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Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral, other
Remarks:
7-week DRF repeat-dose toxicity study ; conducted as a range-finder prior to a chronic Carcinogencity study
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
Sub-chronic range finding assay conducted in rats and mice:
Documented method was conducted in the rat and mouse via diet for 7-weeks (49 days) treatment with 1 week observation period and one rat and two mouse negative control groups (untreated)
Deviations:
yes
Remarks:
See "version / remarks"
Principles of method if other than guideline:
- Principle of test: Sub-chronic range finding assay conducted in rats and mice: Documented method was conducted in the rat and mouse via diet for 7-weeks (49 days) treatment with 1 week observation period and one rat and two mouse negative control groups (untreated)
- Short description of test conditions: To establish the concentrations of the test item for administration to dosed animals in the chronic/carcinogenicity studies, Subchronic toxicity tests were- conducted with both rats and mice. Rats were distributed among ten groups, each consisting of five males and five females. Mice were distributed among ten groups, each consisting of five males and five females. The test item was administered for 7-weeks through basal laboratory diet supplied ad libitum at doses up to 10,000 ppm in rats and 14,700 ppm in mice. With one rat negative control and one mice negative control. Observation continued for one week post administration.
- Parameters analysed / observed: Mortality, clinical signs, bodyweights, necropsy
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
Common rodent species historically used in carcinogenicity assays; note that mice of strain: B6C3F1 (male/female) were additionally dosed in parallel
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: two animal species, Fischer 344 rats and B6C3F1 mice, used – sourced from Recognised Supplier.
- Females (if applicable) nulliparous and non-pregnant: Yes.
- Age at study initiation: ca. 4 weeks old (rats) ; ca. 4 weeks old mice.
- Weight at study initiation:
- Fasting period before study:
- Housing: Group housing four or five by sex, polycarbonate cages and stainless steel mesh. Filter paper was changed every 2 weeks. Clean cages and bedding with hardwood chip bedding renewed twice weekly.
- Diet (e.g. ad libitum): ad libitum, (test item treated/untreated, as applicable) Lab-Blox basal diet
- Water (e.g. ad libitum): ad libitum. Acidulated water..
- Acclimation period: 2 weeks

DETAILS OF FOOD AND WATER QUALITY: Information provided in the full study report.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 26 °C
- Humidity (%): 45 - 55
- Air changes (per hr): Filtered, 12 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 16 hours dark / 8 hours light
Route of administration:
oral: feed
Details on route of administration:
test item was incorporated into the basal laboratory diet and supplied ad libitum
Vehicle:
not specified
Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): The mixture was prepared once weekly.
- Mixing appropriate amounts with (Type of food): The basal laboratory diet for both dosed and control animals consisted of Wayne Lab-Blox meal. Test item was administered to the dosed animals as a component of the diet. The test item was removed from its container and a proper amount was blended with an aliquot of the feed using a mortar and pestle. Once visual homogeneity was attained, the mixture was placed in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in double plastic bags and stored in the dark at 4°C. The mixture was prepared once weekly.
- Storage temperature of food: stored in the dark at 4°C

- Other: Dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed.
Duration of treatment / exposure:
7 weeks (49 days)
Frequency of treatment:
Daily feed
Dose / conc.:
0 ppm
Remarks:
Rat untreated - (control)
Dose / conc.:
680 ppm
Remarks:
Rat group 1 - treated
Dose / conc.:
1 000 ppm
Remarks:
Rat group 2 - treated
Dose / conc.:
1 470 ppm
Remarks:
Rat group 3 - treated
Dose / conc.:
2 160 ppm
Remarks:
Rat group 4 - treated
Dose / conc.:
3 150 ppm
Remarks:
Rat group 5 - treated
Dose / conc.:
4 600 ppm
Remarks:
Rat group 6 - treated
Dose / conc.:
6 800 ppm
Remarks:
Rat group 7 - treated
Dose / conc.:
10 000 ppm
Remarks:
Rat group 8 - treated
Dose / conc.:
0 ppm
Remarks:
Mouse untreated - (control)
Dose / conc.:
680 ppm
Remarks:
Mouse group 1 - treated
Dose / conc.:
1 000 ppm
Remarks:
Mouse group 2 - treated
Dose / conc.:
1 470 ppm
Remarks:
Mouse group 3 - treated
Dose / conc.:
3 150 ppm
Remarks:
Mouse group 4 - treated
Dose / conc.:
4 600 ppm
Remarks:
Mouse group 5 - treated
Dose / conc.:
6 800 ppm
Remarks:
Mouse group 6 - treated
Dose / conc.:
10 000 ppm
Remarks:
Mouse group 7 - treated
Dose / conc.:
14 700 ppm
Remarks:
Mouse group 8 - treated
No. of animals per sex per dose:
5 males / 5 females
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Study was a DRF for a chronic carcinogenicity study.
- Rationale for animal assignment (if not random): Random.
- Rationale for selecting satellite groups: Not applicable.
- Post-exposure recovery period in satellite groups: Not applicable.
- Section schedule rationale (if not random): Not applicable.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Rats: 4600 ppm only, convulsions were reported in this female group only. No effects were reported in males at 4600 ppm or in higher 6800 ppm or 10000 ppm dose level.

No other clinical abnormalities which could be attributed, to administration of the compound were observed.
See table 1.0 and table 2.0 in 'any other information on results incl. tables'
Mortality:
mortality observed, treatment-related
Description (incidence):
10000 ppm: Females 5/5 mortality ; Males 4/5 mortality
6800 ppm: Females 4/5 mortality ; Males 3/5 mortality
4600 ppm: Femles - no mortality ; Males - no mortality
No mortalities were observed in rats at les than 6800 ppm

Mice: no mortality less than 10000ppm (2/5 females only).

See table 1.0 and table 2.0 in 'any other information on results incl. tables'
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean bodweight gain, decreases relative to controls were observed at all dose levels.
See table 1.0 and table 2.0 in 'any other information on results incl. tables'
Food consumption and compound intake (if feeding study):
not examined
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 macroscopic effects post-necropsy were reported in the study report. (Necropsy was conducted)
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
Rats: 4600 ppm only, convulsions were reported in this female group only. No effects were reported in males at 4600 ppm or in higher 6800 ppm or 10000 ppm dose level.

See table 1.0 and table 2.0 in 'any other information on results incl. tables'
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Dose descriptor:
LOAEL
Effect level:
>= 680 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: LOAEL in rats and mice (male/female)
Critical effects observed:
no

Table 1.0 – Rat, 7 week DRF results:

Dose / ppm

Weight gain % *

Survival **

Convulsions **

 

Females

Male

Females

Males

Females

Males

10000

--

-137

0/5

1/5

0/5

0/5

6800

-66

-114

1/5

3/5

0/5

0/5

4600

-43

-99

5/5

5/5

5/5 **

0/5

3150

-27

-59

5/5

5/5

0/5

0/5

2160

-18

-19

5/5

5/5

0/5

0/5

1470

-17

-6

5/5

5/5

0/5

0/5

1000

-13

-18

5/5

5/5

0/5

0/5

680

-2

-26

5/5

5/5

0/5

0/5

0 (control)

N/A

N/A

5/5

5/5

0/5

0/5

 

 

 

 

 

 

 

Where:

* indicative of mean body weight gain less than that of controls.

** number of observed/number originally in group.

 

Table 2.0 – Mice, 7 week DRF results:

Dose / ppm

Weight gain % *

Survival **

 

Females

Male

Females

Males

14700

--

-34

0/5

 

10000

-12

-22

3/5

5/5

6800

-5

-5

5/5

5/5

4600

-7

-9

5/5

5/5

3150

-4

+1

5/5

5/5

1470

-12

-9

5/5

5/5

1000

-6

+2

5/5

5/5

680

-1

-4

5/5

5/5

0 (control)

N/A

N/A

5/5

5/5

 

 

 

 

 

Where:

* indicative of mean body weight gain less than that of controls.

** number of observed/number originally in group.

Conclusions:
Under the conditions of this study, the lowest-observed-adverse-effect level (LOAEL) for males and females is considered to be 680 ppm following 7 weeks test item administration.
Executive summary:

The study was performed as a 7 week dietary range finding sub-chronic study using methods equivalent or similar to the requirements of OECD Guideline 407, to evaluate the potential toxicity of the test item prior to a definitive 2 year carcinogenicity study. Sub-chronic toxicity tests were- conducted with both rats and mice. Fisher 344 male/female rats were distributed among ten groups, each consisting of five males and five females. B6C3F1 strain male/female mice were distributed among ten groups, each consisting of five males and five females. The test item was administered for 7-weeks through basal laboratory diet supplied ad libitum at doses up to 10,000 ppm in rats and 14,700 ppm in mice. With respective negative controls. Observation continued for one week post administration. Rats and mice were necropsied post termination. The basal laboratory diet for both dosed and control animals consisted of Wayne Lab-Blox meal. Test item was administered to the dosed animals as a component of the diet. The test item was removed from its container and a proper amount was blended with an aliquot of the feed using a mortar and pestle. Once visual homogeneity was attained, the mixture was placed in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in double plastic bags and stored in the dark at 4°C. The mixture was prepared once weekly. The report indicated that dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed. Under the conditions of the study, the lowest-observed-adverse-effect level (LOAEL) for males and females is considered to be 680 ppm following 7 weeks test item administration.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
34 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information as a whole meets the tonnage driven information requirements of REACH.

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

Mode of Action Analysis / Human Relevance Framework

Not applicable.

Additional information

Repeated dose – Oral:

7-week DRF, eq. or similar to OECD TG 407, 1979: The study was performed as a 7 week dietary range finding sub-chronic study using methods equivalent or similar to the requirements of OECD Guideline 407, to evaluate the potential toxicity of the test item prior to a definitive 2 year carcinogenicity study. Sub-chronic toxicity tests were- conducted with both rats and mice. Fisher 344 male/female rats were distributed among ten groups, each consisting of five males and five females. B6C3F1 strain male/female mice were distributed among ten groups, each consisting of five males and five females. The test item was administered for 7-weeks through basal laboratory diet supplied ad libitum at doses up to 10,000 ppm in rats and 14,700 ppm in mice. With respective negative controls. Observation continued for one week post administration. Rats and mice were necropsied post termination. The basal laboratory diet for both dosed and control animals consisted of Wayne Lab-Blox meal. Test item was administered to the dosed animals as a component of the diet. The test item was removed from its container and a proper amount was blended with an aliquot of the feed using a mortar and pestle. Once visual homogeneity was attained, the mixture was placed in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in double plastic bags and stored in the dark at 4°C. The mixture was prepared once weekly. The report indicated that dosed feed preparations containing 1500 and 375 ppm were analysed spectrophotometrically. Mean result immediately after preparation was 97 percent of theoretical (ranging from 96 to 98 percent). After 10 days at ambient room temperature the mean result was 78 percent of theoretical (ranging from 73 to 82 percent). Applicant assessment indicates: the test item was stable for ca. 7 days (70 - 110% nominal) under the conditions employed. Under the conditions of the study, the lowest-observed-adverse-effect level (LOAEL) for males and females is considered to be 680 ppm following 7 weeks test item administration.

Justification for classification or non-classification

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for specific organ toxicity repeated exposure (STOT-RE).

 

Since there was no reported significant effects relevant to humans reported at equivalent guidance related levels (28-d ORAL ≤ 300 mg/kg bw/day or 90-d ORAL ≤ 100 mg/kg bw/day) then there is no requirement to classify STOT-RE.

 

References:

1. ECHA Guidance on Application on the CLP Criteria, (v5.0, July 2017), Section 3.9.2 : Table 3.16 - Equivalent guidance values for 28-day and 90-day studies