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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 6 - August 26, 2010
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to guideline
Guideline:
other: OPPTS 870.3650: Combined repeated dose Toxicity study with the Reproduction/ developmental Toxicity screening Test
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Naphthenic acids, reaction products with diethylenetriamine
EC Number:
268-610-1
EC Name:
Naphthenic acids, reaction products with diethylenetriamine
Cas Number:
68131-13-5
Molecular formula:
C16H21N3O2 (minimal)
IUPAC Name:
Naphthenic acids, reaction products with diethylenetriamine
Details on test material:
product name: MK195KSF
Sample description: orange/brown hazy solid
Volatile: no
Density: 0.83
pH: 9.07
Storage conditions: at room temperature

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Young healthy male and nulliparous, non pregnant female rats [strain: Wistar Crl:WI] (Full-Barrier), were used in this study. The animals were derived from a controlled full barrier maintained breeding system (SPF) (Source: Charles River, 97633 Sulzfeld, Germany).
According to Art. 9.2, No. 7 of the German Act on Animal Welfare the animals were bred for experimental purposes.
At the beginning of the study, the age of the animals was 8-9 weeks.
The range of the body weight was:
Females: 154 to 183 g, (mean: 167.93 g, ± 20%= 33.59 g)
Males: 213 to 233 g, (mean: 222.30 g, ± 20%= 44.46 g)

The animals were randomly assigned (using Microsoft Excel template) to the dose/control groups, each animal was assigned a unique identification number and caged individually. The animals were acclimatised for at least five days before the first dose administration.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
Name: Corn oil
Batch No.: 11KBC6753
Storage conditions: at room temperature (RT),
Safety precautions: Routine hygienic procedures were sufficient to assure personnel health and safety
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
The test substance was administered daily during 14 days pre mating and 14 days mating in both male and in female, during gestation period and up to post natal day 3 in females. Males were dosed for 28-30 days.
Frequency of treatment:
daily; The animals were dosed with the test item on 7 days per week basis.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
750 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
80 animals (10 females and 10 males/group) were included in the study.
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Animals were examined for the daily clinical signs, mortality, weekly detailed clinical observations, pre treatment and at termination for functional observations. Body weight and food consumption was measured weekly except food consumption was not measured during the mating period (female) and mating/post mating period (male). Haematological and clinical biochemistry evaluations were performed on blood samples collected at terminal sacrifice from five males and five randomly selected females from each group. Urinalysis was performed on samples collected at terminal sacrifice from five randomly selected males from each group.
Sacrifice and pathology:
Males and females were sacrificed on treatment day 29-31, post natal day 4 respectively and subjected to necropsy. Non Pregnant females were sacrificed on their respective day 26 after the evidence of mating.

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
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LOAEL
Effect level:
<= 100 mg/kg bw/day (nominal)
Based on:
test mat.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Test item related clinical findings viz., piloerection, vocalization, pushing the bedding and salivation were recorded in most animals of treatment groups during the study. Occasionally findings like reduced spontaneous activity, weight loss, dyspnoea, diarrhoea, epistaxis, nasal discharge, dehydration, etc were also observed.

During the study twelve rats were found dead or sacrificed moribund. Out of these, 1 male from control, 1 male and 1 female from LD group and 3 males/ 6 females of HD group died. The death of animals were histopathologically termed possibly due to misgavaging except for three dead females (animal no.s 34, 35, 39) in HD group, whose death could not be determined due to advanced autolysis.

In males, the statistical analysis revealed significantly low body weight development during premating period in HD group and during first week of mating/post mating period in MD group, which further recovered with the progress of the study. But, overall the body weight development was significantly lower in MD and HD group. In females, significantly low body weight development were observed during second week of premating period in HD group and during GD 0-7 (HD group), GD 14-20 (MD group), GD 14-20 (HD group). There was also a consistent dose response pattern observed for all treatment groups when compared to the corresponding controls.

In males and females, statistical analysis reavelaed significantly low food consumption during premating period in HD group when compared to the corresponding controls. In females, significantly low food consumption was also recorded during GD 0-7 and 14-20 in MD and HD groups when compared to corresponding controls.

In males, the macroscopic findings observed were as follows, Control- small testes (1/10), small epididymides (1/10), discoloured axillary lymph node (1/10), discoloured thymus (1/10), small spleen (1/10), large and discoloured lung (1/10); LD- discoloure lung (1/10), enlarged mesenteric lymph node (1/10); MD- discoloured axillary lymph node (1/10), discoloured thymus (1/10), lung with small black spots (1/10); HD- small testes (2/10), small epididymides (1/10), small spleen (2/10), enlarged lung (2/10), discoloured lung (2/10), small Seminal vesicle+coagulating gland (2/10), discoloured liver (2/10), discoloured pancrea (1/10), gas filled stomach and intestine (2/10), small thymus (2/10), foamy nasal discharge (1/10).

In females, control- cyst on ovary (1/10); LD- cyst on ovary (1/10), discoloured intestine (1/10); MD- bloody lung (1/10); HD- bloody lung (2/7), gas filled stomach and intestine (3/7), small spleen (1/7), small liver (1/7), small thymus (1/7), dilated intestine (1/7), enlarged mesenteric lymph node (2/7), discoloured Kidney (2/7).

In males, statistically significant low mean values were observed for absolute weight of heart (MD and HD groups), thymus (HD group) and seminal vesicle + coagulating gland (HD group) when compared with the corresponding controls. But, the relative weight of liver indicated significantly high values for MD and HD groups compared to control. The relative organ weight was significantly deviated for spleen (HD group), testes (MD group), thymus (MD group), Seminal vesicles + coagulating gland (HD group).

In females, statistically significant low values were observed for absolute weight of heart (LD and HD groups) and uterus with cervix (HD group); significantly high value for spleen (MD group). The relative organ weight was significantly higher for liver (HD group), low for heart (LD and HD groups) and uterus with cervix (HD group).

At terminal sacrifice, histopathological changes considered to be directly test item-related and toxicologically relevant were seen in the small intestine (jejunum and ileum), mesenteric lymph node, spleen, lung and adrenal gland in LD or MD or HD group animals. The histopathological organ changes observed in the spleen, lung, liver, bone marrow and thymus were considered secondary to a general inflammatory state caused by test item effects in treated animals, or to stress.

No effects on reproductive organs were noted on terminal sacrifice animals, the minor changes observed histopathologically were not considered to be directly test item-related.

The results of the concentration measurements revealed recoveries between 85.3 % and 98.5% in HD group, between 86.4 % and 97.2 % in MD group and between 87.6 % and 95.5 % in LD group. Homogeneous distribution of the test substance in the preparation was approved.

Applicant's summary and conclusion

Conclusions:
Based on the data generated from this combined repeated dose toxicity and reproduction/ developmental toxicity screening test with MK 195KSF- Naphthenic acids, reaction products with diethylenetriamine, no NOAEL (No Observed Adverse Effect Level) could be established for general toxicity.