Dihydrogen [[N,N'-ethylenebis[N-(carboxymethyl)glycinato]](4-)-N,N',O,O',ON,ON']nickelate(2-)

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

Based on the data available from different studies, the No Observed Adverse Effect Level (NOAEL) for test material was considered to be 500 mg/kg/day for repeated dose oral toxicity study, when rodents were treated with test material orally by gavage.

 

Repeated dose toxicity: Dermal

A short-term toxicity study does not need to be conducted because exposure of humans via dermal in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. 

 

Repeated dose toxicity: Inhalation

A short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. 

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Combined repeated dose repro-devp. Screen

Type of information:

experimental study

Remarks:

Read across data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed publication

Qualifier:

according to guideline

Guideline:

other: under a protocol approved by the RTI Institutional Animal Care and Use Committee (IACUC)

Principles of method if other than guideline:

Combined repeated dose repro-devp. study was performed to determine the oral toxic nature of 1,2,3,4 butane tetra carboxylic acid upon repeated exposure by oral route

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of the test chemical: 1,2,3,4 butane tetra carboxylic acid
- IUPAC name: Butane-1,2,3,4-tetracarboxylic acid
- Molecular Formula: C8H10O8
- Molecular Weight: 234.159 g/mol
- Smile Notation: OC(=O)C[C@H]([C@H](CC(=O)O)C(=O)O)C(=O)O
- InChI : 1S/C8H10O8/c9-5(10)1-3(7(13)14)4(8(15)16)2-6(11)12/h3-4H,1-2H2,(H,9,10)(H,11,12)(H,13,14)(H,15,16)/t3-,4+
- Substance type: organic
- Lot no: Lot No. 07201 DZ
- Purity: >99%

Species:

rat

Strain:

Sprague-Dawley

Remarks:

CrI:CD® (SD)BRVAF/Plus® outbred albino rats (CD® rats)

Details on species / strain selection:

No data

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Age at study initiation: Female (P) 8 to 10 weeks old plus 5 days of quarantine period
- Weight at study initiation: Females (P)- 218 to 269 g on gd0
- Fasting period before study: No data
- Housing: The female rats were housed singly in solid bottom, polycarbonate cages with stainless steel lids and certified sani-chip hardwood cage litter
- Diet (e.g. ad libitum): Purina Certified Rodent Chow, ad libitum
- Water (e.g. ad libitum): tap water, Durham, NC city water, ad libitum
- Acclimation period: 5 days quarantine

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70 to 73°F (21-22 °C)
- Humidity (%): 39 to 60%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 h light, 12 h dark

IN-LIFE DATES: From: To: No data

Route of administration:

oral: gavage

Details on route of administration:

No data

Vehicle:

water

Remarks:

Deionized / distilled water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test chemical was dissolved in deionized / distilled water at dose level of 0, 250, 500 or 1000 mg/Kg/day

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): deionized / distilled water
- Concentration in vehicle: 0, 250, 500 or 1000 mg/Kg/day
- Amount of vehicle (if gavage): 5 ml/Kg
- Lot/batch no. (if required): No data
- Purity: No data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The identity of the bulk chemical was confirmed by infrared (IR) spectroscopy and 1H nuclear magnetic resonance spectroscopy. Purity (>99%) was determined by high-performance liquid chromatography (HPLC). Bulk chemical reanalysis was performed within two weeks of study initiation. Identity was reconfirmed by IR spectroscopy and relative purity was >99% when compared to a frozen reference sample by HPLC.

Dosing solutions (BTCA in deionized/distilled water) were verified to be within 92 to 103% of their theoretical concentrations by HPLC prior to and after the period of administration

Duration of treatment / exposure:

14 days (gd 6 to gd19)

Frequency of treatment:

Daily

Remarks:

0, 250, 500 or 1000 mg/Kg/day

No. of animals per sex per dose:

Total: 100
0 mg/Kg bw: 25 females
250 mg/Kg bw: 25 females
500 mg/Kg bw: 25 females
1000 mg/Kg bw: 25 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses for the main study were selected on the basis of acute, oral toxicity study of BTCA [800, 1260, 1590, 2000, and 3170 mg/kg] in COX-SD rats. The BTCA LD50 for female rats was 1620 mg/kg body weight in that study. Dose range selection was also supported by a study in nonpregnant female CD rats (7 per group) exposed to BTCA [0,50,100,500,750, and 1000 mg/kg/day] for 14 consecutive days and a developmental toxicity screening study in female CD rats (14 confirmed pregnancies per group) exposed to BTCA [0, 62.5, 125, 250, 500, and 1000 mg/kg/day] on gd 6 through 19. In the screening study, maternal toxicity was noted at 1000 mg/ kg/day, including morbidity (1/15 dams; evidence of abortion at necropsy). Developmental toxicity was limited to a decreasing trend for fetal body weight (males only) with a 6% (nonsignificant) reduction at 1000 mg/kg/day. Thus, the high dose for the currently reported study was expected to cause some maternal toxicity and to satisfy the US EPA limit dose for developmental toxicity studies. The mid dose for the present study was set at one-half of the high dose, and the low dose was set at one-half of the mid dose. Doses above 1000 mg/kg/day (i.e. 200 mg/mL 3 5 ml/kg) were not considered feasible due to (a) poor solubility of BTCA at 250 mg/mL in water, (b) morbidity in 1/15 pregnant rats at 1000 mg/kg/day on gd 6 through 19 [29], and (c) mortality in 1/5 female rats given a single oral dose of 1590 mg/kg, and 5/5 female rats given a single oral dose of 2000 or 3700 mg/kg

- Rationale for animal assignment (if not random): Confirmed-mated females were assigned to treatment groups by stratified randomization for body weight on gd 0, so that mean body weight on gd 0 did not differ among treatment groups.

- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data

Positive control:

No data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Throughout the treatment
- Cage side observations checked in table [No.?] were included. The animals were observed for mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily prior to initiation of treatment, and twice daily during the treatment period (i.e. at weighing/dosing and 1 to 2 h after dosing).

BODY WEIGHT: Yes
- Time schedule for examinations: Daily during treatment from gd 6 through 19, and on gd 20 (before and after termination)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, feed weights were taken on gd 0, 6, 9, 12, 15, 18, 19, and 20
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water weights were taken on gd 0, 6, 9, 12, 15, 18, 19, and 20

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified

HAEMATOLOGY: Not specified
- Time schedule for collection of blood: Not specified
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Not specified
- Time schedule for collection of blood: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in table [No.?] were examined. Not specified

URINALYSIS: Not specified
- Time schedule for collection of urine: Not specified
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined. Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Not specified

IMMUNOLOGY: Not specified
- Time schedule for examinations: Not specified
- How many animals: Not specified
- Dose groups that were examined: Not specified
- Parameters checked in table [No.?] were examined. Not specified

OTHER: Not specified

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, timed-mated females were sacrificed by C02 asphyxiation on gd 20. The body, liver, and gravid uterus of each timed-mated female were weighed. Thoracic and abdominal cavities were examined.

HISTOPATHOLOGY: Yes, maternal livers were saved in 10% neutral buffered formalin for optional histopathology.

Other examinations:

No data

Statistics:

The unit for statistical measurement was the pregnant female. Quantitative continuous data were compared among treatment groups by parametric tests if Bartlett’s test for homogeneity of variance was not significant. If Bartlett’s test indicated a lack of homogeneity (p < 0.001), then nonparametric tests were applied. Statistical analyses were based on SAS software.

A one-tailed test (i.e., Dunnett's Test) was used for all pairwise comparisons to the vehicle control group, except that a two-tailed Dunnett’s Test was appropriate for maternal body and organ weight parameters, maternal feed and water consumption.

Nonparametric tests for continuous variables included the Kruskal-Wallis one-way analysis of variance by ranks for among-group differences and, if significant (p < 0.05), the Mann-Whitney U test for pairwise comparisons to the vehicle control group. One- or two-tailed Mann-Whitney U tests were applicable to specific parameters, as noted above for Dunnett’s Test. Jonckheere’s test for k independent samples was used to identify significant dose response trends.

Nominal scale measures were analyzed by x2 Test for Independence for differences among treatment groups and by the Cochran-Armitage Test for Linear Trend on Proportions. None of these tests were statistically significant.

The alpha level for each statistical comparison was 0.05, and the significance levels for trend tests and pairwise comparisons were reported as p < 0.05 or p < 0.01.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Clinical signs and mortality:
Mortality: Treatment related mortality occurred in 4% (1/24) in 1000 mg/Kg/day females. All remaining females survived the treatment

Clinical signs: Treatment related clinical signs included weight loss which occurred in all groups and showed increasing frquency and/or severity with increasing dose on individual days during the treatment period. Piloerection was observed in ≤ 4 females/day at 1000 mg/Kg/day. Rooting in the cage bedding after dosing suggested an aversion to the sensory properties of the 500 and 1000 mg/Kg/day dose formulations (≤ 3 500 mg/Kg/day females/day, and ≤ 5 1000 mg/Kg/day females/ day). Alopecia was noted with a low incidence in all groups but showed no apparent relationship to BTCA exposure

Body weight and weight gain: Maternal body weight was comparable among groups on gd 0 and 6 (i.e. prior to the initiation of dosing). On gd 9, 12, 15, 18, and 19, maternal body weights at the low and mid doses were not affected (98.8 to 100.8% of concurrent controls), but maternal body weight at the high dose was significantly lower than the vehicle control on each of these days, except gd 9. On gd 20, maternal body weight at the high dose was significantly below the vehicle control. Decreases in maternal body weight became larger with repeated dosing, and the maximum reductions occurred at the end of the dosing period (gd 18, 19, and 20). Thus, the effect of BTCA on maternal body weight was restricted to the 1000 mg/Kg/day dose group and the magnitude of this effect was relatively small.

Food consumption and compound intake: Maternal relative feed intake was transiently reduced at 1000 mg/kg/day from gd 6 to 9 and at 500 mg/kg/day from gd 12 to 15, although no changes were noted for the treatment period as a whole.

Food efficiency: No data

Water consumption and compound intake: Maternal relative water intake was increased at 1000 mg/kg/day for gd 12 to 15, 18 to 19, 19 to 20, and the treatment period as a whole.

Opthalmoscopic examination: No data

Haematology: No data

Clinical chemistry: No data

Urinanalysis: No data

Neurobehaviour: No data

Organ weights: Gravid uterine weight and maternal relative liver weight were not affected. Absolute maternal liver weight exhibited a decreasing trend but showed no significant differences between control

Gross pathology: The animals that died due to the misdirected dose revealed dark red, mottled lungs and pink discharge from the vagina

Histopathology: No data

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No significant alteration were noted at the mentioned dose level w.r.t. clinical signs, mortality, body weight, food and water intake, organ weights, gross pathology

Remarks on result:

other: NOAEL was found to be 500 mg/kg bw/day

Critical effects observed:

not specified

Table 1: Toxicity in CDt rats exposed to 1,2,3,4-butanetetracarboxylic acid on gestational days 6 through 19

Doses (mg/Kg/day)	0	250	500	1000
Total No. Assigned Females	25	25	25	25
Maternal Body Weight (g)
Gd 0	247.6±2.0	246.9±1.9	246.5±2.5	242.8±2.7
Gd 6	275.7±2.5	277. 3±2.7	278.0±3.1	269.8±2.9
Gd 20 (in life)^c,e	387.7±3.9	387.4±3.8	388.8±4.7	361.1±7.0*
Maternal Weight Gain (g)
Treatment (gd 6 to 20)^c	112.0±2.6	109.1±2.4	110. 8±2.9	91.8±6.1*
Treatment (gd 6 to 20)^c	135.7±3.4	135.3±3.3	135. 6±3.4	113.0±6.3*
Corrected^c,d,e	51.5±2.8	53.8±2.6	50.3±2.9	35.6±4.7*
Maternal Relative Feed Intake (g/kg/d)^e
Treatment (gd 6 to 20)	75.5±1.0	75.4±0.7	72.4±1.0	73.6±1.4
Maternal Relative Water Intake (g/kg/d)^e
Treatment (gd 6 to 20)	121.7±4.0	120.2±4.0	123.5±5.8	141.1±5.8*
Gravid Uterine Weight (g)	84.2±2.2	81.6±2.2	85.3±2.3	77.4±3.2
Maternal Liver Weight
Absolute (g)c	16.42±0.23	16.45±0.23	16. 19±0.33	15.21±0.40
Relative (% body weight)	4.28±0.04	4.30±0.05	4.23±0.07	4.27±0.08

^aIn the high dose, one animal was removed due to a dosing error (misdirected dose). Another high-dose animal was found dead on gd 17; necropsy revealed dark red, mottled lungs and pink discharge from the vagina, but no definite evidence of a misdirected dose. This animal exhibited piloerection as the only clinical sign during treatment.

^cP<0.05; test for linear trend, or Jonckheere’s Test.

^dWeight gain during gestation minus gravid uterine weight.

^eOne body weight in the low-dose group on gd 6 was invalid (n524 for gd 6 body weight and gd 6 to 20 weight gain). For feed and water intake n:17 to 23 due to removal of statistical outliers, spillage etc.

* P<0.05; pairwise comparison to controls, by Dunnett’s Test or Mann-Whitney U Test.

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 1,2,3,4 butane tetra carboxylic acid is considered to be 500 mg/Kg/day when Sprague Dawley rats were exposed to the test chemical repeatedly by gavage route for 14 days.

Executive summary:

Combined repeated dose repro-devp. study was performed to determine the oral toxic nature of 1,2,3,4 butane tetra carboxylic acid upon repeated exposure by oral route. Female Sprague Dawley rats were exposed to the test chemical from gd 6 to gd 19 at dose levels of 0, 250, 500 or 1000 mg/Kg/day. The doses for the main study were selected from preliminary acute toxicity and developmental study. The treated animals were observed for mortality, clinical signs, body weight changes, food and water intake, organ weight changes and gross pathology. Treatment related mortality occurred in 4% (1/24) in 1000 mg/Kg/day females. All remaining females survived the treatment. Treatment related clinical signs included weight loss which occurred in all groups and showed increasing frquency and/or severity with increasing dose on individual days during the treatment period. Piloerection was observed in ≤ 4 females/day at 1000 mg/Kg/day. Rooting in the cage bedding after dosing suggested an aversion to the sensory properties of the 500 and 1000 mg/Kg/day dose formulations (≤ 3 500 mg/Kg/day females/day, and ≤ 5 1000 mg/Kg/day females/ day). Alopecia was noted with a low incidence in all groups but showed no apparent relationship to BTCA exposure. Maternal body weight was comparable among groups on gd 0 and 6 (i.e. prior to the initiation of dosing). On gd 9, 12, 15, 18, and 19, maternal body weights at the low and mid doses were not affected (98.8 to 100.8% of concurrent controls), but maternal body weight at the high dose was significantly lower than the vehicle control on each of these days, except gd 9. On gd 20, maternal body weight at the high dose was significantly below the vehicle control. Decreases in maternal body weight became larger with repeated dosing, and the maximum reductions occurred at the end of the dosing period (gd 18, 19, and 20). Thus, the effect of BTCA on maternal body weight was restricted to the 1000 mg/Kg/day dose group and the magnitude of this effect was relatively small. Maternal relative feed intake was transiently reduced at 1000 mg/kg/day from gd 6 to 9 and at 500 mg/kg/day from gd 12 to 15, although no changes were noted for the treatment period as a whole. Maternal relative water intake was increased at 1000 mg/kg/day for gd 12 to 15, 18 to 19, 19 to 20, and the treatment period as a whole. Gravid uterine weight and maternal relative liver weight were not affected. Absolute maternal liver weight exhibited a decreasing trend but showed no significant differences between control. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for 1,2,3,4 butane tetra carboxylic acid is considered to be 500 mg/Kg/day when Sprague Dawley rats were exposed to the test chemical repeatedly by gavage route for 14 days.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is klimisch 2.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Quality of whole database:

waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Quality of whole database:

waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: Oral

Data available from the various sources was reviewed to determine the toxic nature of the given test chemical. The studies are as mentioned below:

 

Study 1:

Combined repeated dose repro-devp. study was performed to determine the oral toxic nature of 1,2,3,4 butane tetra carboxylic acid upon repeated exposure by oral route. Female Sprague Dawley rats were exposed to the test chemical from gd 6 to gd 19 at dose levels of 0, 250, 500 or 1000 mg/Kg/day. The doses for the main study were selected from preliminary acute toxicity and developmental study. The treated animals were observed for mortality, clinical signs, body weight changes, food and water intake, organ weight changes and gross pathology. Treatment related mortality occurred in 4% (1/24) in 1000 mg/Kg/day females. All remaining females survived the treatment. Treatment related clinical signs included weight loss which occurred in all groups and showed increasing frquency and/or severity with increasing dose on individual days during the treatment period. Piloerection was observed in ≤ 4 females/day at 1000 mg/Kg/day. Rooting in the cage bedding after dosing suggested an aversion to the sensory properties of the 500 and 1000 mg/Kg/day dose formulations (≤ 3 500 mg/Kg/day females/day, and ≤ 5 1000 mg/Kg/day females/ day). Alopecia was noted with a low incidence in all groups but showed no apparent relationship to BTCA exposure. Maternal body weight was comparable among groups on gd 0 and 6 (i.e. prior to the initiation of dosing). On gd 9, 12, 15, 18, and 19, maternal body weights at the low and mid doses were not affected (98.8 to 100.8% of concurrent controls), but maternal body weight at the high dose was significantly lower than the vehicle control on each of these days, except gd 9. On gd 20, maternal body weight at the high dose was significantly below the vehicle control. Decreases in maternal body weight became larger with repeated dosing, and the maximum reductions occurred at the end of the dosing period (gd 18, 19, and 20). Thus, the effect of BTCA on maternal body weight was restricted to the 1000 mg/Kg/day dose group and the magnitude of this effect was relatively small. Maternal relative feed intake was transiently reduced at 1000 mg/kg/day from gd 6 to 9 and at 500 mg/kg/day from gd 12 to 15, although no changes were noted for the treatment period as a whole. Maternal relative water intake was increased at 1000 mg/kg/day for gd 12 to 15, 18 to 19, 19 to 20, and the treatment period as a whole. Gravid uterine weight and maternal relative liver weight were not affected. Absolute maternal liver weight exhibited a decreasing trend but showed no significant differences between control. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for 1,2,3,4 butane tetra carboxylic acid is considered to be 500 mg/Kg/day when Sprague Dawley rats were exposed to the test chemical repeatedly by gavage route for 14 days.

 

Study 2:

Chronic toxicity study was performed to determine the toxic nature of test substance. The study was performed using male rats at dose levels of 3 or 5% for 2 years. The animals were dosed by the feed route of exposure. During the study period, the animals were observed for changes in body weight and food consumption and the major organs were subjected to histopathology. A slight decrease in growth and food consumption was observed in the top-dose group of 5%), but no tissue abnormalities were found on examination of the major organs. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for test substance is considered to be 3.0% (1200 mg/kg bw/day for males) in the 2 years toxicity study performed.

 

Repeated dose toxicity: Dermal

A short-term toxicity study does not need to be conducted because exposure of humans via dermal in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment.

 

Repeated dose toxicity: Inhalation

A short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment. 

Justification for classification or non-classification

Based on the data available, the given test chemical does not exhibit toxic nature upon repeated exposure by oral route of exposure. Hence, it is not likely to classify as toxic as per the criteria mentioned in CLP regulation. For repeated inhalation and repeated dermal toxicity wavier was added so, not possible to classify