Copper, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, sulfo [[4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs.

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No assessment of reproductive hazard has been undertaken at this tonnage threshold. This is due to the following considerations:

1)    The substance was not found to be harmful to reproductive developmental processes in a developmental study. No abnormalities of offspring were noted in this study at the maximum dose tested (1000 mg/kg/day).

2)    The substance was negative in mutagenicity assays involving animal cells, and did not have any effects at the highest dose thresholds noted.

3)    A repeat-dose study with oral treatment in rats did not reveal any proliferative properties which could be related to the administration of the test substance. Histopathological evaluation of reproductive organs from the 28-day study indicated no effects. Consequently, the substance is considered not to have the potential to cause reproductive effects.

4)    The substance has been in use for many years without effects associated with reproductive toxicity being noted.  

As such, on animal welfare grounds it is not considered appropriate to conduct a further developmental screening test, as the evidence indicates that there is no associated potential teratogenic or reproductive effect associated with the substance. 

Effects on developmental toxicity

Description of key information

No teratogenic effect was observed

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993/94

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

yes

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG
- Age at study initiation: 65 to 75 days
- Weight at study initiation: 193.2 +/- 14 g
- Fasting period before study: NA
- Housing: single
- Diet: Altromin 1310 ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22°C
- Humidity (%): 48 to 61%
- Air changes (per hr): 16 to 20
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 14. Sep To: 25. Nov 1993

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

- Frequency of preparation: daily
- Administration: within 3 hours after preparation


VEHICLE
- Concentration in vehicle: 200 mg/kg nominal
- Amount of vehicle (if gavage): 5 ml/kg

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

-

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Length of cohabitation: over night (3:30 pm to 7:30 am next day)
- Verification of same strain and source of both sexes: yes - own breeding facility
- Proof of pregnancy: sperm in vaginal smear, referred to as day 1 of pregnancy

Duration of treatment / exposure:

7. - 16. day of pregnancy

Frequency of treatment:

daily

Duration of test:

cesarean section on Day 21 of pregnancy

Remarks:

Doses / Concentrations:
1000 mg/kg bw
Basis:
nominal in water

No. of animals per sex per dose:

21 to 24 mated females

Control animals:

yes

Details on study design:

- Dose selection rationale: test item was tolerated in the acute and subacute studies without adverse effects
The study compound was suspended fresh daily in a concentration of 200 g/L in distilled water and administered daily to all the animals within three hours of preparation.
All animals received the same volume of liquid, 5 ml/kg body weight. After each weighing of the animals, the compound doses were adjusted according to body weight. The stability and homogeneity of the soiutions were guaranteed over a period of 4 hours

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE : Yes
- Time schedule for examinations: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/100 g body weight/day: Yes


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: all organs examined macroscopically
uterus - live and dead fetuses, resorption sites, placentas
ovaries - corpora lutea


OTHER:
- diameter of conceptuses undergoing resorption
- placenta weights
- presence of iron in uterus walls with ammonium sulphide to detect invisible implantation sites

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Placenta weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Body weight: Yes: all per litter
- Crown-rump length: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data

Statistics:

comparison to actual control group and historical controls
MANOVA: body weight development, fetal weight, placental weight
PURI&SEN rank order test: food intake
Mantel-Haenszel's chi-squared test: live fetuses, intrauterine fetal death, number of implants, number of corpora lutea
multivariate analysis of variance: litter means of fetal weights, crown-rump length, placental weights
Fisher test: autopsy findings, body cross-sections, skelettal examination

Dams which had no live fetuses were excluded from the calculation of mean values and statistical evaluation

Indices:

No data

Historical control data:

Yes

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
The dams of the compound group and the control dams showed no impairment to behaviour and general condition and survived until the scheduled study end. All dams in the compound group excreted blue-discoloured faeces on at least 10 days during and after the treatment period, mostly in the period from day 8 - 19 of pregnancy, blue-discoloured urine was voided by 9 dams from day 8 - 13 of pregnancy. Slight amounts of compound solution escaped on occasion from the mouths of eight dams when removing the tube from the oesophagus of the animals. This was due to the dosing method; the amounts, however, were small and without relevance for assessing the test compound. local hair loss at the thorax, abdomen, flanks and forelimbs was noted in three dams of the compound group on several days, in one from the beginning of pregnancy onwards, On one day, one of the dams exhibited pallor.
19 dams in the compound group and 19 dams in the control group carried live conceptuses to term and were delivered by caesarean section. One control and one compound dam each had no live foetuses, but merely 6 or 8 empty implantation sites in the uterus indicating early embryonic death shortly after implantation. In these two animals, the corpora lutea were quite small and could not therefore be determined exactly. The number of corpora lutea, which provides information on the number of ovulations prior to start of treatment, and the number of implants and live foetuses in the remaining dams of the compound group did not differ markedly from those of the control animals and lay in the range of our previous control values .

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: other:

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
only minor anomalies or variation within the historical range of spontaneous findings were observed

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

No adverse effects were observed after daily administration of 1000 mg/kg/day Reactive Blue 21 in dams or their fetuses.
Maternal NOEL: 1000 mg/kg/day
Fetal NOEL: 1000 mg/kg/day

Executive summary:

In a limit test for developmental effects, Reactive Blue 21, dissolved in distilled water, was administered orally by stomach tube in a single daily dose of 1000 mg/kg body weight to a group of 20 pregnant female Wistar rats from the 7th - 16th day of pregnancy. A simultaneous control group of the same size received the vehicle without test compound. On the 21st day of pregnancy, the dams were killed and delivered by caesarean section. The foetuses were then examined morphologically for developmental disorders.

The studies showed that the repeated oral administration of Reactive Blue 21, at a dose of 1000 mg/kg body weight in the sensitive phase of organogenesis for the conceptuses, did not lead to any impairment of the general physical condition of the dams or impaired intrauterine development of conceptuses.

The morphological examination of the foetuses with regard to stage of development, outwardly detectable anomalies as well as anomalies of the internal (organs and the skeleton showed no Indication of an embryotoxic or teratogenic effect of the compound. The findings observed are to be regarded as spontaneous in origin.

On the basis of the results of this limit test, the "no observed adverse effect level" for Reactive Blue 21 in rats following oral administration lies at 1000 mg/kg body weight with regard to maternal and embryofoetal toxicity and teratogenicity.

No teratogenic effect was observed.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The above study has been ranked reliability 1 according to the Klimisch et al system. This ranking was deemed appropriate because the study was conducted to GLP and in compliance with agreed protocols. Sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds.

Additional information

In a limit test for developmental effects, Reactive Blue 21, dissolved in distilled water, was administered orally by stomach tube in a single daily dose of 1000 mg/kg body weight to a group of 20 pregnant female Wistar rats from the 7th - 16th day of pregnancy. A simultaneous control group of the same size received the vehicle without test compound. On the 21st day of pregnancy, the dams were killed and delivered by caesarean section. The foetuses were then examined morphologically for developmental disorders.

The studies showed that the repeated oral administration of Reactive Blue 21, at a dose of 1000 mg/kg body weight in the sensitive phase of organogenesis for the conceptuses, did not lead to any impairment of the general physical condition of the dams or impaired intrauterine development of conceptuses.

The morphological examination of the foetuses with regard to stage of development, outwardly detectable anomalies as well as anomalies of the internal (organs and the skeleton showed no Indication of an embryotoxic or teratogenic effect of the compound. The findings observed are to be regarded as spontaneous in origin.

On the basis of the results of this limit test, the "no observed adverse effect level" for Reactive Blue 21 in rats following oral administration lies at 1000 mg/kg body weight with regard to maternal and embryofoetal toxicity and teratogenicity.

No teratogenic effect was observed.

Justification for classification or non-classification

The above results triggered no classification under the Dangerous Substance Directive (67/548/EEC) and the CLP Regulation (EC No 1272/2008). No classification for reproductive effects is therefore required.