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REACH

1-hydroxy-4-[[4-[(methylsulphonyl)oxy]phenyl]amino]anthraquinone

EC number: 216-475-4 | CAS number: 1594-08-7

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

The No Observed Adverse Effect Level (NOAEL) for Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test by Oral Gavage in Wistar rats for FAT36038/J TE is determined to be 1000 mg/kg bw/day.

Key value for chemical safety assessment

Toxic effect type:: concentration-driven

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 August, 2020 - 25 March, 2021

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

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)

Limit test:

Specific details on test material used for the study:

Batch No.: 1404301
Manufactured Date: 20.09.2014
Expiry Date: 08.04.2024
Physical Appearance: Black powder
Storage Conditions: Ambient (+15 to +25 ºC)
Physical-chemical properties: pH: 5.0, Density: 1.2654 g/cm³

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were housed in an environment controlled room. The temperature maintained during the experiment was between 21 to 25°C and relative humidity between 49 and 66 %. The photoperiod was a 12 hours light and 12 hours dark cycle. Adequate fresh air supply of 12.8– 12.9 air changes/hour was maintained in the experimental room. The maximum and minimum temperature in the experimental room was recorded once daily. The relative humidity in the experimental room was calculated daily from dry and wet bulb temperature recordings.

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

The test item was administered by oral gavage in graduated doses to three groups of male and female rats. The males were dosed for 52 days, up to and including the day before scheduled sacrifice (this includes two weeks prior to mating, during mating period and approximately, two weeks post mating period). Females were dosed throughout the treatment period. This includes two weeks prior to mating (with the objective of covering at least two complete oestrous cycles), the variable time to conception, the duration of pregnancy and up to and including the day before scheduled sacrifice (i.e., up to LD13). Animals in the recovery groups were kept only for observations of reversibility, persistence or delayed occurrence of systemic toxic effects for 14 days of recovery period and these animals were not mated and consequently were not used for assessment of reproduction/developmental toxicity. The recovery period of the study started from the first scheduled kill of dams.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

For homogeneity and test item concentration analysis, prepared formulation samples were sampled in duplicate sets on Day 1 and during Week 4 (Day 32) of treatment period and was analysed in-house. For each set, duplicate samples were drawn from the top, middle and bottom layers of each preparation and in case of the control duplicate samples from the middle layer were drawn.
The analysis was done as per the method validated under Eurofins Advinus Study No.: G19993. One set of samples (first set) were analysed for test item concentration analysis and other set (second set) of samples were stored at ambient condition for reanalysis purpose as a backup.
On Day 1(21 September 2020), the analysis results of G2 was out of specification. Hence, the backup samples were analysed and results were within the specified limit. This could be due to sampling or processing error.
During 2nd month (Day 32, 22 October 20202), the analysis results were out of specification in all the doses. Hence, the samples collected from the freshly prepared formulations on 23 October 2020 were sent for analysis. The analysed results were within the specified limit as per study plan except G4. Hence, freshly prepared formulation from G4 group was sent for analysis on 25 October 2020 and the results were within the specified limit.
On both these occasions, the error could happen while during sampling or processing. Throughout the study period, the same procedure for the formulation preparation was followed. The formulations were freshly prepared on daily basis prior to administration. Further, the degree of the deviation of results that failed to be within the given specification limits was rather low or high when compared to the dose spacing. Hence, this does not affect the integrity of the study results.
Formulations were considered acceptable when the mean results (calculated using all the replicate values) of all the layers and mean of each layer was within ±15.0 % of the claimed concentration and the relative standard deviation (% RSD) was equal to or less than 10.0 %.

Duration of treatment / exposure:

Males: The dose formulation was administered orally by gavage to the rats of the specific groups once daily at approximately the same time each day (varying by ± 3 hours) for 52 days which includes 2 weeks prior to mating, during mating and post-mating, up to and including the day before scheduled sacrifice.
Females: The dose formulations were administered orally by gavage to the specific group of rats once daily at approximately the same time each day (varying by ± 3 hours) for total of 43-58 days which includes 2 weeks prior to the mating, during mating, pregnancy and up to LD 13.

The dose formulations were administered to the high dose recovery group of rats once daily at approximately the same time each day (varying by ± 3 hours).
The dose volume administered to each rat was at an equivolume of 10 mL/kg body weight throughout the study. The dose volume was adjusted based on the most recent body weight of individual rat.
Similarly, vehicle was administered to rats in the vehicle control and vehicle control recovery groups at an equivolume of 10 mL/kg bwt.
The vehicle and the test item were not administered for vehicle control recovery and high dose recovery groups, respectively for 14 days from the first scheduled kill of dams.

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

control

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

low dose

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Main groups: 10 males and 10 females
Recovery groups: 5 males and 5 females

Control animals:

yes

Details on study design:

Group
No. Group Colour
of
cage card Dose
(mg/kg bwt/day) Concen-tration (mg/mL) Dose volume (mL/ kg bwt/day) No. of rats Sex Rat Numbers
From To
Main Groups
G1 Vehicle Control White 0 0 10 10 M Rx8921 Rx8930
10 F Rx8931 Rx8940
G2 Low dose Yellow 100 10 10 10 M Rx8941 Rx8950
10 F Rx8951 Rx8960
G3 Mid dose Green 300 30 10 10 M Rx8961 Rx8970
10 F Rx8971 Rx8980
G4 High dose Pink 1000 100 10 10 M Rx8981 Rx8990
10 F Rx8991 Rx9000
Recovery Groups
G1R Vehicle Control recovery White 0 0 5 M Rx9001 Rx9005
5 F Rx9006 Rx9010
G4R High dose recovery Pink 1000 10 5 M Rx9011 Rx9015
5 F Rx9016 Rx9020

Observations and examinations performed and frequency:

All rats were observed for clinical signs once daily. Body weight was recorded prior to the start of treatment on Day 1 and at weekly intervals thereafter. The body weights were also recorded at termination. Food consumption was recorded at weekly intervals except during the cohabitation period. After confirmation of mating by vaginal smear, the dams were weighed on presumed Gestation Days (GDs) 0, 7, 14 and 20 and the food consumption was recorded on GD 7, 14 and 20.
The littered dams were weighed on LDs 0, 4 and 13 and the food consumption was recorded on LD 0, 4 and 13. The number, survival and mortality of pups were observed during the lactation period. The body weight and ano-genital distance of each live pup was measured on LD 0. The size of each litter was adjusted by eliminating extra pups by random selection on LD 4 after recording the body weight of each live pup. After standardization, the individual pup body weight was recorded on LD 13. All the surviving male pups were examined for the appearance of nipples/areolae on LD 13. Neurological examinations were conducted for randomly selected 5 main group females on LD 13 and randomly selected 5 main group males on treatment day 47 and towards the end of recovery period (Day 66) for the recovery group animals. Laboratory investigations such as hematology, coagulation, clinical chemistry and urinalysis were performed on randomly selected 5 parental males and females from each group at the end of the pre-mating period after overnight fasting. Thyroxine 4 (T4) and Thyroid Stimulating Hormone (TSH) analysis were performed in all main group males at termination, all dams on LD 13 and from available pups on LD 4 and 13. At sacrifice, the parental males (Day 52), parental females (LD14) and the recovery animals (Day 67) were subjected to detailed necropsy after overnight fasting (water allowed) and the study plan specified tissues were collected. The pups were sacrificed on LD 13 after examining the external reproductive genitals for signs of altered development. Histopathology examination was carried out on the preserved organs from randomly selected 5 males and 5 females in the control and high dose groups (including reproductive organs) and on all gross lesions. Histopathological examination of testes included a qualitative assessment of stages of spermatogenesis. Thyroids were examined from all adult males and females and in LD 13 pups. The reproductive organs were examined from the non-pregnant females (Rx8975, Rx8958 and Rx8995).

Sacrifice and pathology:

All adult animals including one pre-terminally dead dam (Rx8951) and pups were subjected for detailed necropsy and findings were recorded. The adult animals killed at term were fasted overnight (water allowed), weighed and exsanguinated under isoflurane anaesthesia. All the surviving pups were necropsied on lactation Day 13 and findings were recorded with particular attention to the external genitals for the altered development. Dead pups were examined for possible defects and/or cause of death. For apparently non-pregnant rats (Rx8975, Rx8958 and Rx8995), the uteri were stained with Salewski stain to identify the post implantation loss of the embryos. The number of implantation sites were recorded for all the dams.

Statistics:

Data was captured using the ProvantisTM laboratory information management system (LIMS).
Parameters such as body weight, body weight change, body temperature, hindlimbs footsplay, grip performance, food consumption, organ weights, organ weight ratios (organ to body weight and organ to brain weight), laboratory Investigations – Haematology, Coagulation & Clinical Chemistry, oestrous cycle, ano-genital distance, post implantation loss (%), no. of implantations, mean litter size, sex ratio, survival index, gestation length (days), pups data and transferred (motor activity, thyroid profile) data was evaluated using the Levene Test for homogeneity of variances and the Shapiro-Wilks Test for normality of distributions. When data found to be homogeneous and of normal distribution, was analysed by analysis of variance (ANOVA), when data found to be nonhomogeneous or of nonnormal, the data was subjected for transformation and ANOVA was performed on transformed data. When ANOVA found to be significant, pairwise comparisons of treated groups to the control group was made using a parametric test, Dunnett, to identify statistical differences.
Data like pre-coital interval, mating and fertility indices were analysed using Chi-square test. When Chi-square is found to be significant, pairwise comparisons of treated groups to the control group was made using a Fisher Exact test, to identify statistical difference in ProvantisTM built-in statistical tests.
Data captured outside of ProvantisTM: The statistical analysis of the experimental data was carried out using licensed copies of SYSTAT Statistical package Ver.12.0.

*: Statistically significant difference from the control group at p <0.05

Clinical signs:

effects observed, non-treatment-related