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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1995
Report date:
1995
Reference Type:
publication
Title:
Preliminary Reproduction Toxicity Screening Test of Phthalocyanine Blue in Rats
Author:
Japan Existing Chemical Data Base (JECDB)
Year:
2009
Bibliographic source:
http://dra4.nihs.go.jp/mhlw_data/home/file/file147-14-8.html (original report is in Japanese; the web site was translated to English using the Google language tool http://www.google.de/language_tools?hl=de)

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32 copper
EC Number:
205-685-1
EC Name:
29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32 copper
Cas Number:
147-14-8
Molecular formula:
C32H16CuN8
IUPAC Name:
[29H,31H-phthalocyaninato(2-)-kappa~2~N~29~,N~31~]copper
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
- Analytical purity: 99.55 %
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Japan
- Age at study initiation: 8 weeks
- Weight at study initiation: females: ca. 232 g; males: ca. 372 g
- Housing: bracket type metal wire mesh floor cages (260 x 380 x 180 mm)
- Diet: Feed-solid diet (CRF-1, Oriental Yeast Co, Ltd., Inc.), ad libitum)
- Water: tap water, ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature: 23 +- 3 °C
- Humidity: 55 +- 10 %
- Air changes: 10-15 times per hr
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
The test substance was dosed orally to male rats for 46 days included before mating and mating period, and to female rats from day 14 before mating to day 3 of lactation.

The test substance was administered into the stomach by gavage.
10 ml per kg body weight was calculated based on the weight
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
According to OECD Guideline 421, 1:1 (one male to one female) matings were used. The female was placed with the same male until pregnancy occured or two weeks had elapsed. Each morning the females were examined for the presence of sperm or a vaginal plug. Day 0 of pregnancy was defined as the day a vaginal plug or sperm was found.
Duration of treatment / exposure:
Administration period (males): from 14 days before mating, during the mating period and copulation, until 46 days
Administration period (females): from 14 days before mating to day 3 of lactation
Duration of test: Males were killed on days 28 and 47, females on day 28 and on day 4 of lactation
Frequency of treatment:
daily; administration time was between 10 h and 13 h.
Duration of test:
Parental males were killed on days 28 and 47, parental females on day 28 and on day 4 of lactation
Doses / concentrationsopen allclose all
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12 animals per sex per dose
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: at least once every day visual inspection, observation of appearance and palpation
DETAILED CLINICAL OBSERVATIONS: reproductive capacity, examination of the oestrous cycle, the recording of occurrence of copulation and gestation, fertility, implantation, delivery and nursing indices, maternal behaviour, birth rate, pregnancy period
BODY WEIGHT: examination of body weight was conducted
FOOD CONSUMPTION: examination of feed intake was conducted
POST-MORTEM EXAMINATIONS: Organs were removed, reproductive organs were weighed
HISTOPATHOLOGICAL EXAMINATION: Ovaries, uterus, harderian gland, eyeball, mammary gland, spleen

Ovaries and uterine content:
The ovaries and uterine content were examined after termination
The examinations included:
- Gravid uterus weight
- Number of corpora lutea
- Number of implantations
Fetal examinations:
- General observations about the state (clinical signs, body weight change) and neonatal survival status
- Post-mortem: The whole body was fixed in formalin solution

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
A blue coloration of faeces was noted in all animals of the groups receiving 40 mg/kg bw or more; moreover blue-green or grayish blue discolorations of the contents of the stomach and intestines were noted in a few animals of the 200 mg/kg group and in almost all animals of both sexes in the 1000 mg/kg group. These changes were caused by the colour of the test substance and merely indicated the passage through the gastrointestinal tract.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
not examined
Early or late resorptions:
not examined
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
No effects were noted on the following endpoints: Reproductive ability of either sex (assessment of this endpoint included the examination of the oestrous cycle, the recording of occurrence of copulation and gestation, the calculation of copulation, fertility, implantation, delivery and nursing indices, the weight of testes and epididymis as well as histopathological examination of the reproductive organs), delivery, maternal behavior, viability, clinical signs and body weight changes.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
not examined
Visceral malformations:
not examined
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
No significant differences were observed in rate of live/dead pups born: In the control group, 1 out of 69 male and 3 out of 75 female pups were born dead. In the 40 mg/kg bw/day group, 4 out of 60 males and 2 out of 48 females as well as 1 pup of unknown sex were born dead. In the 200 mg/kg bw/day group, 3 out of 75 male and 2 out of 78 female pups were born dead. In the 1000 mg/kg bw/day group, 3 out of 64 male and 5 out of 69 female pups were born dead.
No evidence was found suggesting a relation with the administration of the tested substance and clinical signs, body weight change or autopsy findings for both male and female pups.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
not examined

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion