Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

NOAEL 30 days (male/female): 250 mg/kg bw day (nominal), 214 mg/kg bw day based on active ingredient.

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:
short-term repeated dose toxicity: oral
Type of information:
other: read across from supporting substance
Adequacy of study:
key study
Study period:
From September 23,1985 to October 23,1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP compliant with international guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hoechst A.G
- Age at study initiation: 6 weeks
- Housing: in fully air-conditioned rooms in Makrolon cages (type 4) on softwood granules (lignocellulose) into groups of 5 animals
- Diet: Altromin 1323, ad libitum, no food consumption between 9.30 to 12 (administered test item dose by gavage)
- Water: tap water in plastic water bottles ad libitum, no drink consumption between 9.30 to 12 (administered test item dose by gavage)
- Acclimation period: 5 days
- Health check: The behavior and general health of all animals used during the experiment was 2 x daily, checked on weekends and holidays, 1 x daily. Every week the rats to neurological disorders, clouding of the eye media, adverse effects on oral mucosa and disorders of tooth development were examined.

ENVIRONMENTAL CONDITIONS
- Temperature:22 ± 3° C
- Humidity: 50 ± 20 %
- Air changes (per hr):romm fully air conditioned
- Photoperiod: 12 hours cycle dark/light

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

dose mg/kg bw day concentration %(w/v) appl. Volume ml/kg vehicle
0 0 5 water
62.5 1.25 5 water daily
250 5 5 water daily
1000 20 5 water daily
Duration of treatment / exposure:
30 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 62.5 , 250, 1000 mg/kg bw day
Basis:
actual ingested
No. of animals per sex per dose:
5 animals x sex x 4 doses
Control animals:
yes
Observations and examinations performed and frequency:
The behavior and general health of all animals used during the experiment was checked twice a day, on weekends and holidays, once a day. Every week the rats were examined for neurological disorders, clouding of the eye, adverse effects on oral mucosa and disorders on teeth development .

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

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: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes

CLINICAL CHEMISTRY: Yes
sodium
potassium
inorg. phosphorus
uric acid
total bilirubin
creatinine
Glucose in serum
Urea-N (BUN)
calcium
chloride
ASAT (G0T)
ALT (GPT)
alkaline phosphatase (AP)
y-glutamyl
Total protein
Electrophoresis

URINALYSIS: Yes
The urine production was carried out overnight on 29-30. The experiment (16 hours) to non-fed animals and not soaked in metabolic cages (single urine). The urine analyzes were performed on all males and females performed and extended to the following parameters:
Parameters. method
appearance
color
pH hemoglobin
protein
glucose
ketone bodies
bilirubin
urobilinogen
density
sediment

NEUROBEHAVIOURAL EXAMINATION: Yes

HAEMATOLOGY: Yes
The following haematological parameters were determined:
parameter method
hemoglobin
Erythrocyte count
Leucozytenzahl
hematocrit
reticulocyte*
Differential blood count
Platelet count

* Was performed only on the control group and the 1000 ppm group Furthermore, the calculated values ​​for MCV, MCH and MCHC were determined.

Sacrifice and pathology:
Sacrifice:
After the retro-orbital blood sampling for hematological tests, the animals were killed in nembutal narcosis (injection of approximately 50 mg / kg ip) by transection of the vena cava cranialis and exsanguination.

GROSS PATHOLOGY: Yes
After killing and bleeding, the animals were dissected in accordance with Section I Procedure (Prof. K / G of 02.04.1982). Sections have been taken from skin, body orifices, eyes, teeth, oral mucosa and the inner.
Organs were assessed macroscopically. Abnormal findings were recorded.

HISTOPATHOLOGY: Yes
In accordance with Section I Procedure (Prof. K / G of 04.02.1982), from the animals of the main groups 1 - 4 fragments of the following organs were fixed and delivered for histological examination:
heart
lung
liver
kidneys
spleen
stomach
jejunum
Colon
bladder
testicle
epididymis
prostate
seminal vesicle
ovaries
uterus
thyroid
pancreas
adrenal
thymus
pituitary
brain
Eye with N. optic
Bone marrow (femur)
Statistics:
The following measurements were evaluated statistically at a significance level of p = 0.05:
Body weights on the individual time points
Body weight during the first interval
1- 15 experiment
15 - 29 experiment
29 - 31 experiment
Hematological parameters (except for differential blood count)
Clinical-chemical parameters
Absolute and relative organ weights
Urine analysis (pH and specific gravity)
The evaluation was carried out with the aid of a program package for evaluating toxicological tests, according to the Standard Operating Procedure
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
at 1000 mg/kg bw day
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
red urines
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
The behavior and general health of the animals in Groups 1, 2 and 3 (0, 62.5 and 250 mg / kg bw. / Day) were not mentioned during the study period. Only a male of 62.5 mg / kg bw. / Day group was injured in the nek. For this reason, the animal was kept individually.
Two females and one male of the 1000 mg / kg bw. / Day group showed the following symptoms: ruffled fur, crouching position, long-legged speed, tumbling and passivity. One of the two females died on 29° day of test, may be by cannibalism.
Neurological disorders, eye opacity, disorders of tooth development and oral lesions, which could be attributed to the administration of the test substance were noted in any dose group.

BODY WEIGHT AND WEIGHT GAIN
The statistical analysis of body weight gain in males was observed that in the highest dose group (1000 mg / kg bw. / Day) was a statistically significant delay of body weight. All other treated groups showed no statistically significant differences compared to control.

WATER CONSUMPTION
The relative water consumption was after administration of 1000 mg / kg bw. / Day significantly increased.
In the other dose groups, the relative water consumption by Council abreichung the test substance was unaffected.

HAEMATOLOGY
All parameters are normal.

CLINICAL CHEMISTRY
All tested parameters showed no significant deviations from the normal, except inorganic phosphorous (both male and female), sodium (female), chloride (female), bilirubin (female), urea (female), Alanine transaminase (female).
These deviations are still all within the normal range of biological rat strain used.
The differences are therefore particularly suitable for the animals in groups 2 and 3 (62.5 and 250 mg / kg bw); therefore it is not of toxicological relevance.
The serum electrophoresis showed no evidence of compound-related changes.
The only result is a decrease in the α-globulins in the animals of the 1000 mg / kg bw. Group.

URINALYSIS
Changes in the urinalysis were not observed. The sediments content were normal. It was only a statistically significant increase in specific gravity in females of the 250 mg / kg bw. Group. The urine samples of 250 and 1000 mg / kg bw. Group were found in red colour.

ORGAN WEIGHTS
In the 62.5 ppm group, there were no statistically significant changes in absolute and relative organ weights.
In the 250 mg/kg bw. Group, the absolute kidney weights of males were increased, but not statistically significant. This differences are very minimal and there isn't a dose-dependence of histologically detectable changes, then no toxicological significance can be derived.

MACRO AND MICROSCOPICAL ANALYSIS
The macroscopic studies in animals showed the highest dose (1000 mg / kg bw. / Day) a pink discoloration of the gastro-intestinal tract. The sex organs of male animals (seminal vesicle, testis) of 1000 mg / kg bw. Group were partially reduced.
Microscopically resulted in male and female rats, no compound-related organ damage morphologically tangible.
Dose descriptor:
NOEL
Effect level:
ca. 250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight; food consumption; food efficiency; water consumption ; ophthalmoscopic examination; haematology; clinical chemistry; urinalysis; gross pathology; organ weights; histopathology
Dose descriptor:
NOEL
Effect level:
ca. 214.5 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight; food consumption; food efficiency; water consumption ; ophthalmoscopic examination; haematology; clinical chemistry; urinalysis; gross pathology; organ weights; histopathology
Critical effects observed:
no

Neurological disorders, eye opacity, disorders of tooth development and oral lesions, which could be attributed to the administration of the test substance were noted in any dose group.

The behavior and general health of the animals of 62.5 mg / kg and 250 mg were / kg bw / Day group during the study period without special features. Only a male of 62.5 mg / kg bw. / Day group was from 15 Experiment to test the end of an injury in the neck.

Two female and one male of the 1000 mg / kg bw. / Day group hava had , from day 22 of experiment to the end, the following symptoms: ruffled fur, crouching position, long-legged speed, tumbling and passivity.

One of the two females died on day 29 of the experiment.

The statistical analysis of body weight gain in males was the highest dose group (1000 mg / kg bw. / Day) from 15 The experiment, a statistically significant retardation of body weight. All other treated

deltas groups showed no statistically significant differences compared to control.

The relative water consumption was after administration of 1000 mg / kg bw. / Day significantly increased.

In the other dose groups, the relative water consumption was unaffected by the administration of the test substance.

The haematological and clinical chemistry tests did not reveal any clues about toxicological changes.

The urinalysis was normal and also showed 'no evidence of toxic damage to the animals. It was only in the 250 and 1000 mg / kg bw. Group in both sexes to a reddish to red discoloration of urine.

Conclusions:
In a 30-day test by daily gavage administration, the similar substance 1 showed significative adverse effects at the dose of 1000 mg / kg body weight on rat. These symptoms are presented in the form of impairment of body weight and development of drinking water consumption. Two female and one male showed the following symptoms: ruffled fur, crouching position, long-legged speed, tumbling and passivity. A female died on 29° day of the experiment. The hematology, clinical chemistry, and macroscopic and histological studies revealed no evidence of specific toxicity. A NOEL of 250 mg/kg bw was determined.
Executive summary:

The test substance was administered orally by gavage (total 30 applications, 7 x per week) in a 30-day study on SPF-Wistar rats at doses of 0 / 62.5 / 250/ 1000 mg / kg body weight per day. In all experimental groups the daily behaviorwas assessed and the general state of health tested. The body weight gain and food consumption were assessed twice a week, the water consumption determined weekly.

Hematological, clinical chemistry and urinalysis tests were performed on the study. At necropsy, the animals were examined macroscopically for gross pathology, the major organs weighed and calculated the relative organ weights. of a large number of tissues of these animals were made​ ​histological preparations and examined. The body weights, haematological and clinical chemistry parameters and urinalysis (specific gravity, pH) and the absolute and the relative weights were statistically tested and the differences are compared to the control groups.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
214.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP compliance with international guideline

Additional information

Three studies are available to assess with read across the repeated dose toxicity by oral route. All parameter examined: clinical sings, mortality, body weight and body weight gain, water consumption, haematology, clinical chemistry, uranalysis, organ weight, micro and macro analysis; shows a very low toxicity effect. All studies indicate a NOAEL that is greather than 200 mg/kg bw day.

All studies are in agreement and all results are in the same range, all test results shows a NOAEL above 200 mg/kg bw day. Based on Regulation 1272 -2008 Table 3.9.3 (repeated dose) no classification is necessary

In a 30-day test by daily gavage administration of similar substance 1 resulted, in a dose of 1000 mg / kg body weight of rats, intoxicated. These symptoms are presented in the form of impairment of body weight and development of drinking water consumption. Two female and one male showed the following symptoms: ruffled fur, crouching position, long-legged speed, tumbling and passivity. A female died on 29° day of the experiment. The hematology, clinical chemistry, and macroscopic and histological studies revealed no evidence of specific toxicity.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Two studies has been performed on similar substances. The main study is  a read across with Similar Substance 1. It is a good study , GLP compliant and conducted according to OECD guideline. The supporting study is a read across  with Similar substance 3 conducted with no international guideline and not in GLP. Both studies are in agreement with the conclusions.

Justification for classification or non-classification

Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within 100 mg/kg bw day. Based on Regulation 1272 -2008 Table 3.9.3 (repeated dose) no classification is required.