Trilead dioxide phosphonate

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

effects on testes

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1984

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male rats were administered lead acetate in drinking water at concentrations of 0, 0.25, 0.5, and 1 g/L over 60 days and biochemical and histopathological analyses were performed on the testes.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Lead di(acetate)

EC Number:

206-104-4

EC Name:

Lead di(acetate)

Cas Number:

301-04-2

IUPAC Name:

lead (II) acetate trihydrate

Test material form:

not specified

Test animals

Species:

rat

Strain:

other: Albino

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Initial weight at study initiation: 70-80 g.
- Water: Deionized water was available ad libitum.

ENVIRONMENTAL CONDITIONS
Not specified.

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

Animals of the control group received deionized water ad libitum. Three other groups of animals received lead acetate in deionized drinking water ad libitum. Fresh solutions of lead acetate were prepared every day and a few drops of acetic acid were added to optimize solubility of the lead acetate.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Animals were dosed for 60 days.

Frequency of treatment:

Animals drank lead acetate-containing water ad libitum.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 other: g/L (nominal in water)

Doses / concentrations 2

Dose / conc.:

0.25 other: g/L (nominal in water)

Doses / concentrations 3

Dose / conc.:

0.5 other: g/L (nominal in water)

Doses / concentrations 4

Dose / conc.:

1 other: g/L (nominal in water)

No. of animals per sex per dose:

15

Control animals:

yes, concurrent no treatment

Details on study design:

One day prior to sacrifice, the animals were kept individually in metabolic cages and 24-hour urine samples were collected for ALA estimation.

Positive control:

None

Examinations

Parental animals: Observations and examinations:

Weight gain and fluid intake were recorded twice a week and the animals were observed for any overt signs of lead toxicity over a period of 60 days.

Postmortem examinations (parental animals):

All animals were lightly anesthetized with ether for collection of blood via heart puncture for blood lead estimation. Animals were then sacrificed by cervical dislocation, and testes were weighed and used for determining testicular concentrations of lead, ascorbic acid, and cholesterol. Testes were also fixed and sectioned for histopathological and histometric analyses.

Statistics:

All statistical analyses were performed by Student's t-test.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight was statistically significantly decreased at all tested doses.

Water consumption and compound intake (if drinking water study):

not specified

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Statistically significant increase in urinary δ-aminolevulinic acid (ALA).

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

There were statistically significant decreases in seminiferous tubule diameter and spermatid count at 0.5 g/L and above, and in spermatogenic count and Leydig cell number and nuclear diameter at 1 g/L. Spermatocytes and spermatids were in degenerative condition, and the lumen of the seminiferous tubules was filled with cellular debris at 0.5 g/L. At 1 g/L, the cellular pattern of the seminiferous tubules was disintegrated, spermatogenic inhibition was at the stage of spermatogonia, and Leydig cells were in atrophic condition.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

BIOCHEMICAL: There were statistically significant increases in blood and testicular lead concentrations, urinary δ-aminolevulinic acid (ALA), and testicular cholesterol at all tested doses. There was a statistically significant decrease in testicular ascorbic acid at all tested doses.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Details on results (P0)

BODY AND ORGAN WEIGHTS: Body weight was statistically significantly decreased at all tested doses. Testicular weight was statistically significantly decreased at 1 g/L lead acetate.

BIOCHEMICAL: There were statistically significant increases in blood and testicular lead concentrations, urinary δ-aminolevulinic acid (ALA), and testicular cholesterol at all tested doses. There was a statistically significant decrease in testicular ascorbic acid at all tested doses.

HISTOPATHOLOGICAL: There were statistically significant decreases in seminiferous tubule diameter and spermatid count at 0.5 g/L and above, and in spermatogenic count and Leydig cell number and nuclear diameter at 1 g/L. Spermatocytes and spermatids were in degenerative condition, and the lumen of the seminiferous tubules was filled with cellular debris at 0.5 g/L. At 1 g/L, the cellular pattern of the seminiferous tubules was disintegrated, spermatogenic inhibition was at the stage of spermatogonia, and Leydig cells were in atrophic condition.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

reproductive

Effect level:

250 mg/L drinking water

Based on:

not specified

Sex:

male

Basis for effect level:

other: Based on inhibition of spermatogensis (i.e., seminiferous tubular diameter, spermatid count, number of gametogenic cells in seminiferous tubules) at or above 0.5 g/L.

2

Dose descriptor:

LOAEL

Effect level:

250 mg/L drinking water

Based on:

not specified

Sex:

male

Basis for effect level:

body weight and weight gain

Results: P1 (second parental generation)

Effect levels (P1)

Remarks on result:

other: See 'Remarks':

Remarks:

Study investigated relative sensitivity of testicular physiology in rats exposed to lead via drinking water.

Results: F1 generation

Effect levels (F1)

Remarks on result:

other: See 'Remarks'

Remarks:

Study investigated relative sensitivity of testicular physiology in rats exposed to lead via drinking water.

Results: F2 generation

Effect levels (F2)

Remarks on result:

other: See 'Rmarks':

Remarks:

Study investigated relative sensitivity of testicular physiology in rats exposed to lead via drinking water.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The authors concluded that lead may inhibit spermatogenesis at the pre-meiotic stage via lack of testosterone production from Leydig cells.

Executive summary:

Male rats were administered lead acetate in drinking water at concentrations of 0, 0.25, 0.5, and 1 g/L over 60 days and biochemical and histopathological analyses were performed on the testes. Body weight was statistically significantly decreased at all tested doses. Testicular weight was statistically significantly decreased at 1 g/L. There were statistically significant increases in blood and testicular lead concentrations, urinary δ-aminolevulinic acid (ALA), and testicular cholesterol at all tested doses. There was a statistically significant decrease in testicular ascorbic acid at all tested doses. There were statistically significant decreases in seminiferous tubule diameter and spermatid count at 0.5 g/L and above, and in spermatogenic count and Leydig cell number and nuclear diameter at 1 g/L. Spermatocytes and spermatids were in degenerative condition, and the lumen of the seminiferous tubules was filled with cellular debris at 0.5 g/L. At 1 g/L, the cellular pattern of the seminiferous tubules was disintegrated, spermatogenic inhibition was at the stage of spermatogonia, and Leydig cells were in atrophic condition. The reproductive NOAEL and systemic LOAEL from this study were both 0.25 g/L. The authors stated that high levels of cholesterol and decreased ascorbic acid along with atrophic Leydig cells in animals exposed to 1 g/L suggests non-utilization of cholesterol towards the synthesis of testosterone from Leydig cells. They concluded that lead may inhibit spermatogenesis at the pre-meiotic stage via lack of testosterone production from Leydig cells.