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Description of key information

Daily dosages of 0, 100, 400, and 1600 mg ASC plus/kg bw. were administered by stomach tube to groups of 12 male rats for 54 days. Satellite animals in a control and the highest dose group (1600mg/kg bw) with 5 individual each were also included. The test-article was formulated in drinking water and administered in 10 ml/kg bw..
At dosages of 100 and 400 mg/kg bw. the animals showed no differences to the control animals (NOAEL).
1600 mg ASC plus/kg bw. , considered as the LOEL, may have induced an influence on the body weight gain of the males (and the survival of pups until day 4 after birth).
The NOAEL of 400 mg/kg bw/day based on influence on the body weight gain of the males (and the survival of pups until day 4 after birth).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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:
2012-2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study with no deviations
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Principles of method if other than guideline:
daily administration by stomach tube for 54 days
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Germany, D-97633 Sulzfeld
- Age at purchase: 11 weeks
- weight rage at time of grouping: males, 175-200 g
- Fasting period before study: no
- Housing: 2 per cage,
- Cages: TECHNIPLAST filter top cages type 2145 F with an G-Temp (PSU) durable filter cover, 480x265x210 mm³, floor area 940 cm²,
- Source: Techniplast Company, Italy
- Diet: ad libitum, M3, BONAGRO Ltd., reg. CZ 10174, Czech Republic
- Water: ad libitum, tap water
- Acclimation period: 9 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE: Suspension in water

- Amount of vehicle: 10 ml/kg
- single daily adminisration at similar times each day
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
54 administrations, (2 weeks before mating, 2 weeks during mating and 26 days after mating)
dissection ca. 24 hours after the last administration
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 100, 400, 1600 mg/kg body weight (mg/kg bw)
Basis:
actual ingested
No. of animals per sex per dose:
12 males, satelite groups (control and highest dosage): 5 males each
Control animals:
yes
Details on study design:
- Control groups: drinking water
- Dose selection rationale: Results of an acute toxicity study with oral administration to male and female rats
- Result: no effects up to and including 2000 mg/kg bw.
- Rationale for animal assignment: randomly grouped
- Section schedule rationale: all animals were sacrificed
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: on administration days 1, 8, 15, 22, 29, 36, 42, 50 and on day of autopsy

FOOD CONSUMPTION : 2 weeks before mating, after 2 week mating period and weekly until the end of the study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 14 (before mating) and prior to autopsy from the satelite groups and from the control and highest dose group.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:day 14 (before mating) and prior to autopsy from the satelite groups and from the control and high dose group.

URINALYSIS: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Organ weights: brain, heart, thymus, spleen, liver, testis, epididymis, kidney, adrenal gland

HISTOPATHOLOGY: Yes: high dose and control animals
- Organ: medulla oblongata, brain, heart, pancreas + lymphnode, spleen, liver, lung, small intestine, stomach, kidneys, adrenal gland, testes, prostrate, urinary bladder, bone + bone marrow, thymus, trachea, white + brown fat, muscle, pituitary gland
Statistics:
Statistical evaluation was operated using the software SPPS version 16.0. Group data were represented by mean, standard deviation and median. Statistical analysis in case of data measured once during the study (organ weight, haematology, clinical chemistry) : Mann-Whitney U test for pairwise comparison between control and individual experimental groups on significance level alpha = 0.05.
Statistical analysis in case of repeated data measurement (body weight, food intake): Repeated measures ANOVA (procedure General Linear Model (GLM) for Repeated Measures in SPSS statistical software).
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
statistically significant decrease after dosages of 1600 mg/kg bw./day
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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS:
- 100, 400 and 1600 mg/kg bw/day:
no differences to the control animals observable

MORTALITY: no

BODY WEIGHT GAIN: 1600 mg/kg bw: reduced

FOOD CONSUMPTION: no statistical differences

HAEMATOLOGY/ CLINICAL CHEMISTRY:
Haematology and clinical chemistry reveales some statistically significant differences, but these were neither related to dosage not confirmed by the findings in other groups, for example by the results of the satelite groups, or the effects are of biological low relevance i.e..

URINALYSIS: not examined

NEUROBEHAVIOUR: not examined

ORGAN WEIGHTS: no statistical differences

GROSS PATHOLOGY: no dosage related effects

HISTOPATHOLOGY: NON-NEOPLASTIC: no statistical differences

HISTOPATHOLOGY: NEOPLASTIC: no statistical differences

HISTORICAL CONTROL DATA: not given

Dose descriptor:
NOEL
Effect level:
400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Dose descriptor:
LOEL
Effect level:
1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: decrease in body weight (not exeeding 10%)
Critical effects observed:
not specified
Conclusions:
Daily dosages of 0, 100, 400, and 1600 mg ASC plus/kg bw. were administered by stomach tube to groups of 12 male rats for 54 days. Satellite animals in a control and the highest dose group (1600mg/kg bw) with 5 individual each were also included.The test-article was formulated in drinking water and administered in 10 ml/kg bw..
At dosages of 100 and 400 mg/kg bw. the animals showed no differences to the control animals (NOAEL).
1600 mg ASC plus/kg bw. , considered as the LOEC, may have induced an influence on the body weight gain of the males (and the survival of pups until day 4 after birth).
NOAEL: 400 mg/kg bw.
Executive summary:

Daily dosages of 0, 100, 400, and 1600 mg ASC plus/kg bw. were administered by stomach tube to groups of 12 male rats for 54 days. The test-article was formulated in drinking water and administered in 10 ml/kg bw..

At dosages of 100 and 400 mg/kg bw. the animals showed no differences to the control animals (NOEL).

All examined organs and tissues showed a normal histological structure.

1600 mg ASC plus/kg bw. may have induced an influence on the body weight gain of the males (and the survival of pups until day 4 after birth).

In regard to the results of the present study 400 mg ASC plus/kg bw. per day can be defined as "No Observed Adverse Effect Level" (NOAEL) for the systemic toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
reliable OECD Guideline under GLP, The NOAEL of 400 mg/kg bw/day based on influence on the body weight gain of the males (and the survival of pups until day 4 after birth).

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

According to the present data the toxicity and the toxicokinetics of ASC plus (6-[[(4-methylphenyl)sulphonyl]amino]hexanoic acid) can be described as follows:

 

1.     ASC plus has a relatively low toxicity.

2.     Repeated oral dosages up to 1600 mg/kg b.w. caused only reduced body weight increase with the male rats and slightly increased number of dead pups 5 days after birth. Such effects are of minor toxicological relevance. They might be caused by unspecific influences such as high amount of administered substance.

3.     ASC plus is nearly completely eliminated from serum within 24 hours after administration. There is no potential for accumulation in the body.

4.      ASC plus seems to be excreted mainly as unchanged substance via the urine.

5.     This is in good accord with the data from ecotoxicity studies showing a slow but steady degradation together with a low toxicity.

 

In summary the present studies seem to be sufficient for the toxicological evaluation of ASC plus.

In accordance with Annex XI (3) of REACH:

Further testing in accordance with Annex IX is omitted, based on the exposure scenario(s) developed in the Chemical Safety Report (chapter 9).

It is demonstrated and documented that all of the following conditions are fulfilled:

(i) the results of the exposure assessment covering all relevant exposures throughout the life cycle of the substance demonstrate the absence of or no significant exposure in all scenarios of all identified uses (see chapter 9 of the CSR);

(ii) DNELs (see table 19 in section 5.11.2 of the CSR/ summary in IUCLID section 7) and PNECs (Table 28 in section 7.6 of the CSR/ summary in IUCLID-Section 6) were derived from results of available test data for the substance concerned taking full account of the increased uncertainty resulting from the omission of the information requirement. The DNELs and PNECs were derived according to the ECHA-REACH-guidance and are relevant and appropriate both to the information requirement to be omitted and for risk assessment purposes;

(iii) the comparison of the derived DNEL or PNEC with the results of the exposure assessment shows that exposures are always well below the derived DNEL or PNEC (see Chapter 9 of the CSR);

 

Therefore, no further studies on Reproductive toxicity (Annex IX, 8.7) and on Repeated dose toxicity (Annex IX, 8.6) are necessary.

Justification for classification or non-classification

There was no treatment related effect that would fullfill any criteria for classification and labelling according to the criteria laid out in

Regulation (EC) No.: 1272/2008 (especially 3.7 "Reproductive toxicity" and "3.9. Specific target organ toxicity — repeated exposure"). Also, according to the criteria specified by Directive 67/548/EEC the substance is not classified.