Calcium 4-chloro-2-(5-hydroxy-3-methyl-1-(3-sulfonatophenyl)pyrazol-4-ylazo)-5-methylbenzenesulfonate

Endpoint summary

Description of key information

Repeated oral toxicity:
An OECD test guideline (OECD 407) and GLP-compliant Combined Repeated Dose Toxicity Study was performed with the test item

(Pigment Yellow 191). Groups of 5 male and 5 female Wistar rats received doses of 0, 62.5, 250 and 1000 mg/kg bw by daily gavage for 28 days . No toxicologically significant changes were noted in any of the parameters investigated in this study (such as clinical signs, neurological examinations, body weight, food consumption, macroscopic examination, organ weights, or microscopic examination). Only minor effects were observed in the clinical laboratory investigations and a decreased specific urine weight was determined in both sexes of the high dose group.
A No Observed Adverse Effect Level (NOAEL) for the test item of 1000 mg/kg/day was established.
Repeated dermal toxicity:
The dermal route was waived. The substance is considered not to exert adverse effects.
Repeated inhalation toxicity:
The inhalation route was waived. The substance is considered not to exert adverse effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

well performed GLP and OECD guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

1981

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: HOECHST AG, company breeding colony
- Age at study initiation: ca. 6 weeks
- Weight at study initiation:
-- control male: 124 +/- 2 g
-- control female: 130 +/- 5 g
-- low dose male: 124 +/- 8 g
-- low dose female: 131 +/- 9 g
-- mid dose male: 128 +/- 7 g
-- mid dose female: 133 +/- 5 g
-- high dose male: 128 +/- 5 g
-- high dose female: 133 +/- 5 g
- Fasting period before study: none
- Housing: Makrolon(R) cages, groups of five animals of the same sex, air-conditioned
- Diet (e.g. ad libitum): rat diet Altromin 1324(R), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: daily, immediately before application

VEHICLE
- Concentration in vehicle: 0.00 / 0.63 / 2.50 / 10.00 % (w/v)
- Amount of vehicle (if gavage): Applied Volume = 10 ml/kg bw

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

28 applications within 29 days, one application per day, 7 times a week

Frequency of treatment:

once a day

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Remarks:

Doses / Concentrations:
0.0 mg/kg bw
Basis:
actual ingested

Dose / conc.:

62.5 mg/kg bw/day (actual dose received)

Remarks:

Doses / Concentrations:
62.5 mg/kg bw
Basis:
actual ingested

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Remarks:

Doses / Concentrations:
250.0 mg/kg bw
Basis:
actual ingested

Dose / conc.:

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

Remarks:

Doses / Concentrations:
1000.0 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes (absolute and relative)

WATER CONSUMPTION): Yes

OPHTHALMOSCOPIC EXAMINATION: Yes (macroscopic examination and opacity)

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
ORGAN WEIGHT: Yes

Statistics:

Statistics applied for differences (p=0.05) betweeen control and dose groups for: Body weight, body weight gain, hematology parameters, clinical parameters, albumin, globulin, organ weight (absolute and relative), pH and specific weight of urine

Clinical signs:

no effects observed

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):

no effects observed

Ophthalmological findings:

no effects observed

Description (incidence and severity):

based on examination of macroscopic effects and opacity

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Female, 1000 mg/kg bw group: statistically increased Alpha1-Globulin, decreased Alpha3- and Beta1-Globulin but within the range of historical controls. Decreased inorganic phosphate.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Male and female, 1000 mg/kg bw group: decreased specific urine weight

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed at 1000 mg/kg bw, the highest dose tested.

Critical effects observed:

not specified

Conclusions:

Based on the findings in this oral 28-day repeated dose toxicity study the NOAEL was determined to be >= 1000 mg/kg bw, which was the highest dose tested.

Executive summary:

The test item was tested for subacute oral toxicity according to OECD guideline 407. Following this protocol male and female Wistar rats were treated once daily by oral gavage with 0.00, 62.50, 250.00, or 1000.00 mg/kg bw (28 applications).

 

Behavior and health condition were observed twice daily and once a day at weekends and at public holidays. Body weight and food consumption were determined twice a week and water consumption once a week. At the end of the study hematology, clinical chemistry and urine parameters were collected. At necropsy macroscopic investigations were performed, organ weights were determined, and relative organ weights were calculated. Heart, lung, liver, kidney, spleen, stomach, jejunum, colon, thymus, testes, adrenal gland, and bone marrow were subject of histopathological examinations.

 

Behavior, health condition, food and water consumption, and body weight gain were not affected by the treatment. Hematological examinations revealed no signs of toxicity. From the clinical chemistry parameters phosphate was decreased, alpha1-globulin was increased and alpha3- and beta1-globulin were decreased in females of the high dose group. Except the specific urine weight which was decreased in males and females of the high dose group no other urine parameters were affected by the treatment.

 

Necropsy revealed no macroscopic or microscopic abnormalities that could be attributed to the treatment. Organ weights of the dose groups showed no treatment related differences as compared to the control groups.

 

In conclusion it can be stated that doses up to 250 mg/kg bw didn't cause any signs of toxicity. Although single urine and clinical parameters showed differences between the control and the 1000 mg/kg bw groups, the values were still within the range which is typical for rats of this strain. Moreover there are neither signs of morphological and functional impairments nor any other indications for adverse effects caused by the test item. Therefore the findings were considered to be accidental and/or of no toxicological relevance.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

GLP compliance:

yes

Limit test:

no

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed at 1000 mg/kg bw, the highest dose tested.

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Quality of whole database:

1 (reliable without restriction)
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or no or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available

Justification for classification or non-classification

Pigment Yellow 191 does not have to be classified regarding systemic and specific target organ toxicity after repeated exposure according to the criteria laid down in Directive 67/548/EEC and in Regulation (EC) No 1272/2008, because:

• Pigment Yellow 191 caused no relevant systemic effects and revealed a NOAEL of 1000 mg/kg/day in a Repeated Dose Toxicity Study after oral application.

 

It can reasonably be deduced that Pigment Yellow 191 does not exert systemic toxic effects after repeated dermal application and thus does not have to be classified according to the criteria laid down in Directive 67/548/EEC and in Regulation (EC) No 1272/2008 and that testing is not scientifically necessary, because:

• Pigment Yellow 191caused no relevant systemic effects and revealed a NOAEL of 1000 mg/kg/day in a Repeated Dose Toxicity Study after oral application,
• the repeated dose toxicity after dermal application is not considered to be higher than after oral administration,
• testing for acute dermal toxicity revealed no signs of bioavailability or toxicity.
• Pigment Yellow 191 does not have to be classified as skin sensitizing or as skin or eye irritating,

 

It can reasonably be deduced that Pigment Yellow 191 does not exert systemic toxic effects after repeated inhalation exposure and thus does not have to be classified according to the criteria laid down in Directive 67/548/EEC and in Regulation (EC) No 1272/2008 and that testing is not scientifically necessary, because:

• Pigment Yellow 191 caused no relevant systemic effects and revealed a NOAEL of 1000 mg/kg/day in a Repeated Dose Toxicity Study after oral application,
• testing for acute dermal toxicity revealed no signs of bioavailability or toxicity.
• Pigment Yellow 191 does not have to be classified as skin sensitizing or as skin or eye irritating, indicating that its chemical inertness prevent interaction with living cells and tissues,
• Pigment Yellow 191, when aerosolized in respirable form, is likely to behave like an inert dust.