Lithium benzoate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Dosing up to 4 weeks prior to mating and after mating

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Since lithium benzoate will dissociate in biological systems, it is considered valid to assess separately lithium and benzoate.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2003

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Principles of method if other than guideline:

Female Rats were treated with lithium chloride in food at 280 mg lithium per kg food (ca 7 mg/Li day, or ca 28 mg/kg/day Li, based on typical diet and animal weight). The dose was increased by 50% after mating. There were initially 6 females/group. Females were allowed to give birth. Both groups were split so that half received control diet and half received lithium in food at 280 mg Li/kg during lactation. Pups were assessed at 8-10 weeks postnatal.

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Lithium chloride

EC Number:

231-212-3

EC Name:

Lithium chloride

Cas Number:

7447-41-8

Molecular formula:

ClLi

IUPAC Name:

lithium chloride

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

Males exposed for 90 days prior to mating

Details on mating procedure:

Untreated females

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg diet

Doses / concentrations 2

Dose / conc.:

500 mg/kg diet

Remarks:

As lithium carbonate = 5 mg/kg diet Li
At 125 g/day/kg bw per rat = 0.625 mg/kg Li

Doses / concentrations 3

Dose / conc.:

800 mg/kg diet

Remarks:

As lithium carbonate = 8 mg/kg diet Li
At 125 g/day/kg bw per rat = 1 mg/kg/day Li

Doses / concentrations 4

Dose / conc.:

1 100 mg/kg diet

Remarks:

As lithium carbonate = 11 mg/kg diet Li
At 125 g/day/kg bw per rat = 1.4 mg/kg/day Li

No. of animals per sex per dose:

20 males per group for effects on reproductive organs
Study was repeated at same dose levels with further 20 rats per dose to confirm reproductive indices. Mating took place from 90 days exposure.
A further set of animals were given a treatment free period of 45 days after 90 days treatment before mating and reproductive incides checked

Control animals:

yes, concurrent no treatment

Details on study design:

Rats received a diet containing 0, 500, 800, or 1100 mg lithium carbonate/kg diet for 90 days.

Examinations

Parental animals: Observations and examinations:

Body weight, daily intake of food and water were determined

Sperm parameters (parental animals):

intact spermatids were counted in a hemocytometer
Two hundred sperm from at least five different areas on the slide were studied microscopically and sperm with abnormal heads and/or abnormal tails were scored

Litter observations:

Number and viability of foeti were recorded 21 days post mating

Postmortem examinations (parental animals):

After 90 days of treatment, the testes, epididymis, prostate glands and seminal vesicles were removed and their wet weight was
determined.
The organ weight/body weight ratio was calculated and histological studies on testis, epididymis, vasdeferens,
seminal vesicle and prostate were carried out

Reproductive indices:

The females were killed on 21 days post-conception, and fertility index was analysed

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

The higher doses of lithium significantly reduced serum testosterone level in treated animals as compared to control
group

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: sperm measures:

effects observed, treatment-related

Description (incidence and severity):

The alterations observed consisted mainly of abnormal tail with or without abnormal head at the higher treatment levels

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

No effects at 500 mg/kg diet (0.625 mg/kg Li)
At higher treatment levels, there was a dose response in fertility measured by viable implants
Mating indices were not affects

Effect levels (P0)

1

Key result

Dose descriptor:

NOEL

Effect level:

ca. 0.625 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

Lithium

Sex:

male

Basis for effect level:

haematology

organ weights and organ / body weight ratios

gross pathology

reproductive function (sperm measures)

reproductive performance

2

Dose descriptor:

LOAEL

Effect level:

ca. 1 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

Lithium

Sex:

male

Basis for effect level:

haematology

organ weights and organ / body weight ratios

gross pathology

reproductive function (sperm measures)

reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:

yes

Lowest effective dose / conc.:

1 mg/kg bw/day (actual dose received)

System:

male reproductive system

Organ:

testes

Treatment related:

yes

Dose response relationship:

yes

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Description (incidence and severity):

Study for fertility was terminated prior to birth

Mortality / viability:

no mortality observed

Description (incidence and severity):

Based on health foeti

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 1.4 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

Lithium

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

1 mg/kg bw/day (nominal)

Treatment related:

yes

Relation to other toxic effects:

not specified

Dose response relationship:

yes

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, treatment of 1 mg/kg/day and higher led to a reduction in fertily through lower sperm viability and possible damage to testis. At 0.625 mg/kg/day, there were no adverse effects.

It should be noted that company data used by registrants of other litium salts cite regulatory studies showing that a higher dose, up to parental toxicity levels, does not impact on fertility. Access to these company studies is being sought, but it is concluded by other registrants of Li salts that lithium does not affect fertily at concentrations up to parental toxic limits.

As a result, based on conclusions drawn by those with access to study reports for other lithium salts, it is not proposed to classified as toxic to reproduction on the basis of this publication.

However, other published reports (with less detail on methods and results) do suggest damage to male and demal reproductive organs at dose levels higher than the theraputic dose levels used for medicinal purposes.