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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well performed study according to GLP
Objective of study:
other: absorption, distribution, metabolism, excretion
Principles of method if other than guideline:
The purpose of the study was to analyse the content of the test item in rat plasma, samples obtained in the course of a one to two generation reproduction oral toxicity study (RTC study 46350, see 7.8.1)
Blood samples were collected on days 10 and 61 of the study for males and on days 5 and 15 post coitum for females. In addition, blood samples were collected from the pups (both sexes) on the last day of dosing at 1, 3, 6, 24 and 48 hours after dosing.
GLP compliance:
yes
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Italy S.r.l., San Pietro al Natisone (UD)
- Age at study initiation: (P ) Males: 5 wks; Females: 8-9 wks at receipt
- Weight at study initiation: (P) Males: 134.1-159.3 g; Females: 200.6- 229.4 g at receipt
- Housing: In a limited access rodent facility. At arrival, the animals were housed up to 5 of one sex to a cage, after allocation, during the pre-pairing period, the animals were housed 4 of one sex to a cage, during the mating period, the rats were housed one male to one female, males were re-caged after mating as they were before mating, after mating, the females were transferred to individual breeding cages.

- Diet (e.g. ad libitum): laboratory rodent diet (4RF21, Mucedola S.r.l., Via G. Galilei 4, 20019 Settimo Milanese (MI), Italy) ad libitum
- Water (e.g. ad libitum): Drinking water ad libitum
- Acclimation period: approximately 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): 15 to 20
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: carboxymethylcellulose 1% in water
Details on exposure:
see IUCLID chapter 7.8.1 or RTC study No 46350 "One to Two Generation Reproduction Oral Toxicity Study in Rats (Including Sperm Analysis)"
Duration and frequency of treatment / exposure:
see IUCLID chapter 7.8.1 or RTC study No 46350 "One to Two Generation Reproduction Oral Toxicity Study in Rats (Including Sperm Analysis)"
Remarks:
Doses / Concentrations:
see IUCLID chapter 7.8.1 or RTC study No 46350 "One to Two Generation Reproduction Oral Toxicity Study in Rats (Including Sperm Analysis)"
No. of animals per sex per dose / concentration:
see IUCLID chapter 7.8.1 or RTC study No 46350 "One to Two Generation Reproduction Oral Toxicity Study in Rats (Including Sperm Analysis)"
Positive control reference chemical:
see IUCLID chapter 7.8.1 or RTC study No 46350 "One to Two Generation Reproduction Oral Toxicity Study in Rats (Including Sperm Analysis)"
Details on dosing and sampling:
Plasma samples of different rats treated with the test item were collected and stored at - 80°C until analysis.

Blood samples were collected from the tail vein of the first 5 high dose and 5 control male rats on days 10 and 61 of dosing, 4 h after administration.
For females, blood samples were collected from the tail vein of the first 5 high dose and 5 control rats, 4 h after administration on day 5 of dosing and during pregnancy (day 15 post coitum).
For the pups, blood samples were collected from the tail vein of the first 8 male and 8 female pups of the high dose group (week 5 of study) at 1, 3, 6, 24, 48 h after dosing (4 rats per sampling time; 2 or 3 blood samples from each animal).
Blood samples were transferred into tubes containing lithium heparin as anticoagulant and centrifuged at room temperature at 3000 rpm for 10 min. For each sample the content of the test item was determined.
Statistics:
Mean, standard deviation (SD) and coefficient of variation (CV) of the individual data of the test item were calculated and used for the assessment of toxicokinetic data at RTC S.p.A.
The toxicokinetic analysis was conducted according to a standard non-compartmental analysis.
The following toxicokinetic parameters were obtained or calculated from the mean plasma values instead of the individual plasma levels as specified in the study protocol:
Cmax: maximum observed plasma concentration
tmax: time to Cmax
AUC0-48 h: area under the concentration-time curve calculated by the linear trapezoidal rule.

All the toxicokinetic parameters were estimated or calculated by the Kinetica (TM), version 4.4.1, PK/PD Analysis (Thermo Electron Corporation Informatics, Philadelphia - USA) software


For statistical evaluation and assessment of toxicokinetic parameters all values below the limit of quantitation (LLOQ = 49.752 ng/mL) were set to 0 (zero).
For the AUC0-48h calculation, zero was set at a 24 hour time for the male pups and at a 48 hour time for the female pups. In addition, for female pups the mean from the two numerical values was set at 24 hours.
Key result
Toxicokinetic parameters:
Cmax: 191.39 ng/mL; male pups, mean of 4 animals
Toxicokinetic parameters:
Tmax: 1 h after dosing; male pups
Key result
Toxicokinetic parameters:
Cmax: 169.66 ng/mL; female pups, mean of 4 animals
Toxicokinetic parameters:
Tmax: 1 h after dosing; female pups
Metabolites identified:
no
Bioaccessibility (or Bioavailability) testing results:
Detectable plasma concentrations of the test item were found in male and female pups from 1 hour after dosing. The test item was below the limit of quantitation (LLOQ = 49.752 ng/mL) in 3 out of 4 male pups at 24 h after dosing and in all male pups at 38 h after dosing. For female pups the test item was below LLOQ in 2 out of 4 at 24 h after dosing and in 3 out of 4 at 48 h after dosing. The maximum plasma concentration of the test item was found 1 hour after dosing in pubs of both sexes.

For male and female rats the test item was detectable 4 hours after dosing on days 5 and 15 (females) and on days 10 and 61 (males)

Table 1: individual plasma concentrations of the test item in male pups collected on the last day of dosing (1000 mg/kg bw/day)

Animal No

Pub sex

Sampling Time

[hours after dosing]

Test item concentration [ng/mL]

66340386

male

1

219.49

66340388

male

1

158.63

66340390

male

1

245.57

66340392

male

1

141.88

mean

                 

 

191.39

SD

 

 

49.16

CV %

 

 

25.69

66340394

male

3

111.50

66340396

male

3

232.35

66340398

male

3

169.05

66340400

male

3

147.04

mean

                 

 

164.98

SD

 

 

50.78

CV %

 

 

30.78

66340386

male

6

127.19

66340388

male

6

105.85

66340390

male

6

269.95

66340392

male

6

97.30

mean

                 

 

150.07

SD

 

 

80.90

CV %

 

 

53.91

66340394

male

24

BLOQ

66340396

male

24

BLOQ

66340398

male

24

BLOQ

66340400

male

24

98.26

mean

                 

 

24.57

SD

 

 

49.13

CV %

 

 

200.00

66340386

male

48

BLOQ

66340388

male

48

BLOQ

66340390

male

48

BLOQ

66340392

male

48

BLOQ

mean

                 

 

0

SD

 

 

0

CV %

 

 

0

 

Table 2: individual plasma concentrations of the test item in female pups collected on the last day of dosing (1000 mg/kg bw/day)

Animal No

Pub sex

Sampling Time

[hours after dosing

Test item concentration [ng/mL]

66340385

female

1

144.16

66340387

female

1

185.17

66340389

female

1

179.39

66340391

female

1

169.92

mean

                 

 

169.66

SD

 

 

18.13

CV %

 

 

10.68

66340393

female

3

99.80

66340395

female

3

75.78

66340397

female

3

86.23

66340399

female

3

95.89

mean

                 

 

89.43

SD

 

 

10.74

CV %

 

 

12.00

66340385

female

6

182.98

66340387

female

6

59.13

66340389

female

6

82.36

66340391

female

6

192.88

mean

                 

 

129.36

SD

 

 

68.35

CV %

 

 

52.84

66340393

female

24

94.42

66340395

female

24

BLOQ

66340397

female

24

66.43

66340399

female

24

BLOQ

mean

                 

 

40.71

SD

 

 

48.58

CV %

 

 

119.32

66340385

female

48

BLOQ

66340387

female

48

BLOQ

66340389

female

48

BLOQ

66340391

female

48

113.24

mean

                 

 

28.31

SD

 

 

56.62

CV %

 

 

200.00

Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2020
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Details on absorption:
A prerequisite for a relevant absorption is that the substance can be dissolved in either aqueous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. C.I. Pigment Yellow 191 can be considered very poorly soluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that C.I. Pigment Yellow 191 becomes systemically bioavailable in relevant concentration after oral, dermal or inhalation exposure.
Based on the sub-acute oral toxicity study and the one generation reproduction study with C.I. Pigment Yellow 191 absorption of toxicologically significant amounts via the gastrointestinal tract is considered unlikely, since C.I. Pigment Yellow 191 did not show any effects on inner organs and blood or urine. Only traces of the test material could be detected in blood plasma.For parental male and female rats the test item was detectable 4 hours after dosing on days 5 and 15 (females) or on days 10 and 61 (males). Cmax varied between ca. 94 and 145 ng/ml in males and between ca. 74 and 76 ng/ml in females
The skin sensitisation study with C.I. Pigment Yellow 191 indicates no local dermal bioa-vailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 500 mg C.I. Pig-ment Yellow 191 per kg body weight in rabbits in the acute dermal irritation study.
Dermal absorption is, therefore, considered unlikely.
In the unlikely event of exposure to aerosolized pigment in respirable form, the substance is considered to behave like an inert dust. Therefore, the deposited pigment particles will mostly be cleared from the lung via the muco-cilliary transport. As the pigment will dissolve very slowly in the lung surfactant, the only relevant way the pigment can enter the body is via phagocytosis of pigment particles by lung macrophages followed by migration of the macrophages into the interstitium and into the draining lymph nodes. However, the internal dose delivered via this mechanism can be considered negligible.

Details on distribution in tissues:
The reproduction toxicity test as well as all other studies employing repeated exposure with C.I. Pigment Yellow 191 did not indicate any relevant histopathological changes in any of the investigated organs. This may indicate that the pigment either does not affect specific organs as targets, i.e., is non-toxic, or is not distributed within the body in significant amounts. As indicated above, the physico-chemical parameters of the pigment support the conclusion that the pigment is not absorbed sufficiently into the body and thus does not be-come systemically available in relevant amounts. There were also no other signs of deposition of the pigment in any organ including excretory organs, like the kidney, indicating that even exposure to high doses of the pigment does not lead to bioaccumulation in special compartments of the body.
Based on the available information on absorption distribution of the test material in the body in significant amounts is unlikely and specific hotspots of distribution cannot be identified.
Thus, it is concluded, that C.I. Pigment Yellow 191 is not systemically available at relevant concentrations within the organism.
There were no signs of bioaccumulation of the test material. This view is supported by the physical-chemical properties (solubility in water and octanol).
Details on excretion:
Considering the physico-chemical properties and the molecular structure and size of the mol-ecules and the absence of any indication of absorption and/or metabolism it is assumed that excretion, if any, is likely to occur mostly via faeces. This notion is confirmed by the discol-oration of faeces observed in the oral studies as the only alteration. The trace amounts ab-sorbed into the blood may also be excreted via the kidneys into urine.
Details on metabolites:
Since the solution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is unlikely that the insoluble pigment becomes accessible for metabolizing systems in relevant amounts.
Pigment Yellow 191 is not or only to a negligible extend cleaved, taking into account the negative results obtained with C.I. Pigment Yellow 191 in investigations on repeated dose toxicity
The results of the mutagenicity tests provide qualitative information on the metabolic fate of C.I. Pigment Yellow 191. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the pigment, even directly exposed to metabolizing enzymes, is not converted into toxic or genotoxic metabolites. This conclusion is also supported by the lack of any morphological and histopathological changes of organs involved in xenobiotic metabolism, such as the liver, in the sub-acute toxicity and reproduction studies with C.I. Pigment Yel-low 191. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Yellow 191 is considered to just pass through the intestinal tract without significant metabolism.
Conclusions:
Based on all available data, C.I. Pigment Yellow 191 does not exhibit conspicuous toxicoki-netic behaviour in the sense of accumulative and/or delayed effects with regard to the indi-vidual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that C.I. Pigment Yellow 191 has a no relevant dermal absorptive potential. C.I. Pigment Yellow 191 is not absorbed from the gastrointestinal tract in significant amounts.
Indications of an intense metabolism or a bio-accumulative potential do not exist as no tox-icity occurred even after exposure for 61 days (females in the one generation study), which points to no bio-accumulation potential and complete excretion of all possibly available C.I. Pigment Yellow 191 and/or metabolites.
Executive summary:

Based on the available data base on C.I. Pigment Yellow 191 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation. The substance is available in bulk- as well as nano-form. The available data have mostly been generated with bulk material, but the conclusions drawn are considered valid for the nano form as well, because the material is chemically identical, and the physical properties are widely overlapping.

The results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxico-kinetics of C.I. Pigment Yellow 191. C.I. Pigment Yellow 191 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. The data indicate that there is no relevant dermal absorption. After inhalation unspecific reactions to unreactive dust can be expected. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of traces of possibly systemically available C.I. Pigment Yellow 191 and/or metabolites via faeces and urine is likely.

Description of key information

Based on the available data base on C.I. Pigment Yellow 191 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation. The substance is available in bulk- as well as nano-form. The available data have mostly been generated with bulk material, but the conclusions drawn are considered valid for the nano form as well, because the material is chemically identical, and the physical properties are widely overlapping.

The results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxico-kinetics of C.I. Pigment Yellow 191. C.I. Pigment Yellow 191 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. The data indicate that there is no relevant dermal absorption. After inhalation unspecific reactions to unreactive dust can be expected. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of traces of possibly systemically available C.I. Pigment Yellow 191 and/or metabolites via faeces and urine is likely.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information