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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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

Read-across to 109-d OECD TG 416 study in rats, NOAEL: 50 mg/kg bw/d;

Read-across to 28-d OECD TG 407 equivalent study in rats, LOAEL: 125 mg/kg bw

Key value for chemical safety assessment

Toxic effect type:
concentration-driven

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
other: OECD 416 2-generation reproductive study
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Housing: wire mesh cages
- Diet: Ralson Purina commercial laboratory feed, ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65 - 79
- Humidity (%): 17 - 76
- Photoperiod (hrs dark / hrs light): 12

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
Daily
Frequency of treatment:
F0: Treatment was started 10 weeks before mating.
For males, dosing continued for 2 weeks after mating (total of 105 days). For females, dosing continued through lactation for a total of 127 treatment days.
Dose / conc.:
5 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
30
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: males - weekly, females - weekly before mating, days 0, 7, 14, and 20 of gestation, and days 0, 4, 14, and 21 of lactation

FOOD CONSUMPTION: weekly
Sacrifice and pathology:
SACRIFICE
- Male animals: All surviving animals 2 weeks after mating.
- Maternal animals: All surviving animals at weaning.

GROSS NECROPSY
- Gross necropsy consisted of examination for gross lesions.

HISTOPATHOLOGY / ORGAN WEIGHTS
pituitary glands, testes and epididymides, prostate and seminal vesicles, vagina, uterus, ovaries, and gross lesions.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Description (incidence):
No mortality attributed to treatment was observed.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights of high-dose-group (500 mg/kg bw/d) males were significantly and consistently reduced (12 = 0.01) in the F0 (since premating week); mean body weights of high-dose females were significantly decreased in the F0 generation since the 9th week of premating until the first week of lactation (p = 0.05); body weight reduction was significant on day 20 of gestation in both generations (p = 0.01)
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross postmortem findings.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No histopathological findings.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Key result
Critical effects observed:
not specified
Conclusions:
Under the conditions in this study the NOAEL was 50 mg/kg bw/day in both male and female rats.
Executive summary:

In this study in accordance with OECD TG 416 and in compliance with GLP the effects of repeated exposure to the test substance was examined. Groups of 30 female and 30 male rats were exposed to concentrations of 0, 5, 50 and 500 mg/kg day of test substance by oral gavage beginning ten weeks before mating. Animals were then mated. The resulting generation was also exposed to the test substance and mated. Exposure continued through the mating period, and in females through the gestation and lactational periods. Males were exposed for a total of 105 days, and females 127 days. All animals were sacrificed and necropsied after exposure. During the study, animals were observed for clinical signs, mortality, and body weight. The NOAEL was 50 mg/kg/day and the LOAEL was 500 mg/kg/day based on reduced weight gain in the high dose group.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
not specified
Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
Test material was given daily in the diet for 4 weeks.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
Daily
Dose / conc.:
2 500 mg/kg bw/day (nominal)
Remarks:
Dietary equivalent to 125 mg/kg bw/day.
Dose / conc.:
5 000 mg/kg bw/day (nominal)
Remarks:
Dietary equivalent to 250 mg/kg bw/day.
Dose / conc.:
7 500 mg/kg bw/day (nominal)
Remarks:
Dietary equivalent to 375 mg/kg bw/day
Dose / conc.:
20 000 mg/kg bw/day (nominal)
Remarks:
Dietary equivalent to 1000 mg/kg bw/day
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
body weight and food consumption
Sacrifice and pathology:
Histopathology was not done.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduction in body weight were observed at all exposure levels.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduction in food consumption were observed at all exposure levels.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross pathological changes were noted. Histopathology was not carried out.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
LOAEL
Effect level:
2 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Key result
Critical effects observed:
not specified
Conclusions:
In the current study the NOAEL was less than the lowest dose tested (2500 ppm, equivalent to 125 mg/kg bw/day).
Executive summary:

In this study in compliance with GLP and similar to OECD TG 407 the effects of dietary exposure of rats to the test substance were assessed. Groups of rats were given diets containing 0, 2500, 5000, 7500, or 20000 ppm test substance for 28 days. Animals were observed for food consumption and body weight changes. At the end of the study, the animals were sacrificed and examined for gross pathology. Reduced food consumption and body weight gain was noted at all dose levels. The NOAEL was < 2500 ppm in the diet. The LOAEL was 2500 ppm in the diet. No abnormalities were seen in the gross pathology examinations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP compliant OECD 416 and 407-like read across studies
Organ:
other: body weight

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Two experimental studies have been conducted that provide information on the repeated dose toxicity of the test substance. At very high daily dietary doses to the test substance in a 28 -day study, rats exhibited reduced food consumption and body weight gains beginning at the lowest dose of 2500 ppm. No other effects or abnormalities were observed. In rats exposed to daily oral gavage doses ranging from 5 to 500 mg/kg bw/day of the test substance through two generations (109 days, NOAEL = 50 mg/kg bw/d), no adverse effects were observed except for reductions in body weight gain at the highest dose. Therefore it is clear that the primary effect of the test substance at high daily doses is reduced body weight gain, probably as a function of the poor palatability of the test substance.

Justification for classification or non-classification

Based on the available information classification upon repeated exposure is not warranted according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008