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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL of Amidoaminethoxylate (REWOSOFT TE 19L) for reproductive and developmental toxicity screening on rats was 500 mg/kg bw/day.

From the findings of a two-generation reproductive study of Amidoaminethoxylate (REWOSOFT TE 19L), the NOAEL for F0 rats was 1000 mg/kg and for F1 and F2 pups was 500 mg/kg.

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013/2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to guideline
Guideline:
other: Technical Guidelines for Drug Reproductive Toxicity Study, China Food and Drug Administration,
Version / remarks:
March 2005
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: ST02697671
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Beijing Vital River Test Animals Technology Co., Ltd.
- Weight at study initiation:(P) 195 - 390 g
- Housing: SPF class test animal room
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24°C
- Humidity (%): 50 - 65 %
- Air changes (per hr): 10-20 times/h
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Concentration in vehicle: 100 mg/mL
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Female rats were continuously treated until day 4 after birth of their offspring.
Frequency of treatment:
once daily
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
15 male + 15 female per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of a sub-chronic oral toxicity test (90 days).
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: on first day of exposure and once a week thereafter;
during pregnancy on 0d, 4d, 7d, 10d, 14d, 17d and 20d;
after delivery 0d and 4d.

FOOD CONSUMPTION The weekly food consumption was recorded before and during the mating period, respectively.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities,

GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities;
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
Following tissues were prepared for microscopic examination and weighed, respectively.: heart, liver, spleen, lungs, kidneys, thymus, ovary, testis, epididymis, other reproductive accessories and all organs showing macroscopic lesions.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

Statistics:
Mean +- standard deviation, t-test.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Changes with respect to the uterine wall where the placenta was atteched, was reported. the tissue structure inside the uetrine wall was disordered and arrangement disorder of smooth muscle was evident. Other lesions observed were local tissue cell degeneration, necrosis, vascular dilation, congestion and hemorrhage. In terms of changes with uterus recovery after delivery such as remaining decidual cells, the recovery progress of high-dose group was worse conpared to the intermediate dose group, the low dose group and the blank control group.
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Changes with regard to the uterine wall where the placenta was attached are reported. The tissue structure was disordered. Other lesions observed were local tissue cell degeneration, necrosis, vascular dilation, congestion and hemorrhage. High-dose mildly delayed uterine recovery of female placental attachment.
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Clinical signs:
no effects observed
Mortality / viability:
not specified
Body weight and weight changes:
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: neoplastic
Remarks on result:
not measured/tested
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
The NOAEL of REWOSOFT TE 19L for reproductive and developmental toxicity screening on rats was 500 mg/kg bw/day.
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013/2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Qualifier:
according to guideline
Guideline:
other: Chemicals-Test Method of Two-generation Reproduction Toxicity Study (GB 21758-2008), Guidelines for the Testing of Chemicals of China
Version / remarks:
March 2005
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: ST02697671

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Beijing Vital River Experimental Rat Technology Co. Ltd., China
- Weight at study initiation: (P) Males: 120 -143 g; Females: 170 - 190 g;

- Housing: SPF experimental room
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: quarantine for 5 days at least
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24°C
- Humidity (%): 50 - 65 %
- Air changes (per hr): 10 - 20 times/h
- Photoperiod (hrs dark / hrs light):12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
VEHICLE
- Concentration in vehicle: 100 mg/ml
- Amount of vehicle (if gavage): 0.5 - 2.0 ml/100 g
Details on mating procedure:
- M/F ratio per cage:1/1
- Length of cohabitation: 3 weeks
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 21 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
F0 male rats were treated 10 weeks prior to mating and continuously treated during the mating period.
F0 female rats were treated 2 weeks prior to mating and continuously treated during mating, gestation and lactation period.
F1 males were traated continuously from ablactation to mating period.
F1 female rats were treated 10 from ablactation to mating and continuously treated during mating, getsation and lactation period.
Frequency of treatment:
once daily
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
15 males + 15 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: basing on results of a subchronic oral toxicity studa (90 days)
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain,

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities;

:
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination and weighed, respectively:
The ovary, uterus, cervix, vagina, testis, epididymis seminal vesicles, prostrate and other reproductive tissues and internal organs of all dams, possible target organs like brain, heart, lung, liver, kidney, adrenal glands, spleen, stomach, duodenum, thymus, etc.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed
- These animals were subjected to postmortem examinations macroscopic

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

HISTOPATHOLOGY / ORGAN WEIGTHS
The following tissues were prepared for microscopic examination and weighed, respectively:
The ovary, uterus, cervix, vagina, testis, epididymis seminal vesicles, prostrate and other reproductive tissues and internal organs of all dams, possible target organs like brain, heart, lung, liver, kidney, adrenal glands, spleen, stomach, duodenum, thymus, etc
Statistics:
group means and standard deviation, t-test
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
Significant difference in sperm deformity rate was obsrved in the high-dose group compared to the control group.
Reproductive performance:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (sperm measures)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significant difference was observed in average body weight during the period from birth to day 28 of F1 pups in the medium and high-dose group compared to the vehicle control group. The crown-rump length of the high-dose group was significantly shorter than the vehicle control group. No significant difference was observed in the body weight of day 42 male and female rats.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In F1 rats treated with the high-dose of REWOSOFT TE 19L incomplete occipital ossification was observed in 9 cases and significant difference was observed compared to the vehicle control group.
Histopathological findings:
no effects observed
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
gross pathology
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In F2 rats of the high-dose group incomplete occipital bone ossification was observed in 6 cases and significant difference was observed with the vehicle control group.
Histopathological findings:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
Key result
Reproductive effects observed:
no

Impact of REWOSOFT TE 19L on skeleton of F1 generation of fetal rats

   Vehicle Control  Low-dose 500 mg/kg  Medium-dose 1000 mg/kg  High-dose 2000 mg/kg
 Number of pups  176  185  158  183
 Skull  1  2  3  11**
 Sternum  0  0  0  0
 Rib  1  1  3  1
 Limbs  0  0  0  0
Vertebra   0  0  0  0
 Pelvis  0  0  0  0
 Coccyx  0  0  0  0

compared to the vehicle control group "**" represents P<0.01

Impact of REWOSOFT TE 19L on skeleton of F2 generation of fetal rats

   Vehicle Control  Low-dose 500 mg/kg  Medium-dose 1000 mg/kg  High-dose 2000 mg/kg
 Number of pups  168  157  165  142
 Skull  1  0  1  6*
 Sternum  0  0  0  0
 Rib  0  0  0  0
 Limbs  0  0  0  0
Vertebra   0  0  0  0
 Pelvis  0  0  0  0
 Coccyx  0  0  0  0

compared to the vehicle control group "*" represents P<0.05

Conclusions:
From the findings of this two-generation reproductive study of REWOSOFT TE 19L, the NOAEL for F0 rats was 1000 mg/kg and for F1 and F2 pups was 500 mg/kg.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Additional information