Aluminium sulphate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Reliable without restrictions. Well-presented study, with relevant measurement of chemical concentrations

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Materials and methods

Principles of method if other than guideline:

Method: other: OECD TG No. 422 "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test"

GLP compliance:

yes

Remarks:

Tested by LG Life Science/Toxicology Center, Korea,(Test No. S506),

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Calcium sulfate, dihydrate

IUPAC Name:

Calcium sulfate, dihydrate

Constituent 2

Reference substance name:

10101-41-4

EC Number:

600-148-1

Cas Number:

10101-41-4

IUPAC Name:

10101-41-4

Test material form:

solid: compact

Details on test material:

- Name of test material: Calcium sulfate, dihydrate
- Molecular formula (if other than submission substance): CaSO4•2H2O
- Molecular weight (if other than submission substance): 172.171
- Smiles notation (if other than submission substance): O.O.[O-]S(=O)(=O)[O-].[Ca+2]
- Structural formula attached as image file (if other than submission substance): see Fig.1
- Substance type:inorganic
- Physical state:solid
- Density -2.32 g/cm3)
- Solubility in water - 2.05 g/L at 20 °C
- Synonyms: Alabaster
Annaline
C.I. Pigment white 25
Gypsum
Gypsum stone
Land and plaster
Light spar
Magnesia white
Mineral white
Native calcium sulfate
Precipitated calcium sulfate
Sainite
Satin spar
Sulfuric acid, calcium(2+) salt, dihydrate
Terra alba
- Calcium sulfate, dihydrate consists of colorless, monoclinic and hygroscopic crystals

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

Test organism
- Sex: male/female
- Age of animals at study: 8 weeks old for males and females
- Weight at study repeated dose toxicity: 254.2 - 297.8 g for males and
182.7 - 208.2 g for females
- Number of test animals: 60 animals for each sex

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Dose level : 0, 100, 300 and 1,000 mg/kg/day; pre-treatment (Test No. P705) had conducted with 0, 125, 250, 500 and 1,000 mg/kg/day of test substance for 7 days to determine the appropriate starting dose level.
Exposure period : 35 days for male animals and 41 to 45 days for female animals
Frequency of treatment : Daily
Control group : Yes Concurrent no treatment

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Mating procedure: each male and female animal was selected from the same test group in order to copulate. It spent 4 days in terms of mating.
The day after the copulating, mating would be determined through the observation of sperm in a vaginal rinse.
- Clinical observations performed and frequency: Clinical symptoms were observed once a day but were observed once a week in detail; a
death rate was observed twice a day; and body weight was observed once a week and just before the necropsy but in case of pregnant
females, it was measured on the day 0, 7, 14, 20 of gestation period, date of delivery, and 4 days after the delivery; consumption rate of
fodder was observed once a week except mating period.

Duration of treatment / exposure:

35 days for male animals and 41 to 45 days for female animals

Frequency of treatment:

Daily

Duration of test:

35 days for male animals and 41 to 45 days for female animals

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300 and 1,000 mg/kg/day; pre-treatment (Test No. P705) had conducted with 0, 125, 250, 500 and 1,000 mg/kg/day of test substance for 7 days to determine the appropriate starting dose level.
Basis:
nominal in diet

No. of animals per sex per dose:

- Number of test animals: 60 animals for each sex

Control animals:

yes, concurrent no treatment

Details on study design:

Sex: male/female
Dose level : 0, 100, 300 and 1,000 mg/kg/day; pre-treatment (Test No. P705) had conducted with 0, 125, 250, 500 and 1,000 mg/kg/day of test substance for 7 days to determine the appropriate starting dose level.
Exposure period : 35 days for male animals and 41 to 45 days for female animals
Frequency of treatment : Daily

Examinations

Maternal examinations:

- Clinical observations performed and frequency: Clinical symptoms were observed once a day but were observed once a week in detail; a
death rate was observed twice a day; and body weight was observed once a week and just before the necropsy but in case of pregnant
females, it was measured on the day 0, 7, 14, 20 of gestation period, date of delivery, and 4 days after the delivery; consumption rate of
fodder was observed once a week except mating period.
Organs examined at necropsy:
Organ weight: testes, epididymider (all males) liver, kidney, adrenals, thymus, spleen, brain, and heart (5 male and female animals from each
test group).
Fixation: 22 kinds of tissues were fixed to do histopathologic tests such as testes, epididymides, ovaries, accessory sex organs for all animals,
brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including peyer’s patches), liver, kidneys,
adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes (cervical mesenteric), peripheral nerve (sciatic or
tibial), bone marrow.

Ovaries and uterine content:

Fixation: 22 kinds of tissues were fixed to do histopathologic tests such as testes, epididymides, ovaries, accessory sex organs for all animals,
brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including peyer’s patches), liver, kidneys,
adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes (cervical mesenteric), peripheral nerve (sciatic or
tibial), bone marrow.

Fetal examinations:

Fixation: 22 kinds of tissues were fixed to do histopathologic tests such as testes, epididymides, ovaries, accessory sex organs for all animals,
brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including peyer’s patches), liver, kidneys,
adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes (cervical mesenteric), peripheral nerve (sciatic or
tibial), bone marrow.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
- Pregnancy and delivery: There was no significant difference between the treatment and the control group in terms of delivery and; the number
of corpus luteum and implantation. Some test groups including the control group had quite higher loss rate of the embryo prior to the
implantation and the fetus after the implantation but significant difference was not observed between the treatment and the control
group. These higher loss rate were occurred spontaneously and no dose-response correlation. Thus no influence under test substance. In
addition, there were no premature pups.
- Clinical signs: In male control group, a case of salivation and bloodylike secretion was observed on the day 11 and 12. In the 1,000
mg/kg/day treatment group, a case of depilation, dcab and pus was observed on the left cheek between the day 25 and the closing day.
However, the frequency of occurrence was low and no dose-response correlation, thus these symptoms were not influenced by test substance.
In female control group, a case of genitalia bloody-like secretion was observed at day 29. In the 100 mg/kg/day treatment group, each case of
hypoactivity and depilation was observed on the day 8 and 9, and between day 44 and the closing day, respectively. However, these
symptoms were disappeared in short, thus these did not have relationship with test substance.

- Necropsy opinions: For male animals, in the control group within the recovery group, a case of left and right caput epididymis cyst was
observed and the 1,000 mg/kg/day recovery group had symptom of right caput epididymis cyst. However, its frequency of occurrence was low
and it was even observed at the control group within the recovery group, so it did not have relationship with test substance.
For female animals, in the 300 mg/kg/day treatment group, each animal was dead on the day 7 and 14 and; each case of lung dark-red
discolouration was observed, but white particles in a lobe of the lung was observed just from one of carcasses. A case of spleen white nodule
was observed for an animal in the 300 mg/kg/day treatment group. There was a case of right adrenal gland white spots at the 1,000
mg/kg/day treatment group. In the control group within the recovery group, each case of right adrenal gland hemorrhagia and atrophy and
liver adhesion with diaphragm was observed. However, their frequencies of occurrence were low and no dose-response correlation,
so these did not have relationship with test substance.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Results for F1
- Examination of the external surface of pups: At the time of the delivery
and on the day 4, in the every test group including the control group, no
observation in relation to runt, malformation, and variance was found. A
case of malrotated limb was observed at the 1,000 mg/kg/gay treatment
group but its frequency was insignificant and no relation with test
substance.
- Body weight of pups: In the male pups, total 3 cases of underweight
were observed from the control group and the treatment group with
administration of 100 mg/kg/day, but no significant difference was found
between the two. On the day 4 after the delivery, in the nursing pups, 1,
1, 2 cases of underweight were observed for the control group, the 100
mg/kg/day treatment group and the 1,000 mg/kg/day treatment group,
respectively, and no significant differences was found between the
control group and the treatment group.
In the female pups, total 6 cases of underweight were observed from the
following three groups such as the control group, the 100 mg/kg/day
treatment group and the 1,000 mg/kg/day treatment group. On the day 4
after the delivery, in the nursing pups, 1, 2, 3 cases of underweight were
observed for the control group, the 100 mg/kg/day treatment group and
the 1,000 mg/kg/day treatment group, respectively. In addition, the both
100 mg/kg/day and 1,000 mg/kg/day treatment groups had lower body
weight than that of the control group. However, their weights were in the
normal range of pups.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Results for F0

- Pregnancy and delivery: There was no significant difference between the treatment and the control group in terms of delivery and; the number of corpus luteum and implantation. Some test groups including the control group had quite higher loss rate of the embryo prior to the implantation and the fetus after the implantation but significant difference was not observed between the treatment and the control group. These higher loss rate were occurred spontaneously and no dose-response correlation. Thus no influence under test substance. In addition, there were no premature pups.

- Clinical signs: In male control group, a case of salivation and bloody-like secretion was observed on the day 11 and 12. In the 1,000 mg/kg/day treatment group, a case of depilation, dcab and pus was observed on the left cheek between the day 25 and the closing day. However, the frequency of occurrence was low and no dose-response correlation, thus these symptoms were not influenced by test substance. In female control group, a case of genitalia bloody-like secretion was observed at day 29. In the 100 mg/kg/day treatment group, each case of hypoactivity and depilation was observed on the day 8 and 9, and between day 44 and the closing day, respectively. However, these symptoms were disappeared in short, thus these did not have relationship with test substance.

- Necropsy opinions: For male animals, in the control group within the recovery group, a case of left and right caput epididymis cyst was observed and the 1,000 mg/kg/day recovery group had symptom of right caput epididymis cyst. However, its frequency of occurrence was low and it was even observed at the control group within the recovery group, so it did not have relationship with test substance. For female animals, in the 300 mg/kg/day treatment group, each animal was dead on the day 7 and 14 and; each case of lung dark-red discolouration was observed, but white particles in a lobe of the lung was observed just from one of carcasses. A case of spleen white nodule was observed for an animal in the 300 mg/kg/day treatment group. There was a case of right adrenal gland white spots at the 1,000 mg/kg/day treatment group. In the control group within the recovery group, each case of right adrenal gland hemorrhagia and atrophy and liver adhesion with diaphragm was observed. However, their frequencies of occurrence were low and no dose-response correlation, so these did not have relationship with test substance.

Results for F1

- Examination of the external surface of pups: At the time of the delivery and on the day 4, in the every test group including the control group, no observation in relation to runt, malformation, and variance was found. A case of malrotated limb was observed at the 1,000 mg/kg/gay treatment group but its frequency was insignificant and no relation with test substance.

- Body weight of pups: In the male pups, total 3 cases of underweight were observed from the control group and the treatment group with administration of 100 mg/kg/day, but no significant difference was found between the two. On the day 4 after the delivery, in the nursing pups, 1, 1, 2 cases of underweight were observed for the control group, the 100 mg/kg/day treatment group and the 1,000 mg/kg/day treatment group, respectively, and no significant differences was found between the control group and the treatment group. In the female pups, total 6 cases of underweight were observed from the following three groups such as the control group, the 100 mg/kg/day treatment group and the 1,000 mg/kg/day treatment group. On the day 4 after the delivery, in the nursing pups, 1, 2, 3 cases of underweight were observed for the control group, the 100 mg/kg/day treatment group and the 1,000 mg/kg/day treatment group, respectively. In addition, the both 100 mg/kg/day and 1,000 mg/kg/day treatment groups had lower body weight than that of the control group. However, their weights were in the normal range of pups.

Applicant's summary and conclusion

Conclusions:

NOAEL for developmental : The highest test dose (1,000 mg/kg/day) for male and female animals.