Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Remarks:
other: 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 in accordance to OECD guideline
Reason / purpose:
reference to same study
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
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
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 exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE: suspension in water
- Amount of vehicle: 10 ml/kg at similar times each day
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1 (probably) (male animals: see Endpoint study record in section 7.5.1 "Repeated dose Toxicity")
- Length of cohabitation: until copulation/ up to 14 days
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- M/F ratio per cage: 1/1
- Length of cohabitation: Each morning the females were examined for the presence of sperm in vaginal lavages
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged individually.
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
males: 54 administrations, (2 weeks before mating, 2 weeks during mating and 26 days after mating period)
females: 14 days pre-mating period and until mating, through the pregnancy period (assuming 20 days pregnancy) until lactation day 3 after delivery (4 days lactation period)
Frequency of treatment:
daily by stomach tube
Details on study schedule:
- Age at mating of the mated animals in the study: 14 weeks
Remarks:
Doses / Concentrations:
actual ingested doses
Basis:
actual ingested
0, 100, 400, 1600 mg/kg bw./day
No. of animals per sex per dose:
12
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
Parental animals: Observations and examinations:
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, pups within 24 hours of parturition and on day 4 post-partum

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 high 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
Sperm parameters (parental animals):
Parameters examined in male parental generations: testis weight, epididymis weight, histopathology of testis and epidymidis
Litter observations:
PARAMETERS EXAMINED
numbers of pups born, delivery index, number of pups alive, birth index, live birth index, pup weight on day 0 of lactation, sex ratio, number of pups alive on day 4 of lactation, pup weight on day 4 of lactation, general status of pups, observation of external deformities, corpora lutea, implantations, visible resorptions, early resorptions


GROSS EXAMINATION OF DEAD PUPS: yes, for external and internal abnormalities
Postmortem examinations (parental animals):
POST-MORTEM EXAMINATIONS: Yes

SACRIFICE
- Male animals after 54 days: All surviving animals
- Female animals: Sacrifice on lactation day 4 (starting with day 0),

ORGAN WEIGHTS
- 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
Postmortem examinations (offspring):
Gross pathology: observation of external deformities
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).
Reproductive indices:
number of mated pairs, number of copulated pairs, copulation index, number of pregnant animals, fertility index, pairing days until copulation, frequency of vaginal estrus, number of pregnant females, number of pregnant females with pups alive, gestation index, gestation lenth in days, number of corpora lutea, number of imlantation sites, implantation index, number of pups born, delivery index
Offspring viability indices:
number of pups alive, birth index, live birth index, pup weight on day 0 of lactation, sex ratio, number of pups alive on day 4 of lactation, viability index, pup weight on day 4 of lactation, general status of pups, observation of external deformities
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
f
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
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 not related to dosage or not confirmed by the findings in other groups, for example by the results of the satellite 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
Remarks:
fertility
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: P and F1 (migrated information)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
CLINICAL SIGNS (OFFSPRING): no abnormalities in the general status

BODY WEIGHT (OFFSPRING): no significant differences between the control group and the various dosage groups werde observed in males or females in body weights on day 0

On lactation day 4 a higher number of dead pups was counted in the high-dose level group. Moreover, there was a stastitically significant but very low difference in the body weight between the control group and the 400 and the 1600 mg/kg bw dose groups. However, this difference is considered to be of low biological relevance.

GROSS PATHOLOGY (OFFSPRING): no external deformities were observed in the surviving pups on the day of birth. In autopsies of pups on lactation day 4, no abnormalities were observed in the control, nor were any abnormalities in the autopsy of the dead pup.
Reproductive 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 and female rats. Treatment of males: 54 administrations, (2 weeks before mating, 2 weeks during mating and 26 days after mating period), treatment of females: 14 days pre-mating period and until mating, through the pregnancy period (assuming 20 days pregnancy) until lactation day 3 after delivery (4 days lactation period) for 54 days.
Additional satelite groups of 5 male and 5 female were treated with 0 and 1600 mg ASC plus/kg bw. and used for observation of reversibility, persistence or delayed occurence of systemic toxic effects for at least 14 days post treatment.
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. 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. However NOAEL (Fertility) = 1600 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..

Histopathology and gross necropsy did not reveal any test article related changes.

The organ weights showed some statistically significant differences, but these were not related to dosage or not affirmed by the findings in other groups, for example by the results of the satellite groups.

The same is true for the statistical significant differences of the haematological parameters and the result of the clinical chemistry, especially decreased activities of the liver enzymes in the blood. These are merely statistical effects without biological relevance.

Two effects with a possible relation to the oral administration of ASC plus were observed:

- At birth no differences were observed between the groups, but on day 4 after birth a higher number of dead pups was counted in the high-dose level group.

- With male rats a dose dependent decrease in body weight is observed. This effect is in the highest dose group statistically significant and confirmed by the satelite group but not confirmed by the body weight development of the females and not confirmed by the food consumption of males and females.

Although an influence of an infection with paracites seems possible and may explain both effects, a non-specific influence of ASC plus cannot be excluded. The daily administration of a suspension of ASC plus in 10 ml/ kg bw. may have led to a reduced appetite of the animals. This should be especially true for the highest dosage group, as here the suspension was relatively dense. Imaginable is also an osmotic effect of non-resorbed ASC plus in the intestine. At dosages of 100 and 400 mg/kg bw. the animals showed no differences to the control animals (NOEL).

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.

With regard to effects on fertility of the present study 1600 mg ASC plus/kg bw. per day can be defined as "No Observed Adverse Effect Level" (NOAEL).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 600 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
reliable guideline study performed under GLP.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
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.


Short 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 and female rats. Treatment of males: 54 administrations, (2 weeks before mating, 2 weeks during mating and 26 days after mating period), treatment of females: 14 days pre-mating period and until mating, through the pregnancy period (assuming 20 days pregnancy) until lactation day 3 after delivery (4 days lactation period) for 54 days.
Additional satelite groups of 5 male and 5 female were treated with 0 and 1600 mg ASC plus/kg bw. and used for observation of reversibility, persistence or delayed occurence of systemic toxic effects for at least 14 days post treatment.
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. may have induced an influence on the body weight gain of the males and the survival of pups until day 4 after birth.
overall NOAEL: 400 mg/kg bw.
NOAEL for fertility effects: 1600 mg/kg bw.

Justification for selection of Effect on fertility via oral route:
reliable guideline study performed under GLP used as key study.

Effects on developmental toxicity

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 and female rats. Treatment of males: 54 administrations, (2 weeks before mating, 2 weeks during mating and 26 days after mating period), treatment of females: 14 days pre-mating period and until mating, through the pregnancy period (assuming 20 days pregnancy) until lactation day 3 after delivery (4 days lactation period) for 54 days. 
Additional satelite groups of 5 male and 5 female were treated with 0 and 1600 mg ASC plus/kg bw. and used for observation of reversibility, persistence or delayed occurence of systemic toxic effects for at least 14 days post treatment.
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. may have induced an influence on the body weight gain of the males and the survival of pups until day 4 after birth.
overall NOAEL: 400 mg/kg bw.
NOAEL for fertility effects: 1600 mg/kg bw.
NOAEL for developmental effects: 400 mg/kg bw.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
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 in accordance to OECD guideline
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
other: OECD 422 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
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 exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE: suspension in water
- Amount of vehicle: 10 ml/kg given at similar times each day
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1 (probably) (male animals: see Endpoint study record in section 7.5.1 "Repeated dose Toxicity")
- Length of cohabitation: until copulation/ up to 14 days
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- M/F ratio per cage: 1/1
- Length of cohabitation: Each morning the females were examined for the presence of sperm in vaginal lavages.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged individually.
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
males: 54 administrations, (2 weeks before mating, 2 weeks during mating and 26 days after mating period)
females: 14 days pre-mating period and until mating, through the pregnancy period (assuming 20 days pregnancy) until lactation day 3 after delivery (4 days lactation period)
Frequency of treatment:
daily by stomach tube
Duration of test:
up to 54 days
Remarks:
Doses / Concentrations:
0, 100, 400, 1600 mg/kg bw./day
Basis:
actual ingested
No. of animals per sex per dose:
12
satellite group: (1600 mg/kg bw./day ):5 individuals (5 females and 5 males)
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
Maternal examinations:
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 satellite groups and from the control and high dose group.

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

URINALYSIS: No
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
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 date 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 cas of repeated data measurement (body weight, food intake): Repeated measures ANOVA (procedure General Linear Model (GLM) for Repeated Measures in SPSS statistical software).
Indices:
implantation/fertility index, delivery index, live birth index, neonatal survival rate, copulation index, lactation status
Historical control data:
no
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOEL
Effect level:
400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: other:
Dose descriptor:
LOEL
Effect level:
1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: other:
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental 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 and female rats. Treatment of males: 54 administrations, (2 weeks before mating, 2 weeks during mating and 26 days after mating period), treatment of females: 14 days pre-mating period and until mating, through the pregnancy period (assuming 20 days pregnancy) until lactation day 3 after delivery (4 days lactation period) for 54 days.
Additional satelite groups of 5 male and 5 female were treated with 0 and 1600 mg ASC plus/kg bw. and used for observation of reversibility, persistence or delayed occurence of systemic toxic effects for at least 14 days post treatment.
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. 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..

Histopathology and gross necropsy did not reveal any testarticle related changes.

The organ weights showed some statistically significant differences, but these were not related to dosage or not affirmed by the dindings in other groups, for example by the results of the satelite groups.

The same is true for the statistical significant differences of the haematological parameters and the result of the clinical chemistry, especially decreased activities of the liver enzymes in the blood. These are merely statistical effects without biological relevance.

Two effects with a possible relation to the oral administration of ASC plus were observed:

- At birth no differences were observed between the groups, but on day 4 after birth a higher number of dead pups was counted in the high-dose level group.

- With male rats a dose dependent decrease in body weight is observed. This effect is in the highest dose group statistically significant and confirmed by the satellite group but not confirmed by the body weight development of the females and not confirmed by the food consumption of males and females.

Although an influence of an infection with paracites seems possible and may explain both effects, a non-specific influence of ASC plus cannot be excluded. The daily administration of a suspension of ASC plus in 10 ml/ kg bw. may have led to a reduced appetite of the animals. This should be especially true for the highest dosage group, as here the suspension was relatively dense. Imaginable is also an osmotic effect of non-resorbed ASC plus in the intestine.At dosages of 100 and 400 mg/kg bw. the animals showed no differences to the control animals (NOEL).

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.

With 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 developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
reliable guideline study.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
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 selection of Effect on developmental toxicity: via oral route:
reliable guideline study performed under GLP used as key study.

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.