneys were observed in both generations. Taking into account the steep dose response curve of lithium carbonate, the changes and histopathological findings in kidneys and liver as well as the variations noted with regard to adrenals and thyroids, are considered as an early onset of lithium carbonate systemic toxicity.

 

Evaluation of pups showed that in both generations, the mean weight of male, female and total pups per litter at all the doses tested were unaffected by treatment and that there were no external abnormalities in live or dead pups in any of the groups. No treatment-related changes were observed in the survival data of pups up to lactation day 21 at all the doses tested. No relevant effects were seen for postnatal developmental observations in F1 and F2 pups such as pinna detachment, incisor eruption, ear opening, and eye opening. The mean age and body weights at acquisition of balano-preputial separation and vaginal opening in F1 were not affected by treatment when compared to vehicle control group. Finally, no test item related microscopic findings were observed in both male and female pups of F1 and F2 litters.

In view of the results observed:

- The “No Observed Adverse Effect Level (NOAEL)” for systemic toxicity in parental rats is considered to be 15 mg/kg bw/day. The effects observed at 45 mg/kg are considered to be of toxicological relevance. At this dose, not only various in vivo changes on body weight and water consumption but also pronounced morphological changes in liver and kidneys and some variations noted in one or the other sex on adrenals and thyroid glands ( in P generation), however, not in the F1 or F2 generation were noted.

- The “No Observed Adverse Effect Level (NOAEL)” for reproductive toxicity and foetal toxicity is considered to be 45 mg/kg bw/day as no clear substances related and biologically relevant effects on reproductive parameters were observed in the P, F1 and F2 generations. (Advinus, 2012)

 

Animal studies (literature data)

A literature reporting effects of prolonged subtoxic lithium ingestion on pregnancy in rats supports the lack of toxicity towards reproduction (Trautner, 1958). Other published studies in animals on sperm effects, effects to the male reproductive tract and subsequently impairment to fertility of male rats do not allow conclusion on toxicity to reproduction, in particular in humans, as either the studies describe mechanisms not operating in humans or did not allow discrimination between primary and secondary effects (Gosh, 1991; Gosh, 1991; Thakur, 2003, Zarnescu and Zamfirescut, 2006).

 

Case studies in humans (literature data)

Case reports on men under lithium therapy, also focus on sperm effects (Levin et al, 1981) or reduced libido sexualis (Blay et al, 1982). But the effects noted do not allow any conclusion as the number of cases is very low and confounding factors were not considered or the effects noted are most likely related secondary to the wished effect of lithium treatment.

Conclusion:

Based on available information of Lithium salts on reproductive effects in animals and humans, classification with respect to reproduction / fertility is not justified.

 

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.

 

Lithium neodecanoate

Information on the individual moieties lithium and neodecanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of lithium neodecanoate. For the purpose of hazard assessment of lithium 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 lithium neodecanoate, the NOAEL of 75 mg/kg bw/day for the reproductive toxicity will be used. In case of lithium the NOAEL of 1,21 mg Li/kg bw/day derived from human data, repeated dose toxicity via oral route will be used.

Effects on developmental toxicity

Description of key information

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

Lithium neodecanoate is not expected to impair development, since the two moieties lithium and neodecanoate have not shown adverse effects on development.

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

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

 

Lithium

Prenatal developmental toxicity study of Lithium carbonate in rats by oral administration (LPT, 24635, 2010):

With regard to the developmental toxicity, the most reliable and key study is the prenatal developmental toxicity study performed in Wistar rats (strain: Crl CD (SD)) according to OECD Guideline 414 and EU method B.31. In this rat embryotoxicity study, the test item lithium carbonate was administered to female rats at concentrations of 10, 30 or 90 mg/kg bw/day orally by gavage from the 6th to 19th day of pregnancy. Under the present test conditions, the no-observed-effect level (NOEL) was 30 mg lithium carbonate/kg bw/day for the dams (maternal NOEL). At 90 mg lithium carbonate/kg bw/day, pilo-erection was noted in a few dams. Furthermore, slight but significant reductions were noted for the net weight change and the food intake. The NOEL for the fetuses was >= 90 mg lithium carbonate/kg bw/day. There was no test item-related increase in the incidence of fetal malformations, external/ internal, skeletal or soft tissue variations or skeletal retardations. The toxicokinetic analysis revealed a clear dose-related systemic exposure to lithium.

In conclusion, no embryotoxic properties of the test item were noted during external/ internal, skeletal and soft tissue examinations. No test item-related increase was noted in the incidence of malformations, variations or retardations, not even at the materno-toxic dose level of 90 mg lithium carbonate/kg bw/day.

 

Animal studies (literature data) :

The literature data on the developmental toxicity profile of lithium carbonate in rats generally supported the findings observed in the key study.

 

In a prenatal developmental toxicity study equivalent to former OECD guideline 414, 20 pregnant Charles River female albino rats per group were dosed by gavage from gestation day 5 -15 with lithium carbonate solutions at 49.88, 149.63 and 299.25 mg/kg bw/day (0.675, 2.025 and 4.05 meq/kg/day, Gralla and McIlhenny, 1972). The control group received tap water. A low incidence of maternal mortality occurred at the highest dose level administered. Two pregnant female rats, which had received 299.25 mg/kg bw/day (4.05 meq/kg bw/day) died unexpectedly for unknown reasons. Except of these mortalities, no maternal or developmental toxicity up to the highest dose level occurred. The NOAEL for maternal and prenatal developmental toxicity including teratogenicity of 299.25 mg/kg bw/day in the rat was observed.

A pre- and postnatal developmental toxicity screening study was performed in Charles River albino rats (Gralla and McIlhenny, 1972). Lithium carbonate was administered by gavage to groups of 10 dams at doses of 0, 49.88, 149.63 or 299.25 mg/kg bw/day (0, 0.675, 2.025 or 4.05 meq/kg bw/day) by gastric intubation from gestation day 14 through 21 days of lactation. Body weight gain of neonatal rats was inhibited, when nursing females were given 299.25 mg/kg bw/day (4.05 meq/kg bw/day). Maternal parameters such as fertility, average number of implantation sites, average litter size, body weight gain and offspring body weight at 20 days gestation, offspring mortality and gross appearance or skeletal staining revealed no differences between treated and control group. A NOAEL for maternal toxicity of 299.25 mg/kg bw/day and a NOAEL for developmental toxicity of 149.63 mg/kg bw/day in the rat was observed, respectively.

 

The developmental toxicity of lithium hypochlorite as characteristically similar read across compound was examined in Sprague-Dawley rats in a study similar to OECD guideline 414 (Hoberman et al., 1990). Groups of 25 pregnant rats received lithium hypochlorite at doses of 0 (vehicle-reverse osmosis deionized water), 10, 50,100, or 500 mg/kg bw/day, via oral gavage once daily on days 6 through 15 of gestation. Significant maternal toxicity was observed in the 500 mg/kg bw/day dosage group, which included maternal death, clinical signs, gross necropsy findings, and inhibited maternal body weight gain and feed consumption. At this clearly maternal toxic dose the only effects on embryo-fetal development were small reversible delays in skeletal growth. The NOAEL for maternal and developmental toxicity for lithium hypochlorite was 100 mg/kg bw/day. The NOAEL for teratogenicity for lithium hypochlorite was 500 mg/kg bw/day.

 

There are also reliable literature data available on the developmental toxicity profile of Lithium carbonate in other species beside the rat. These studies are considered as sufficient for a weight of evidence approach (WoE).

In a prenatal developmental toxicity study similar to former OECD guideline 414, ten pregnant female New Zealand albino rabbits per group were dosed orally (capsule) with lithium carbonate in capsules from gestation days 5 -18 at doses of 49.88 or 79.80 mg/kg bw/day (0.675 or 1.08 meq/kg bw/day, Gralla and McIlhenny, 1972). A low incidence of maternal mortality occurred at the highest dose level administered. Three female rabbits, which received 79.80 mg/kg bw/day (1.08 meq/kg bw/day) died late in pregnancy after prolonged anorexia and occasional tremors. One non-pregnant female rabbit receiving 49.88 mg/kg bw/day (0.675 meq/kg bw/day) died unexpectedly overnight. No test item related congenital abnormalities were detected. The NOAEL for maternal toxicity was 49.88 mg/kg bw/day (0.675 meq/kg bw/day) and the NOEL for prenatal developmental toxicity including teratogenicity was the highest dose tested of 79.80 mg/kg bw/day (1.08 meq/kg bw/day).

 

The same group (Gralla and McIlhenny, 1972) performed a prenatal developmental toxicity study in female rhesus monkeys, which were successfully mated with mature males. Six females were dosed with lithium carbonate at 49.51 mg/kg bw/day (0.67 meq/kg bw/day) by capsule during days 14 through 35. Five additional female monkeys served as controls and received empty capsules. The offspring were either developed by cesarean section or the females were allowed to deliver naturally on day 160 +/- 2. Lithium carbonate had no effect on reproduction in rhesus monkeys. A total of 7 normal progeny, 2 females and 5 males, were delivered from treated pregnant rhesus monkeys. All were normal and comparable to 3 females and 1 male delivered by the control group. All parameters examined in all infant monkeys were normal and all grow up without showing clinically any physical defects at 12 -15 month of age. Thus, the dose of 49.51 mg/kg bw/day (0.67 meq/kg bw/day) investigated was a clear NOAEL for maternal and prenatal developmental toxicity including teratogenicity.

 

In a prenatal developmental toxicity screening study in female HaM/ICR mice, 16 - 20 animals were dosed with 200 and 465 mg/kg bw/day lithium carbonate suspended in 0.5 % tragacanth gel by gavage from day 6 to 15 of pregnancy (Szabo, 1970). The control group received the vehicle. The dams were killed on day 18 of pregnancy. The lowest dose of 200 mg/kg bw/day caused neither maternal nor foetal deaths and no relevant increase in cleft palate in the foetuses. The dose of 465 mg/kg bw/day was severely toxic and caused the death of 37 % of the dams. As a consequence of the severe maternal toxicity, 32 % foetal deaths were observed and 19/121 foetuses in 7/15 letters showed cleft palates. The association of severe maternal toxicity (stress) with an increased incidence of foetuses with cleft palates is known to be a common finding, especially in mice. Therefore, the fetal findings at a maternally lethal dose are considered to be not an indication for a substance specific teratogenicity but a consequence of severe maternal toxicity. The NOAEL for maternal and developmental toxicity including teratogenicity was 200 mg/kg bw/day.

 

In a pre- and postnatal developmental toxicity screening study, 12 pregnant pigs were orally exposed to 3000 mg/kg of lithium carbonate in the diet (corresponding to 36 mg/kg bw/day) during gestations days 30 through 114, Kelley et al., 1978). The control group consisted of 11 females. The lithium carbonate treated dams showed reduced body weights after 110 days. Five out of 12 pigs did not complete pregnancy. Average offspring born per litter and birth weight of the piglets did not differ. At this maternally toxic dose, there was a decrease in the number of piglets born alive and an increase in stillbirth and mummies in treated female pigs. In these females the litter weight was reduced. Postnatal mortality in piglets from treated females was increased but growth rates did not differ from control piglets. No abnormalities were reported.

 

Beside the above-mentioned studies there are a number of additional literature data on the developmental toxicity of lithium carbonate in rats (Fritz, 1988; Marathe and Thomas, 1986) and in mice (Smithberg and Dixit, 1982; Loevy and Catchpole, 1973; Szabo, 1970 (range-finding study); Mroczka et al., 1983) available. However, these studies have to be disregarded due to its questionable reliability. All of them have several limitations either due to missing controls and/or a single dose, not appropriate exposure route (intraperitoneal, subcutaneous) and/or limited exposure periods down to single days only. Deficiencies in reporting and assessment were also evident in these studies. Finally, in most cases effects on development were only observed at maternally overt toxic and/or lethal dose levels.

 

Finally, the literature data of lithium carbonate supported the conclusion that in general the developmental toxicity profile of was sufficiently and appropriately examined. All of these studies supported the findings observed in the key study.

 

Moreover, the prenatal developmental toxicity study in rabbits, performed by Gralla und McIlhenny, 1972, is considered as a sufficient study within a weight of evidence (WoE) approach. For WoE this study together with the other prenatal developmental toxicity studies, performed in mice, monkeys and pigs can be used. Within all these studies, fetal effects, especially in mice, occurred exclusively at excessive high dose level. These high dose levels induced overt signs of toxicity up to mortalities. In contrast, lower dose levels with no or only minor signs of maternal toxicity did not led to signs of developmental toxicity. In most of the cases, clear NOAELs for developmental toxicity, generally as high or higher than the NOAELs for maternal toxicity were obtained.

 

Human data (literature):

The effect of lithium carbonate was investigated in a prospective multicentre study of pregnancy outcome after lithium exposure during first trimester in pregnant women using lithium. The study showed that women with major affective disorders who wish to have children may continue lithium therapy, provided that adequate screening tests, including level 11 ultrasound and foetal echocardiography, are done (Jacobsen et al 1992). Babies of mothers treated with lithium carbonate in the first trimester were analysed for the potential malformation to the unborn. The data obtained did not reveal any increased frequency of physical or mental anomalies among the lithium children (Schou, M.; 1973; Schou, M.; 1976). Further studies on effects of lithium during pregnancy with ambiguous results (potential teratogenic target of lithium in humans: cardiovascular system) do not allow any conclusion with regard to the potential effects of lithium carbonate as all patients in this study were ill (manic depressive) and effects of confounding factors cannot be excluded. In addition, the cohort size was too small and bias effects are likely (Kallen, B. (1983). Possibly, cardiovascular malformations are specific to humans or to humans with coexisting psychiatric disorder (Giles, J.J., 2006) but based on a case-control studies, analysing cases of Ebstein's anomaly, also no clear conclusion could be drawn that lithium exposition during pregnancy is linked to an increase rate for Ebstein's anomaly (Zalzstein, E. et al, 1990, Correa-Villasenor, A. et al., 1994). Also in a study to quantify lithium exposure in nursing infants in 10 mother-infant pairs no serious adverse events were observed, and elevations of thyroid-stimulating hormone, blood urea nitrogen, and creatinine were few, minor, and transient and not considered of biological relevance (Viguera, A.C. et al., 2007).

 

Conclusion:

Based on available information of Lithium salts on teratogenic / developmental effects in animals and humans, classification with respect to teratogenicity / developmental toxicity is not justified.

Taken all the studies together, there is no need to investigate lithium carbonate again in a second species as sufficient information on the developmental toxicity profile is available in other species beside the rat.

 

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. 

Justification for classification or non-classification

Lithium neodecanoate is not expected to impair fertility or development, since the two moieties lithium 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.