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Diss Factsheets

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

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Chloro[29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]aluminium
EC Number:
237-998-4
EC Name:
Chloro[29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]aluminium
Cas Number:
14154-42-8
Molecular formula:
C32H16AlClN8
IUPAC Name:
31h-phthalocyaninato(2-)-n29,n39,n31,n32]-chloro[29(sp-5-12)-aluminu; chloro[29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-,(SP-5-12)-Aluminum;CHLOROALUMINUM PHTHALOCYANINE;CHLORO(29H,31H-PHTHALOCYANINATO)ALUMINUM; CHLORO(PHTHALOCYANINATO)ALUMINIUM;ALUMINUM PHTHALOCYANINE CHLORIDE;PHTHALOCYANINE CHLOROALUMINUM; chloro[29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]aluminium
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Species/Strain: CRL Sprague-Dawley CD® IGS rats
The Sprague-Dawley® rat is the system of choice because, historically, it has been a preferred and commonly used species for developmental and reproductive toxicity studies. The current state of scientific knowledge does not provide acceptable alternatives to the use of live animals to accomplish the objective of this study. Because of extensive reporting in the literature, this strain provides a historical reference point to aid in interpretation of the study data.
Sex:
male/female
Details on test animals or test system and environmental conditions:
Number of Animals: 104 (40 virgin male and 64 virgin female rats)
Number of Groups: 8 (2 cohorts of 3 dose levels per sex + 1 control group per sex)
Number of Animals per Group: 10 males and 11 females in Reproduction/Developmental cohort (Groups 1-4), and 5 females in General Toxicity cohort (Groups 5-8).
Species/Strain: CRL Sprague-Dawley CD® IGS rats
Body Weight, Age, and Sex: Male and female rats were ordered from the supplier on the basis of age and birth date. Male and female rats were from different barriers in order to avoid brother-sister mating. Male and female rats were approximately 9 weeks of age at the time of arrival at PSL. The weight variation did not exceed ± 20% of the mean weight.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
After 14 days of treatment, animals were randomly mated by placing one female in the breeding cage of a male from the same dose group. A record of mating pairs was maintained. The cohabitation period consisted of a maximum of 14 days. Vaginal smears were performed daily on females during the mating period, and the presence or absence of sperm or vaginal plug was recorded. Females considered to have successfully mated (determined by the presence of vaginal sperm and/or a vaginal copulation plug) were removed from the cage of the male, assigned a GD 0 and housed individually. Female rats that had not mated within the first seven days of cohabitation were randomly assigned and paired with alternate male rats that have successfully mated. These female rats remained in cohabitation with the second set of males for a maximum of seven additional days. If successful mating had not occurred after 14 days of cohabitation, females were assigned a GD 0 on the morning of the last day of the cohabitation period and were evaluated as if in gestation thereafter. After the mating period, any female with no positive evidence of mating was individually housed in a plastic solid bottom polycarbonate shoebox cage containing nesting material.
Duration of treatment / exposure:
The animals were dosed daily for 7 days a week.
Frequency of treatment:
Each animal was dosed by oral intubation using a stainless steel ball-tipped gavage needle attached to an appropriate syringe. Dose administration was daily (7 days/week) for all adult animals as follows:
• Group 1-4 male rats were dosed during pre-mating (14 days) and mating/post-mating (14 days) periods, for at least 28 days of administration.
• Group 1-4 female rats in the - Reproduction/Developmental Toxicity Cohort were dosed during pre-mating (14 days), mating (up to 14 days), gestation (approximately 22 days), and lactation (13 days) periods.
• Group 5-8 female rats in the General Toxicity Cohort were dosed for at least 28 days of administration.

The dose mixtures were maintained on a magnetic stir plate during dose administration. The first day of administration was Day 15 of the study. Dosing was at approximately the same time each day (±2 hours) with an exception on the day(s) hematology and/or clinical chemistry samples were collected. Residual dose mixtures were properly discarded following daily administration and sampling (as required).
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 1
REPRODUCTION/DEVELOPMENTAL TOXICITY COHORT
No. Animals/Group: 10M / 11F
Vehicle Control
Dose / conc.:
250 mg/kg bw/day (nominal)
Remarks:
Group 2
REPRODUCTION/DEVELOPMENTAL TOXICITY COHORT
No. Animals/Group: 10M / 11F
Low Dose
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
Group 3
REPRODUCTION/DEVELOPMENTAL TOXICITY COHORT
No. Animals/Group: 10M / 11F
Intermediate Dose
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
Group 4
REPRODUCTION/DEVELOPMENTAL TOXICITY COHORT
No. Animals/Group: 10M / 11F
High Dose
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 5
REPRODUCTION/DEVELOPMENTAL TOXICITY COHORT
No. Animals/Group: 5F
Vehicle Control
Dose / conc.:
250 mg/kg bw/day (nominal)
Remarks:
Group 6
REPRODUCTION/DEVELOPMENTAL TOXICITY COHORT
No. Animals/Group: 5F
Low Dose
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
Group 7
REPRODUCTION/DEVELOPMENTAL TOXICITY COHORT
No. Animals/Group: 5F
Intermediate Dose
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
Group 8
REPRODUCTION/DEVELOPMENTAL TOXICITY COHORT
No. Animals/Group: 5F
High Dose
Control animals:
yes, concurrent vehicle

Examinations

Statistics:
Product Safety Labs performed statistical analysis of all data collected during the in-life phase of
the study as well as organ weight data and clinical pathology results. The use of the word
“significant” or “significantly” indicates a statistically significant difference between the control
and the experimental groups. Significance was judged at a probability value of p<0.05. Male and
female rats were evaluated separately

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no mortalities over the course of the study. There were no adverse clinical or detail observations attributable to the administration of C.I. Pigment Blue 79. Clinical observations of blue stainging or blue discoloration of feces observed in the treated male and female rats were secondary to test substance administration and are considered to have no toxicological relevance.
Mortality:
no mortality observed
Description (incidence):
There were no mortalities over the course of the study. There were no adverse clinical or detail observations attributable to the administration of C.I. Pigment Blue 79. Clinical observations of blue stainging or blue discoloration of feces observed in the treated male and female rats were secondary to test substance administration and are considered to have no toxicological relevance.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no changes in male or female body weight endpoints attributable to the administration of C.I. Pigment Blue 79.
Mean weekly body weights and daily body weight gains for the test substancetreated males and female rats at 250, 500, and 1000 mg/kg/day of C.I. Pigment Blue 79 for the Reproduction/Developmental Toxicity Cohort and General Toxicity Cohort were comparable to control values throughout the study. Mean weekly body weights and daily body weight gains for the test substance-treated females during gestation and lactation periods showed a steady increase appropriate to their physiologic state, were within normal range to that expected for this age and strain of rat, and were comparable to control values throughout the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no changes in male and female mean daily food consumption or food efficiency attributable to the administration of C.I. Pigment Blue 79.
Mean daily food consumption and food efficiency for the test substance-treated males and female rats in administered 250, 500, and 1000 mg/kg/day of C.I. Pigment Blue 79 for the Reproduction/Developmental Toxicity Cohort and General Toxicity Cohort were comparable to the control values throughout the study.
Food efficiency:
no effects observed
Description (incidence and severity):
There were no changes in male and female mean daily food consumption or food efficiency attributable to the administration of C.I. Pigment Blue 79.
Mean daily food consumption and food efficiency for the test substance-treated males and female rats in administered 250, 500, and 1000 mg/kg/day of C.I. Pigment Blue 79 for the Reproduction/Developmental Toxicity Cohort and General Toxicity Cohort were comparable to the control values throughout the study.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were no adverse functional observation battery findings attributed to the administration of C.I. Pigment Blue 79. Mean quantitative measurements of grip strength and foot splay for the test substance-treated male and female rats were comparable to the respective vehicle control group values.
Organ weight findings including organ / body weight ratios:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive performance:
no effects observed
Description (incidence and severity):
In summary none of used doses significantly influenced length of pregnancy, number of implants, survival of pups, anogenital distance, or other variables.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
clinical signs

Overall reproductive toxicity

Reproductive effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
no

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for
reproductive performance and general toxicological assessment of the test substance, C.I.
Pigment Blue 79, was determined to be 1000 mg/kg/day for male and female Sprague-Dawley
rats.
Executive summary:

A combined repeated oral dose gavage toxicity study with reproduction/developmental screening was conducted in Crl: CD® (SD) IGS rats to provide information on male and female general toxicity and reproductive performance, including gonadal function, mating behavior, conception, development of conceptus’, and parturition and lactation following administration of C.I. Pigment Blue 79.

One hundred-four healthy rats (40 virgin male and 64 virgin female) were selected for the test and distributed into four Reproduction/Developmental Toxicity Cohort groups (Groups 1-4; 10 males and 11 females per group) and four General Toxicity Cohort groups (Groups 5-8; 5 females/dose level). Dose levels of 250, 500, and 1000 mg/kg/day of C.I. Pigment Blue 79 for Groups 2-4 and 6-8, respectively, as well as a vehicle control (Groups 1 and 5; 0.5% carboxymethylcellulose (CMC) in water), were selected for the test.

Males and female rats were housed separately for a 14-day pre-dosing, followed by a 14-day premating period. The males and females received the test substance while housed separately for the 14-day pre-mating period, followed by dosing through a 14-day co-habitation period. Estrus cycles were monitored daily for all females in Groups 1-4 during the pre-dosing, pre-mating, and mating periods until evidence of mating. Upon determination of pregnancy or following the prescribed 14-day mating period, females were removed and placed in a separate cage, where dosing continued through the gestation period of pregnancy until Day 13 of lactation. Males were sacrificed following the gestation phase (Day 47), and the first five males in Groups 1-4 were evaluated for fertility, including spermatogenic stage and epididymal effects. The last five males assigned to Groups 1-4 were selected for general toxicity evaluations, along with the five females in Groups 5-8. Blood was sampled from the last five Groups 1-4 males and five Groups 5-8

females on Study Day 45 for hematology and clinical chemistry, and just prior to terminal sacrifice on Day 47 for coagulation assessments. Gross necropsies were performed on all study animals, and the males and females were evaluated histopathologically according to protocol design following scheduled sacrifice on Study Day 47 (Group 1-4 males and Group 5-8 females) and LD14 (Group 1-4 females).

The animals were observed for viability, signs of gross toxicity, and behavioral changes at least once daily during the study, and approximately weekly for a battery of detailed observations (beginning on Day 15 to coincide with initiation of dosing). A Functional Observational Battery (FOB) and a Motor Activity (MA) test were performed on the selected animals (last five Groups 1-4 males and five Groups 5-8 females) on Study Day 45. Individual body weights and food consumption were recorded weekly for both sets of animals. Body weights for females were recorded on GD 0, 7, 14, and 21, as well as on LD 0, 7, and 14. Food consumption for males and females was recorded to coincide with body weight collection exception during the mating period.

The neat test substance was considered to be stable throughout the duration of the study. All dose preparations were homogeneously distributed. In general, the concentration verification results were consistent with the targeted concentrations of 25, 50, and 100 mg/mL.

There were no mortalities over the course of the study. There were no adverse clinical or detail observations attributable to the administration of C.I. Pigment Blue 79. The number of estrus cycles was comparable between the control and test substance-treated females during the predosing and pre-mating periods.

There were no adverse functional observation battery findings attributed to the administration of C.I. Pigment Blue 79. Mean quantitative measurements of grip strength and foot splay as well as motor activity measurements for the test substance-treated male and female rats were comparable to the respective vehicle control group values.

There were no test substance-related changes in mean weekly body weights, daily body weight gain, daily food consumption, or food efficiency for the test substance-treated male and female rats throughout the study.

There were no test substance-related changes in hematology, coagulation and clinical chemistry parameters in test substance-treated male and female rats.

There were no adverse macroscopic findings attributable to the administration of C.I. Pigment Blue 79. Blue tissue discoloration, attributed to the blue dye test substance, was primarily restricted to the gastrointestinal tract and mesenteric lymph nodes and interpreted to be of no toxicological significance as there were no correlating microscopic findings. There were no reproductive or general toxicologic microscopic changes related to C.I. Pigment Blue 79 administration. No test substance-related organ weight changes were found in the test substancetreated male or female rats.

There were no changes in male or female mating, fertility, and fecundity indices attributable to the administration of C.I. Pigment Blue 79. C.I. Pigment Blue 79 administration resulted in no significant changes in any of the gestational or birth parameters evaluated during the course of the present study including gestational length, gestation index, number of implantation sites, corpora lutea, average resorption (early) numbers and pre-implantation and post-implantation loss. In addition, C.I. Pigment Blue 79 administration

resulted no significant differences in earlier stage of gestation indicators such as newborn pup litter size, live birth index, and number of stillborn pups and sex ratio.

In the offspring generation (F1), there were no adverse clinical observations attributable to the administration of C.I. Pigment Blue 79. There were no test substance-related changes in the average pup body weight and body weight gains per litter. There were no adverse necropsy findings in the F1 pups attributed to the test substance administration.

Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for reproductive performance and general toxicological assessment of the test substance, C.I.

Pigment Blue 79, was determined to be 1000 mg/kg/day for male and female Sprague-Dawley rats.