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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
other: the tested substance is the acid of the compound
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-documented study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Code number in testing facility: K-2698- Lot No.: 080108C105- Receipt date: January 14, 2008- Amount of Receipt: 3 kg- Appearance : brown liquid- Purity : 99.5 MIN %- Storage Conditions : Room temperature [archive No.: KIT-401(80)]- Expired date : January 8, 2010

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
1) Test animals- Supplier: Orient Bio Co. Ltd. 143-1, Sangdaewon-dong, Jungwon-ku, Sungnam, Gyunggi-do, 462-120 Korea- Age at study initiation: 7-week-old animals for male and female- No. of animals at receipt: 57 for male and female- Body weights at study initiation: 212.5 – 243.8 g for males and 147.6 -168.6 g for females- Age at the first day of treatment: 8 weeks for male and female- Body weight range at the first day of treatment: 274.2∼311.1 g for males and 175.7∼213.4 g for females- All animals were visually examined on acquisition. Only the animals remained in good physical condition during the 6-day acclimatization in the animal room were selected for the test.
2) Environmental condition- Temperature 23 +/- 3 deg C, relative humidity of 50 +/- 10%; ventilation of 10 to 20 times/hours; light/dark cycle 12 h/12 h- All animals used in this study were cared for in accordance with the principles outlined in the "Guide for the Care and Use of Laboratory Animals", a NIH publication.
3) Monitoring- Room temperature was generally in the range 20 ~ 26 deg C, relative humidity was generally in the range 40 ~ 60%. No significant deviations, which can affect the experiment, were observed.
4) Housing and identification of animals- Equal or less than five for the quarantine and acclimatization- Equal or less than two for the pre-mating, treatment and recovery period5) Diet, water and bedding material- Pelleted maintenance diet and tap water ad libitum; no contaminants (analysed)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: distilled water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test article of the highest dose group was mixed with water for injection, and the low dose group's test article was prepared by dilution of that of the highest dose group. The test article solutions were prepared once a day before completion of the analytical method validation, and after completion the test article was formulated over once a week.
Duration of treatment / exposure:
From 2 weeks before mating to the end of the mating period for male (at least 28 days)From 2 weeks before mating to day 4 of lactation including the mating and gestation periods for female- Post exposure period: 15 days in both sexes
Frequency of treatment:
Once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 200, and 400 mg/kg bw/day (Dosing volume 10ml/kg/day)
Basis:
nominal in diet
No. of animals per sex per dose:
10 males and females for 100 and 200 mg/kg bw/day and 16 males and females for 400 mg/kg bw/day (10 was for test group and 6 was for recovery group), 16 males and females for vehicle control (10 was for test group and 6 was for recovery group)
Control animals:
yes
Details on study design:
- Dose levels determined in a pilot toxicity study of dodecylbenzenesulfonic acid in rats- Constant dosage volume of 10 mL/kg bw/day: calculated with Path/Tox system according to the basis of recently measured body weight.- Dosing of both sexes was begun at 2 weeks prior to mating. Dosing was continued in both sexes during the mating period. Males were dosed after the mating period at least until the minimum total dosing period of 28 days had been completed. Daily dosing of the parental females was continued throughout pregnancy and at least up to day 4 post-partum

Examinations

Statistics:
- Body weights, food consumption, organ weights, and clinical pathology : means the standard deviation of each mean. - Bartlett's test : analyzing for homogeneity of variance- Dunnett's t test : analyzing for the significance of inter-group differences- Analysis of Variance : analyzing for homogeneous data- Kruskal-Wallis test : analyzing for Heterogeneous data- Dunn's Rank Sum test : analyzing for the significance of inter-group differences between the control and treated groups- F test : analyzing the data of recovery groups for homogeneity of variance- Dunnett's t test : analyzing for homogeneous data- Dunn's Rank Sum test : analyzing for the significance of inter-group differences- t test : analyzing for Heterogeneous data- Kruskal-Wallis test : analyzing for the significance of inter-group differences between the control and treated group-Statistical analyses were performed by comparing the different dose groups with the vehicle control group using Path/Tox System. - p<0.05 or p<0.01

Results and discussion

Results of examinations

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
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
-Clinical signs: Treatment-related clinical signs such as salivation and soft feces were observed in all males of the 400 mg/kg bw/day group during the premating and mating periods. Soiled perineal and liquid feces were observed in 2 males of 400 mg/kg bw/day group during the premating. Salivation and soft feces were observed in 9 and 8 females during the premating and in 8 and 5 during the mating period in the 400 mg/kg bw/day group, respectively. Thin appearance, salivation, staining around mouth, soiled perineal region and soft feces were observed in 1, 10, 1, 1 and 4 females during the gestation period in the 400 mg/kg group, respectively. Thin appearance and salivation were observed in 1 and 10 animals in the 400 mg/kg bw/day group during the lactation period, respectively.

- Body weights and food consumption: In males, a statistically significant decrease was observed on days 8 and 14 of premating. In females, there was no statistically significant changes except a decrease on day 20 of gestation at 400 mg/kg bw/day. In males, a statistically significant decrease in food consumption was observed in the 400 mg/kg bw/day group on days 2 and 9 of the premating, and in females it was observed on day 2 of premating and day 8 of gestation.

- Neurobehavioral evaluation: No treatment-related changes were observed in any of the treatment group.- Urinalysis for males: There were no treatment-related changes for males.

- Hematological test : In hematology test, activated partial thromboplastin time (APTT) was statistically significantly decreased in male of the 400 mg/kg bw/day group. No treatment-related changes were observed in females. In recovery group, a statically significant decrease in RBC count (RBC) was observed in males of the 400 mg/kg bw/day group and an increase in mean corpuscular hemoglobin (MCH) was observed in females.

- Biochemical test: In serum biochemistry test, a statistically significant increase in A/G ratio andalanine aminotransferase (ALT) was observed in males of the 400 mg/kg bw/day group. In females, a statistically significant decrease in blood urine nitrogen (BUN) observed in all treatment groups and an decrease in albumin (ALB) was also observed in the 400 mg/kg bw/day group. In recovery group, a statistically significant decrease in ALT and increase in ALP were observed in females of the 400 mg/kg bw/day group.

- Gross findings: There were no treatment-related changes for all animals

- Organ weights: In males, no a statistically significant changes were observed in any of the treatment groups. In females, a statistically significant increase in absolute weight of ovaries was observed in the 200 mg/kg bw/day group, and a decrease in absolute weight of salivary gland and heart was observed in the 400 mg/kg bw/day groups. The mean weight of ovaries for main group was 0.108 g in compared with vehicle control of 0.093 g and the mean weight of salivary glands for main group was 0.462 g in compared with vehicle control of 0.532 g. Also, the mean weight of heart for main group was 0.816 g in compared with vehicle control of 0.955 g. In recovery groups, a significant decrease in liver and kidney was observed in males the 400 mg/kg bw/day group. No significant differences were observed between vehicle control and test group for organ weights in females.

- Histopathological findings: Squamous cell hyperplasia in stomach was observed in males and females at 200 and 400 mg/kg bw/day. Two cases of minimal forestomach erosion/ulcer were also observed in males at 400 mg/kg bw/day.

Effect levels

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Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects to the GI tract
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects to the GI-tract

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral administration of the test substance to rats resulted in soft feces, and squamous cell hyperplasia of stomach in both sexes at 400mg/kg bw/day, and liquid feces and soled perineal region, a decrease in body weight and food consumption in males at 400 mg/kg bw/day. In hematology examination, squamous cell hyperplasia of stomach was observed in both sexes at 200 mg/kg bw/day and forestomach erosion/ulcer was observed in males at 400mg/kg bw/day. Based on these effects the NOAEL value was 100 mg/kg bw/day for male and female rats and the LOAEL value was 200 mg/kg bw/day for male and female rats. From these results, the target organ for oral dosing of dodecylbenzenesulfonic acid was considered to be the stomach.
Executive summary:

Repeated oral dosing of the test substance resulted in soft feces, and squamous cell hyperplasia of stomach in both sexes, and liquid feces and soled perineal region, a decrease in body weight and food consumption, forestomach erosion/ulcer in males at 400 mg/kgbw/day, and squamous cell hyperplasia of stomach in both sexes at 200 mg/kgbw/day.Also,activated partial thromboplastin time (APTT) was statistically significantly decreased in male of the 400 mg/kg bw/day group. Inserum biochemistry test, a statistically significant increase in A/G ratio and alanine aminotransferase (ALT) was observed in males of the 400 mg/kg bw/day group.As a result of organ weight test, no a statistically significant changes were observed in any of the treatment groups in males. A statistically significant increase in absolute weight of ovaries was observed in the 200 mg/kg bw/day group, and a decrease in absolute weight of salivary gland and heart was observed in the 400 mg/kg bw/day groups.

Based on results, all findings were completely or partially reversed during the15daysrecovery period. The target organ for oral dosing of the test substance was considered as stomach. The NOAEL and the LOAEL for repeated toxicity of the test substance was considered to be 100 mg/kg bw/day and 200 mg/kg bw/day in both sexes, respectively.