Aluminium nitrate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test guideline (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Report meets generally accepted scientific standards, well documented and acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

The effects of aluminium ingestion on reproduction and postnatal survival in rats

Author:

Domingo JL, Paternain JL, Llobet JM & Corbella J

Year:

1987

Bibliographic source:

Life Sciences 41: 1127-1131

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:

Male rats were treated orally for 60 days prior to mating and female rats were treated for 14 days prior to and throughout the mating period, gestation, delivery, and lactation.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

aluminium nitrate nonahydrate

IUPAC Name:

aluminium nitrate nonahydrate

Test material form:

not specified

Details on test material:

Al(NO3)3*9H2O (source: Merck)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Interfauna Iberica, Spain
- Weight at study initiation: (P) Males: 240-280 g; Females: 240-280 g
- Diet: ad libitum, high protein rat diet (Panlab, Barcelona, Spain)
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2 °C
- Humidity (%): 55 +- 5 %

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
no data

Dose levels were selected to approximate to 1/20, 1/10, and 1/5 of the acute oral LD50 value estimated for aluminium nitrate.

Male rats were treated by gavage for 60 days prior to mating and the females were dosed for 14 days prior to mating and then throughout the mating period, gestation, delivery and lactation.

Details on mating procedure:

Groups of 25 females were used at each dose level. Following pairing with treated males, proof of pregnancywas indicated by sperm in vaginal smears. The day sperm were observed was referred to as day 0 of pregnancy (Gestation day 0)

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

Male rats were dosed for 60 days prior to mating and female rats were treated for 14 days prior to and throughout the mating period, gestation,
delivery, and lactation.

Frequency of treatment:

Daily

Details on study schedule:

Males were treated for 60 days and females for 14 days prior to pairing. The rats were mated within the dose group. Day 0 of gestation was taken as the day sperm were observed in the vaginal smear. Dams were treated throughout the gestation and lactation phases. On Day 13 of gestation half of the dams in each group were terminated and examined to determine the number of corpora lutea, total number of implantations, early and late resorptions and the number of live and dead foetuses. The remaining dams were allowed to litter and nurse the neonates to day 21 of lactation

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 180, 360, 720 mg/kg bw/d
Basis:
actual ingested
aluminium nitrate nonahydrate

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 102, 204, 409 mg/kg bw/d
Basis:
actual ingested
equivalent dose anhydrous aluminium nitrate

No. of animals per sex per dose:

25

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: doses were selected based on a prior 100 days study at 1/20, 1/10 and 1/5 of the LD50 (gavage)

Positive control:

no data

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Not specified

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Not specified

FOOD CONSUMPTION: Not specified

WATER CONSUMPTION: Not specified

Oestrous cyclicity (parental animals):

Not specified

Sperm parameters (parental animals):

Parameters examined in male parental generations: not specified

Litter observations:

STANDARDISATION OF LITTERS
Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring: mortality, normal body weight gain, body and tail lengths and general symptomatology after 1, 4, and 21 days of nursing

Postmortem examinations (parental animals):

On day 13 of gestation, one-half of the dams from each group were killed. The following examinations were made: determination of the number of corpora lutea, total implantations, living and dead fetuses as well as the number of early and late resorptions.

Postmortem examinations (offspring):

The offspring were killed after 21 days; heart, lungs, spleen, liver, kidneys, brain, and testicles were removed and weighed. The ratios of organ weight/body weight, were calculated.

Statistics:

Statistical analyses were made by means of the distribution-free ranking test according to Wilcoxon in the modified version of Mann-Whitney, and using the chi-square test. The effect of aluminium on relative organ weights of rats pups was evaluated by the Kruskal-Wallis statistical test. In all cases a minimum level of significance of P < 0.05 was used.

Reproductive indices:

not specified

Offspring viability indices:

not specified

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

Fertility rates and reproductive data were unaffected by the treatment. Treatment with aluminium did not affect the survival of adult rats and no deaths were noted in any group. The percentage of pregnant females was similar in each treatment group.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects were reported

2

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects were reported

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not examined

Histopathological findings:

not examined

Details on results (F1)

Data from rat pups nursed by aluminium-treated mothers are presented on days 1, 4 and 21 after birth. The number of litters was lower for the aluminium-treated groups (mid and high dose). Although survival of rats was rather low for all groups, the number of living young per litter was lower for the aluminium-treated groups. On the other hand, the number of dead young per litter was higher for these groups. The differences were more remarkable for the high dose group. Body weight, body length and tail length of the rat pups in the treated groups showed significant decreases when compared with the control group.
The fresh organ weights of rat pups killed after 21 days of lactation were measured in ten animals from each group. There were no significant differences between the control and treated groups when expressed relative to body weight.

The number of litters was decreasing with time, and the dead/living ratio and the number of dead young per litter were increasing during the lactation. Dose-response relationships could be induced.
With regard to the growth of the offspring as a measure of body weight, body length and tail length, it was always significantly lower for the treated groups. These decreases must be imputed to the treatment and an important dose response relationship can be remarked. However, the significance of the differences was decreasing with time.
On the other hand, no hypertrophy or hypotrophy in the organs removed after the treatment could be detected.

Effect levels (F1)

Dose descriptor:

LOAEL

Remarks:

developmental toxicity

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Reduced litter numbers, litter size and offspring viability

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

 

The effect of oral administration of aluminium in Sprague-Dawley rats on gestation day 13

	Dose level mg/kg bw/d  aluminium nitrate nonahydrate (Al(NO3)3.9H2O)
	0	180	360	720
Litters	9	7	10	10
Corpora lutea	18.2	16.9	15.9	14.5^a
Total implants	13.7	13.1	12.5	14.0
Early resorptions	0.1	0.7	0.1	0.8
Late resorptions	1.5	0.9	1.4	1.1
Live foetus	12.1	11.1	10.8	10.8
Dead foetus	0.1	0.4	0.2	0.3
^asignificantly different from controls P<0.05

 

 

 

Summary of data for pups nursed by aluminium treated mothers

	Day	Dose level mg/kg bw/d  aluminium nitrate nonahydrate (Al(NO3)3.9H2O)
		0	180	360	720
No. of litters	1 4 21	9 9 9	10 10 10	7 7 7	7 5 4
No. of living young	1 4 21	108 106 66	115 108 56	91 83 27	66 52 19
No. of dead young	1 4 21	0 2 40	2 7 52	2 8 56	12 14 33
Dead/living ratio (x100)	1 4 21	0.0 1.9 37.7	1.7 6.1 48.1	2.2 8.8 67.5	18.1 21.2 63.5
Male/female ratio	1 4 21	1.00 0.96 0.94	0.90 1.03 1.00	0.65 0.69 0.50	0.94 0.86 1.11
Living young/litter	1 4 21	12.0 11.9 7.3	11.5 10.8 5.6	13.0 11.9 4.5^a	9.4 10.4 4.8^a
Dead young/litter	1 4 21	0.0 0.2 4.4	0.2 0.7 5.2	0.3 1.1 9.3	1.7 2.8 8.3
^asignificantly different from controls P<0.05

 

 

Effects of aluminium nitrate on rat pups nursed by aluminium treated mothers

	Sex	Day	Dose level mg/kg bw/d  aluminium nitrate nonahydrate (Al(NO3)3.9H2O)
			0	180	360	720
Bodyweight (g)	M	1 4 21	7.2 (54) 9.3 (52) 39.9 (32)	6.9 (55) 9.4 (55) 40.7 (28)	6.7 (36)^a 9.4 (34) 32.4 (9)^a	6.2 (32)^c 8.6 (24)^a 29.7 (10)^b
	F	1 4 21	6.9 (54) 9.3 (54) 36.3 (34)	6.3 (60)^a 8.7 (53) 38.1 (28)	6.3 (55)^a 9.2 (49) 38.6 (18)	6.1 (34)^c 8.3 (28)^b 30.9 (9)^a
Body length (mm)	M	1 4 21	55.4 64.0 118.4	54.8 63.0 115.7	53.3^b 62.4 110.3^a	51.8^c 61.2^b 110.3^a
	F	1 4 21	55.3 63.9 116.6	52.6^b 63.8 118.2	52.6^b 60.6^b 116.6	52.0^c 59.8^c 114.0
Tail length (mm)	M	1 4 21	20.4 25.8 77.2	19.8 24.5 76.5	18.7 24.0^b 76.0	17.2^b 23.0^c 62.0^b
	F	1 4 21	20.2 27.3 74.6	18.7^a 24.6^a 75.3	17.9^b 24.0^a 73.8	17.7^c 23.4^b 71.1^b
^a,b,csignificantly different from controls P<0.05; <0.01 or <0.001 M/F male/female (number of animals studied)

 

Applicant's summary and conclusion

Conclusions:

Fertility rates and reproductive indices were unaffected in the parents but numbers of litters reduced in aluminium treated rats and the ratio of dead to living pups and the number of dead pups showed an increase duration lactation. Pup growth as measured by bodyweight, body length and tail length indices was inhibited in treated groups. The lowest dose level, 180 mg/kg bw/d, resulted in some adverse effects in the offspring in this study although no effects were apparent in the parents.

Executive summary:

 Aluminium nitrate was tested for its effects on reproduction, gestation, and lactation in Sprague-Dawley rats, at dosages of 0, 180, 360 and 720 mg/kg bw/d. Mature male rats were treated orally for 60 days prior to mating with mature virgin female rats treated for 14 days prior to mating with treatment continuing throughout mating, gestation, parturition, and weaning of the litters. One-half of the dams in each group were killed on Day 13 of gestation and the remaining dams were allowed to deliver and wean their offspring. Postnatal development was monitored. No adverse effects on fertility or general reproductive parameters were evident at doses employed in these studies, however effects on post-natal pup growth and survival were apparent in all treated groups.