Copper, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl derivs.

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Based on an OECD Guideline 421 and GLP study with CAS number 147-14-8, the NOAEL for reproductive toxicity was considered to be 1000 mg/kg bw/day for all relevant endpoints, which was the highest dose tested.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

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

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

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.

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

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

PARENTAL TOXICITY:
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 colour of the test substance. No changes were observed in terms of mortality, body weight, food consumption, organ weight and histopathological examination.

TOXICITY TO FERTILITY:
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.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: absence of effects

Critical effects observed:

no

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: absence of effects

Critical effects observed:

no

FETOTOXICITY:
No findings were recorded with regard to general condition, survivability, body weights and autopsy (visual observation) of the pups. The number of living and dead pups as well as their sex and external appearance were also not affected.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: absence of effects

Critical effects observed:

no

Remarks on result:

not measured/tested

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A screening study for reproductive toxicity (OECD 421, JETOC 1995) performed with the copperphthalocyanine core was used to fill the data gap for reproductive toxicity. It shows absence of effects at the limit dose of 1000 mg/kg bw. The actual argument is however that the substance is not taken up by the body after oral dosing. In support of this, a fourteen day gavage study with doses of 300 and 1000 mg/kg bw was performed with each five male and female rats (BASF 2015). There was no indication of systemic uptake as judged from unchanged plasma and liver copper levels (see also toxicokinetic section). There were no treatment-related clinical signs, no adverse effects on haematology, clinical chemistry, body weights or organ weights. The NOEL for 14-day oral gavage dosing was 1000 mg/kg bw. This study was to performed to support read-across to the core structure copper phthalocyanine (CAS 147-14-8) and to show absence of systemic uptake. Copperphthalocyanine is an inert pigment of extremely low solubility in water (0.0004mg/L) and octanol (0.009mg/L) that is not taken up by experimental animals after oral dosing. Phthalocyanine IM contains additional 1H-isoindole-1,3(2H)-dion subsitutents attached to the ring via a methylene bridge. The substituents add to the conjugated system and contain no charges that do not affect water solubility, they are no ionisable at environmental pH. They increase the diameter and molecular weight which reduces the already non-existent ability for systemic uptake.

Therefore, the reproductive toxicity screening studies with the core structure are suitable for the hazard assessment of CAS 59160-79-1.

For a detailed read-across justification including a datamatrix, it is referred to the attachment (IUCLID toxicokinetic section).

Effects on developmental toxicity

Description of key information

In an OECD Guideline 421 and GLP study with CAS-nr. 147-14-8 in rats, the NOAEL for development of offspring was at the highest test dose of 1000 mg/kg/day. 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Please refer to the discussion of "Effects on fertility" (see above).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available screening study is reliable and suitable for classification purposes under Regulation 1272/2008. No adverse effects were observed in a screening study regarding fertility and developmental toxicity (OECD 422/421). As a result, the substance is not considered to be classified for fertility or developmental toxicity under Regulation (EC) No. 1272/2008,as amended for the fifteenth time in Regulation (EC) No. 2020/1182.

During the four days covered in the screening study, no effects via lactation were observed.