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Diss Factsheets

Administrative data

Description of key information

One study was performed to determine the acute oral toxicity of N-[4-(2,4-dihydroxyphenyl)-1,3-thiazol-2-yl]-2-methylpropanamide.

There is no need to determine the acute toxicity via the dermal and the inhalation route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
07 Nov 2014 - 18 June 2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Remarks:
GLP-Guideline study similar to OECD 401: It was stated in the report that the study was conducted according to OECD 423. After review of the report, it has been noted that the study was performed similar to OECD 401. The acute oral toxicity study was conducted in China in order to meet Chinese Regulations for cosmetic ingredients. In accordance with Annex VII, 8.5.1, column 1 of the Regulation (EC) No. 1907/2006 (REACH), an acute oral toxicity study needs to be conducted. However, as the test substance is specifically developed for cosmetic purposes and is exclusively used in cosmetic products, Regulation (EC) No. 1223/2009 (Cosmetics Regulation) has to be considered which prohibits any performance of animal testing (Article 18). The European Commission, in cooperation with ECHA, has clarified the relationship between the testing and marketing bans and the REACH information requirements (ECHA factsheet, 2014). It is stated that testing for compliance with the REACH Regulation is considered to be falling outside the scope of the 2013 marketing ban of the Cosmetics Regulation. As the test substance will be employed in cosmetic products marketed in China, acute oral toxicity data are required according to Chinese Regulations for cosmetic ingredients. In order to meet the data requirements in China, an animal study was conducted similar to OECD 401 in an accredited Chinese laboratory. As the acute oral toxicity study is available and as there are currently no validated alternative methods replacing the use of animals in the field of acute toxicity, the acute oral toxicity study was considered in this REACH registration dossier. Reference: ECHA factsheet, 2014, Interface between REACH and Cosmetics regulations, ECHA-14-FS-04-EN
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no step-wise procedure of dosing
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Vital River Laboratory Animal Technology Co. Ltd. (Beijing, China)
- Age at study initiation: 7-9 weeks old
- Weight at study initiation: 221 to 241 g (males) and 186 to 218 g (females)
- Housing: Animals were housed in groups in polycarbonate cages (up to 3 animals/sex/cage)
- Diet: Certified Rodent Diet 5C02 (PMI Nutrition International LLC); ad libitum
- Water: reverse osmosis water; ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 40-70
- Air changes (per hr): ≥ 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14 Nov 2014 To: 28 Nov 2014
Route of administration:
oral: gavage
Vehicle:
other: PEG 300
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw

DOSE CONCENTRATION: 2.5, 25, 250 mg/mL
Doses:
50, 500 and 5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were checked twice daily for mortality, abnormalities and signs of pain or distress.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, food consumption, biochemical and hematological examinations
Statistics:
Levene’s test was done to test for equality of variances between groups.

Where Levene’s test is significant (p < 0.05), a rank transformation (to stabilize the variances) was applied before the analysis of variance (ANOVA) is conducted (note: Levene’s test was not be applied to the rank-transformed data).

Where Levene’s test is not significant (p > 0.05), ANOVA was conducted. One-way ANOVA was used (if applicable) to analyze the data types listed previously.

If the group effect of the ANOVA is significant (p < 0.05), Dunnett’s t-test was used for pairwise comparisons between each treated and control group. Group
comparisons (Groups 2 through 4 versus Group 1) was evaluated at the 5.0%, two-tailed probability level. If the ANOVA is not significant (p > 0.05), no further
analyses were conducted.

Due to system limitations, additional statistical analyses may be run but are not be reported or used to interpret study data.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
50 mg/kg bw: 0/5 males and 0/5 females died
500 mg/kg bw: 0/5 males died; 3/5 females died at Day 1 post-dose (Two of these females were found dead and one female was sacrificed for animal welfare reasons due to moribund status.)
5000 mg/kg bw: 0/5 males and 0/5 females died
Clinical signs:
other: On Day 1 of the dosing phase, abnormal clinical signs included mild hypoactivity (5/5 males and 4/5 females given 50 mg/kg bw), moderate hypoactivity (2/5 females given 50 mg/kg bw), and severe hypoactivity (5/5 males and 5/5 females given 500 or 5000 mg/
Gross pathology:
At necropsy, the three dead females from the 500 mg/kg bw group showed a clear or brown fluid in the gastrointestinal tract. No other abnormal findings were noted.
No macroscopic findings were present in scheduled sacrificed animals.
Other findings:
- Other observations:
Food consumption:
No obvious changes were noted in the food consumption throughout the study, except that slightly lower food intake (approximately 81.5% of the control group) in males given 5000 mg/kg bw was noted from Days 1 to 8 of the dosing phase. The food consumption in the treatment groups was comparable to the concurrent controls in other intervals or in animals given 50 or 500 mg/kg bw from Days 1 to 8.

Hematology:
Hematological changes on Day 3 of the dosing phase were few and consisted mainly of minimally decreased neutrophil counts in males given 5000 mg/kg bw. This finding was not present on Day 15 of the dosing phase.
Hematological changes on Day 1 (post dose) in moribund sacrificed females given 500 mg/kg bw consisted of the following:
- Markedly increased red cell mass (hemoconcentration) indicative of marked dehydration and most likely cause of moribundity
- Slightly decreased lymphocyte and eosinophil counts, indicative of stress

Clinical chemistry:
Clinical chemistry changes on Day 3 of the dosing phase consisted of the following:
- Minimally to moderately increased total and/or direct bilirubin in animals given 500 or 5000 mg/kg bw
- Minimally increased cholesterol levels in animals given 5000 mg/kg bw
These findings were resolved and not present on Day 15 of the dosing phase.
Clinical chemistry changes in moribund sacrificed females on Day 1 (post dose) consisted of the following:
- Moderately increased total protein concentration together with evidence of hemoconcentration (hematology) was indicative of dehydration
- Slightly increased blood urea nitrogen and creatinine concentration, indicative of renal injury and/or dehydration
- Moderately increased phosphorus concentrations, suggestive of renal injury
- Slightly increased calcium, most likely secondary to hyperalbuminemia (increased albumin concentration)
- Markedly increased sodium and chloride concentrations, possibly secondary to dehydration
- Markedly increased total and direct bilirubin concentrations indicative of altered biliary metabolism; and slightly increased cholesterol concentration, most likely secondary to altered biliary metabolism
It must be noted that the increase in bilirubin on Days 1 and 3 was in indirect/unconjugated bilirubin. This finding was reversible: on Day 15 no changes were measured.
Other clinical chemistry changes present in moribund sacrificed females were consistent with those seen in moribund animals and consisted of slightly increased creatine kinase activity and potassium concentration, suggestive of muscle injury (probably secondary to the poor clinical condition of the animals); and decreased triglycerides, most likely secondary to reduced food consumption.
Interpretation of results:
GHS criteria not met
Conclusions:
Interpretation of results:
In the acute oral toxicity study, W630 dissolved in PEG 300 was administered via gavage to 5 rats/sex/dose at the following dose levels: 50, 500 and 5000 mg/kg bw. A vehicle control group receiving PEG 300 was included. All animals were observed for 14 days post dosing.
No rats died in the low (50 mg/kg bw) and high (5000 mg/kg bw) dose group. Moreover, no mortality was noted in the vehicle control group.
In the mid dose group (500 mg/kg bw), 3 of 5 female rats died on Day 1 of the study period. Two of these animals were found dead and one animal was sacrificed for animal welfare reasons due to moribund status on Day 1. All male rats survived until study termination. Thus in total, 3 of 10 animals died in the mid dose group.
The decedent animals (3/3) displayed abnormal clinical signs after dosing of 500 mg/kg bw: severe hypoactivity and sternal recumbent. In addition, myoclonic jerking of all legs, cold to touch and decreased reactivity to stimulus were observed for the animal found moribund. The clinical signs observed for all surviving animals included in particular mild to severe hypoactivity on Day 1. No abnormal clinical signs were noted on Day 2 for all surviors.
At necropsy, a clear or brown fluid was noted in the gastrointestinal tract of three decedent animals. But no other abnormal macroscopic findings were reported in any of these animals. Also hematological and biochemistry examinations did not determine the underlying cause of death of the three animals in the mid dose group. All surviving animals were necropsied at the end of the study period. The pathological examination of the scheduled sacrificed animals did not reveal any abnormalities.
Having regard to the outcome of the acute oral toxicity study, no cause of death of the three animals in the mid dose group could be determined. Furthermore, the deaths were not dose-related. Thus, there is no indication that the mortality (3/10 animals) in the mid dose group is caused by the test substance.
Moreover, in a long-term toxicity study (Harlan study number D58371), W630 was administered via gavage to male and female rats at doses of 50, 200 and 800 mg/kg bw/day for 90 days. During the treatment period, there were no substance-related deaths at any dose level. The three animals found dead or moribund during the study period were considered likely to be the result of a dosing error. One male treated with 200 mg/kg bw/day was found dead on Day 38 of treatment. At 800 mg/kg bw/day, one male was found dead on Day 2 of treatment and a second male was sacrificed for ethical reasons due to marked loss of body weight on Day 29 of treatment. At necropsy, there were no treatment-related macroscopic or microscopic findings.
Taking into account that no substance-related mortality was noted at 800 mg/kg bw/day in the 90-day oral toxicity study and no deaths occurred at 5000 mg/kg bw in the acute oral toxicity study, the three decedent rats in the mid dose group (500 mg/kg bw) of the acute oral toxicity study can be considered as incidental. Thus, the oral LD50 value for W630 is considered to be greater than 5000 mg/kg bw.
Executive summary:

The purpose of this study was to evaluate the toxicity of the test article, W630, when

administered once via oral gavage to Sprague Dawley rats following 14-day

observation period to assess the reversibility, persistence, or delayed occurrence of

any effects after observation period.

Male and female Sprague Dawley rats were assigned to four groups, and doses were

administered as indicated in the following table. Animals were dosed via oral gavage

once on Day 1 at a volume of 20 mL/kg.

All study animals survived to the scheduled necropsy, except that three females given

500 mg/kg (Animal Nos. B30026, B30027, and B30029) were early sacrificed under

moribund condition or found dead on Day 1 of the dosing phase.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The LD50 (oral) might be > 5000 mg/kg due to the lack of early death in the high dose group.

Therefore the substance needs not to be classified as toxic.