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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / 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:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
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)
Sex:
male/female
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 including pre-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 at a volume of 10 ml/kg bw.
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.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Administration period (males): from 14 days before mating, the mating period until copulation, and also 46 days after the start of copulation
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.
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
Details on study design:
Parental males were killed on days 28 and 47, parental females on day 28 and on day 4 of lactation

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: at least once every day visual inspection, observation of appearance and palpation
DETAILED CLINICAL OBSERVATIONS: reproductive capacity, 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
Oestrous cyclicity (parental animals):
examination of the oestrous cycle was conducted
Litter observations:
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
Postmortem examinations (parental animals):
POST-MORTEM EXAMINATIONS: Organs were removed, reproductive organs were weighed
HISTOPATHOLOGICAL EXAMINATION: Ovaries, uterus, harderian gland, eyeball, mammary gland, spleen, testes, epididymis (left and right)
Postmortem examinations (offspring):
Post-mortem: The whole body was fixed in formalin solution

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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/day 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 bw/day group and in almost all animals of both sexes in the 1000 mg/kg bw/day group. These changes were due to the color of the test substance.
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
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

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 (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse findings
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: P1 (second parental generation)

General toxicity (P1)

Details on results:
The offspring was only observed until postnatal day 4. No adverse effects were observed on survival, body weights and gross pathology.

Details on results (P1)

Reproductive performance of the P1 generation is not determined in a screening study.

Results: F1 generation

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse findings
Remarks on result:
other:
Remarks:
F1 was only observed until postnatal day 4.

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

No effects were noted in reproductive ability of either sex, or in delivery-and maternal behavior, viability, clinical signs, body weight change or autopsy findings of pups.

Applicant's summary and conclusion