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EC number: 248-003-8 | CAS number: 26787-78-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 450 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available study is a high quality subacute assay (Klimish score =1).
Additional information
Key study: A combined repeated dose toxicity study with reproduction/developmental toxicity screening was conducted with amoxicillin trihydrate according to OECD 422 under GLP conditions. The treatment of male and female rats with amoxicillin trihydrate at dose levels up to 2450 mg/kg-bw/day by repeated oral (gavage) administration revealed no adverse effects on the reproductive performance or fertility of Wistar rats. The no-observed-adverse-effect-level (NOAEL) of amoxicillin trihydrate was determined to be 2450 mg/kg b.w./day for reproductive toxicity.
Short description of key information:
Key study: Test method OECD 422. GLP study. The NOAEL of the parental toxicity and reproductive toxicity for amoxicillin trihydrate in rats by oral route was determined to be equal or higher than 2450 mg/kg bw/day since no adverse effects were observed at the highest dose tested.
Justification for selection of Effect on fertility via oral route:
Only one study is available.
Effects on developmental toxicity
Description of key information
Key study: Test method OECD 422. GLP study. The NOAEL of the parental toxicity and developmental toxicity for amoxicillin trihydrate in rats by oral route was determined to be equal or higher than 2450 mg/kg bw/day since no adverse effects were observed at the highest dose tested.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Test method according to OECD 422. GLP study.
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 422 Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- EST ANIMALS
- Source: Husbandry of laboratory animals of the Experimental Medicine Centre at the Medical University in Białystok.
- Age at study initiation: 12-14 weeks old.
- Weight at study initiation: Males 390.2-410.9 g and females 247.7-248 g
- Fasting period before study: No
- Housing: Same conditions during acclimatisation and experiment, air-conditioned rooms.
- Diet:Altromin 1324 P TPF ad libitum.
- Water: Tap water ad libitum.
- Acclimation period: 7 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24ºC
- Humidity (%): 35-57 %
- Air changes: 13times/hour
- Photoperiod: 12 hours dark/12 hours light - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- (0.5 % CMC sodium salt)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Suspensions of the test item in vehicle (0.5% Carboxymethylcellulose sodium salt) were prepared once a week (the stability of Amoxicillin in a vehicle in a temperature 4-8ºC during 7-days period was evaluated). During administration, suspensions were kept at room temperature and they were thoroughly mixed.
DIET PREPARATION
- Rate of preparation of diet (frequency): Standard diet was given.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Vehicle control was selected on the basis of solubility of the test item in water.
- Concentration in vehicle: 40mg/mL, 140 mg/mL, 490 mg/mL
- Amount of vehicle (if gavage): 0.5 mL/100 gr
- Lot/batch no. (if required): 1296363
- Other: Name: Carboxymethylcellulose sodium salt, ultra high viscosity, highly purified, purchased from Sigma Aldrich. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analytical concentration was measured using a validated HPLC method with DAD detector. The analytical method was validated (Linearity= 1-500 mg/L; Specifity was evaluated with fortitied samples and the matrix. No signal was overlapping. Recovery=92-102.41 %. Precision= Assessed with repetability, RSD= 0.055-0.27 %. LOQ= 1mg/L. LOD= 0.25 mg/L).
The analytical concentrations were measured weekly and ranged as follows:
35.8 – 46.4 mg/mL for the concentration of 40 mg/mL in vehicle (89.5 – 115.9%)
129.0 – 163.9mg/mL for the concentration of 140 mg/mL in vehicle (92.1 – 117.1 %)
442.3 – 574.4 mg/mL for the concentration of 200 mg/mL in vehicle (90.3 – 117.2%).
The results were within the range of 80 -120%.
The test item was stable in vehicle, minimum for one week: Initial concentration = 40 mg/L, after 7 days 34.6-40.2 mg/L. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1 or 1:2
- Length of cohabitation: . The average number of days needed for copulation (the day when males and females were placed together was day 0) was 1.5 in the control group, 1.3 in group 1, 1.0 in group 2 and 1.2 in group 3.
- There was no need of replacement of males for unsuccessful pairing.
- Verification of same strain and source of both sexes: [yes / no (explain)
- Proof of pregnancy: vaginal plug or sperm in vaginal smear]referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Males were dosed for 28 days: 14 days pre-mating and 14 days during mating.
Females were dosed throughout the study. This included 2 weeks prior to mating, the variable time to conception, the duration of pregnancy, and at least 13 days after delivery (51 – 60 days in total, 53 average). - Frequency of treatment:
- Once daily seven days a week.
- Duration of test:
- 66 days.
- No. of animals per sex per dose:
- 10 males/dose
12 females/dose
10 animals/sexe/dose in the satellite groups - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels for the study were selected on the basis of bibliographic and registrant information.
- Rationale for animal assignment: Animals were randomly assigned to the groups.
- Other: in the study there were satellite groups, however since they were not mated, findings are considered irrelevant for the reproductive/developmental screening half. - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily.
BODY WEIGHT: Yes
Time schedule for examinations: Twice a week during the entire experiment.
Body weights of females were measured twice a week before gestation, on days 0, 7, 14, and 20 of gestation, within 24 hours of parturition (day 0 or 1 post-partum), and day 4, 7, 10 and 13 post-partum. Body weights of pups were measured on day 0 (within 24 hours of parturition), 4, 7 and 13 post-partum
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 4 and 13
- Organs examined: The animals were subjected to detailed gross examination which involved observations of the external body surface, all natural apertures and the cranial, thoracic, and abdominal cavities with their content. Special attention was paid to the reproductive system and thyroid glands. Absolute and relative weights of the brain, thymus, heart, liver, spleen, kidneys, and adrenals of 5 adult males and 5 adult females from each group were determined. Additionally, absolute and relative weights of the testes, epididymides, accessory sex organs (prostate with the seminal vesicles and coagulating glands), thyroid glands and ovaries of all adult animals were determined with the exception of the female no. 17 in group 3, in which only the absolute and relative weights of the thyroid glands was determined, without the weights of the ovaries, as it was non-pregnant.
The histopathological examination of the following organs and tissues collected from five adult males and females from group 0, 0 SAT, 3 and 3 SAT was conducted: brain with the cerebellum and pons, pituitary gland, eyeball with optic nerve, lymph nodes, spinal cord, muscle with the peripheral nerve, trachea, thyroid with the parathyroids, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, liver, spleen, lungs, heart, thymus, kidneys, adrenals, urinary bladder, ovaries, uterus with the cervix and horns, vagina, mammary glands, testes, epididymides, accessory sex organs (prostate with the seminal vesicles and coagulating glands), and all organs with gross lesions. The following organs and tissues of animals were examined: testes, epididymides and accessory sex organs (prostate, vesicular and coagulating glands) from all adult males; ovaries from all adult females; thyroid glands from all adult rats.
Please refer to Endpoint specific 7.5.1 For repeated dose toxicity parameters. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes (separately in the left and the right ovary)
- Number of implantations: Yes, sites were also determined separately in the left and the right horn of the uterus
- Number of early resorptions: No
- Number of late resorptions: No
- Other: ovary weights, histological examination of ovaries, uterus with the cervix and horns, vagina. - Fetal examinations:
- - External examinations: Yes: all per litter, they were carefully examined for gross abnormalities. The examinations involved observations of the external body surface, all natural apertures, and the cranial, thoracic, and abdominal cavities with their content
- Soft tissue examinations: Yes: all per litter The tissues and internal organs were examined.
- Skeletal examinations: The gross examination included observations of the external body surface, all natural apertures, and the cranial, thoracic, and abdominal cavities with their content .
- Head examinations: Yes: all per litter
Other: The level of thyroid hormone, i.e. total T4 (TT4) in serum were determined once from
- two pups per litter on day 4 after birth,
- two pups per litter on day 13 after birth.
- The anogenital distance was measured on day 4 afterbirth.
- The number of nipple/areolae were determined on day 13 after birth. - Statistics:
- The treated groups, i.e. groups 1, 2, and 3 were compared to the control group.
The clinical results were statistically analyzed using the one-way analysis of variance and the Dunnet’s test and Student’s t-test (group 0 SAT, 3 SAT) (p ≤ 0.05).
The clinical-chemical results were statistically analyzed using the one-way analysis of variance and Dunnet’s test (p ≤ 0.05).
The results, i.e. absolute and relative weights of internal organs as well as the numbers of implantation sites and corpora lutea were statistically evaluated using Dunnett’s test (p≤0.05). - Indices:
- The following elements were determined for each group:
Fertility of parental animals:
Mating index for males:
the number of males showing evidence of copulation/the total number of mated males x 100
Mating index for females:
the number of sperm-positive females/the total number of mated females x 100
Fertility index for males:
the number of males that impregnated females/the total number of mated males x 100
Fertility index for females:
the number of pregnant females/the total number of sperm-positive females x 100
Pregnancy index:
the number of litters with live births/the number of pregnant females x 100.
Offspring survival:
Index of live births:
the total number of live newborns/the total number of newborns x 100
Index of 4-day survival:
the number of live sucklings after 4 days/the number of live newborns x 100
Index for 13-day survival:
the number of live sucklings after 13 days / (the number of live newborns – number of sucklings transferred to examination in day 4) x 100 .
The following parameters were also assessed:
the average number of days required for copulation (the day when males and females were placed together was day 0);
the length of gestation. - Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
No adverse dose-related effects were found (for more details please refer to endpoint specific 7.5.1 repeated dose toxicity). - Dose descriptor:
- NOAEL
- Effect level:
- 2 450 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 2 450 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
There were not observed any pathological changes and malformations. The macroscopic evaluation of the offspring did not reveal any lesions or malformations in live-born and stillborn pups.
There were no statistically significant changes in average body weights of the pups per litter between the treated and the control groups.
There were no statistically significant changes in AGD measurment in male and female pups between the treated and the control groups.
There were no statistically significant changes in number of nipples / areolae in male pups on 13th day of life between the treated and the control groups.
The results of the hormonal examinations (TT4) in pups 13 days after birth did not show statistically significant changes.
The following clinical observations were recorded
temporary hematoma on the neck in one male from group 2;
temporary hematoma on the back in one male from group 0 and one male from group 2;
temporary hematoma on the head in one male from group 0 and one male from group 2;
temporary hematoma on the hindlimb in two male from group 2, and one male from group 3;
temporary scab on the left ear in one male from group 0;
thinning hair in three males and two females from group 0, and four males and two females from group 1;
smaller body in one male and one female from group 0;
smaller and livid body in one male from group 0.
However considering the distribution in the control and test item-treated groups, considering the severity and persitence of such findings, they are considered not to be related to the test item. - Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- The NOAEL of the parental toxicity and developmental toxicity for amoxicillin trihydrate in rats by oral route was determined to be equal or higher than 2450 mg/kg bw/day since no adverse effects were observed at the highest dose tested.
- Executive summary:
- A combined repeated dose toxicity study with reproduction/developmental toxicity screening was conducted with amoxicillin trihydrate according to OECD 422 under GLP conditions. Twuelve to fourteen weeks old Wistar rats were exposed to amoxicillin trihydrate at concentrations of 0 (vehicle control), 200, 700 and 2450 mg/kg-bw/day by oral gavage in 0.5 % carboxymethyl cellulose sodium salt. There were 10 males and 12 females in each group. The test item was administered for 28 days(14 days premating, during mating and post mating period) to males and for 51-60 days to females (premating, conception, pregnancy and at least 13 days after delivery, average 53 days). All offspring was weighed on day 4 after birth, that day blood from 2 pups was collected for analysis of total TT4 thyroid hormone, the anogenital distance and the number of nipple/areolae was measured on day 13.The euthanized and the dead animals were subjected to the post-mortem examinations. Their tissues and internal organs were examined. The treatment of male and female rats with amoxicillin trihydrate at dose levels up to 2450 mg/kg-bw/day by repeated oral (gavage) administration revealed no parental toxicity nor adverse effects on the reproductive performance or fertility. There were no indications of developmental effects in the offspring. The no-observed-adverse-effect-level (NOAEL) of amoxicillin trihydrate was determined to be 2450 mg/kg bw/day for parental, reproductive and developmental toxicity.
Reference
Table 1. Amoxicillin trihydrate. Mating of parental animals – list of results
Parameter |
GROUP |
|||
0 |
1 |
2 |
3 |
|
Number of males to mating |
10 |
10 |
10 |
10 |
Number of females to mating |
12 |
12 |
12 |
12 |
Number of males which copulated |
10 |
10 |
10 |
10 |
Number of females which were mated |
12 |
12 |
12 |
12 |
Average number of days to copulation |
1.5 |
1.3 |
1.0 |
1.2 |
Number of fertilized females |
12 |
12 |
12 |
11 |
Number of pregnant females |
12 |
12 |
12 |
11 |
Number of females which delivered |
12 |
12 |
12 |
11 |
Number of not pregnant females |
0 |
0 |
0 |
1 |
Number of females which delivered offspring |
12 |
12 |
12 |
11 |
Number of females which delivered live offspring |
12 |
12 |
12 |
11 |
Table 2. Amoxicillin trihydrate. Indices concerning fertility of parental animals
Parameter |
GROUP |
|||
0
|
1
|
2
|
3
|
|
Mating index for males |
100.0 |
100.0 |
100.0 |
100.0 |
Mating index for females |
100.0 |
100.0 |
100.0 |
100.0 |
Fertility index for males |
100.0 |
100.0 |
100.0 |
90.0 |
Fertility index for females |
100.0 |
100.0 |
100.0 |
91.7 |
Pregnancy index |
100.0 |
100.0 |
100.0 |
100.0 |
Length of gestation |
22.3 ± 0.5 |
22.4 ± 0.5 |
22.2 ± 0.4 |
22.6 ± 0.5 |
Table 3. Amoxicillin trihydrate. Average number of pups in litter
Parameter |
GROUP |
|||
0 |
1 |
2 |
3 |
|
Total number of pups in litter |
11.8 ± 2.3 |
12.3 ± 1.6 |
12.2 ± 2.2 |
12.3 ± 2.1 |
Number of live births in litter |
11.7 ± 2.2 |
12.3 ± 1.5 |
11.8 ± 3.0 |
11.7 ± 2.4 |
Number of pups in litter, min.– max. |
9 - 15 |
8 - 14 |
9 - 15 |
7 - 15 |
Percentage of males in litter |
48.6 |
51.4 |
52.7 |
50.4 |
Percentage of females in litter |
51.4 |
48.6 |
47.3 |
49.6 |
Table 4. Amoxicillin trihydrate. Indices connected with survival of offspring
Parameter |
GROUP |
|||
0
|
1 2 |
2
|
3
|
|
Index of live births |
98.6 |
99.3 |
96.6 |
95.6 |
Index of 4-day survival |
97.1 |
98.0 |
97.2 |
99.2 |
Index of 13-day survival |
95.8 |
97.6 |
96.6 |
99.1 |
Mortality [%] |
4.2 |
2.4 |
3.4 |
0.9 |
Table 5. Amoxicillin trihydrate. Average AGD [mm] in male pups in litter on 4th day of life (statistically analyzed)
Day |
GROUP |
|||||||||||
0 n=12 |
1 n=12 |
2 n=12 |
3 n=11 |
|||||||||
4 |
5.16 |
± |
0.43 |
5.13 |
± |
0.10 |
5.20 |
± |
0.16 |
5.13 |
± |
0.16 |
Table 6. Amoxicillin trihydrate. Average AGD [mm] in female pups in litter on 4th day of life(statistically analyzed)
Day |
GROUP |
|||||||||||
0 n=12 |
1 n=12 |
2 n=12 |
3 n=11 |
|||||||||
4 |
3.31 |
± |
0.16 |
3.28 |
± |
0.11 |
3.28 |
± |
0.15 |
3.25 |
± |
0.15 |
Table 7. Amoxicillin trihydrate. Average number of nipples / areolae in male pups in litter on 13th day of life(statistically analyzed)
Day |
GROUP |
|||||||||||
0 n=12 |
1 n=12 |
2 n=12 |
3 n=11 |
|||||||||
13 |
0.10 |
± |
0.25 |
0.02 |
± |
0.06 |
0.09 |
± |
0.15 |
0.01 |
± |
0.04 |
There were 571 pups. 10 animals were eaten by mother. Among the remaining 561 animals, 14 of them were stillborn pups (2 females in the control group, 1 male in group 1, 4 males and 1 female in group 2, 3 males and 3 females in group 3), whereas 3 died during observation after the birth (1 female in group 0, and 2 males in group 1).The macroscopic examination of the all pups (without pups eaten by mothers) did not reveal any pathological changesor malformations.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 450 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available study is a high quality subacute assay (Klimish score =1).
Additional information
Justification for selection of Effect on developmental toxicity: via oral route:
Only one study is available.
Justification for classification or non-classification
Based on available data, the substance is not classified for reproductive or developmental toxicity according to CLP Regulation (EC) No. 1272/2008.
Additional information
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Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.