Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 935-847-3 | CAS number: 1369773-39-6
- 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
Description of key information
Single dose oral toxicity studies in mice and rats revealed NOELs of 2000 mg/kg in both species. In single dose intraperitoneal studies in mice and rats, a NOEL of 300 mg/kg was reported in mice but a NOEL was not identified in rats.
The inhalatory LC50, 4h value of the substance in Wistar rats was established to exceed 5 mg/L.
The dermal LD50 value of the substance in Wistar rats was established to exceed 2000 mg/kg body weight.
Key value for chemical safety assessment
Acute toxicity: via oral route
Link to relevant study records
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Nov 2004
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- other: Single dose acute toxicity testing for pharmaceuticals: Revised guideline. Federal Register, August 26. 1998. p 43934-43935
- Version / remarks:
- Chengelis 1995
- GLP compliance:
- yes
- Test type:
- acute toxic class method
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- 3 males and 3 females/ group ( Groups 1 - 4)
5 males and 5 females/group (Group 5)
Room temperature: 18° to 26°C
Room relative humidity: 30 to 70%
Lighting cycle: Artificial light for a 12-hour light/12-hour dark cycle
Animal caging: In stainless steel wire cages in compliance with the NRC
(National Research Council) Guide for the Care and Use of Laboratory Animals.
Diet: Teklad Certified LM-485 Rodent Diet #7012C ad libitum. except approximately 4 hours prior to dose (fast) until approximately 2 hours post-dose.
Analysis of diet: The lot number(s) and specifications of each lot used are archived at Calvert.
Water was provided to the animals ad libitum
Periodic analyses of the water were performed and the results are archived at Calvert.
Animals were housed individually and in compliance with the National Research Council
"Guide for the Care and Use of Laboratory Animals". Temperature and relative humidity
were monitored daily. Calvert is USDA registered and a fully accredited AAALAC facility.
There were no known contaminants in the diet or water which, at the levels detected.
interfered with the purpose, conduct or outcome of the study. - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5% (w/v) sodium carboxymethylcellulose [CMC] (high viscosity 1500-3000 cps)
- Details on oral exposure:
- Route and frequency: Oral, once to each rat
Dose volume: 20 mL/kg
AI-IU377 in 0.5% (w/v) sodium carboxymethylcellulose (0.5% CMC). The actual dose preparation procedures were documented in the raw data and presented as follows:
The amount of AHU3 77 required for each batch was based on the batch size.
Dosing formulations were prepared by gradual addition of 0.5% CMC to the calculated amount of test article, using a mortar and pestle. The suspensions were transferred to an appropriate HPDE container and the mortar and pestle were rinsed with vehicle. A stir bar was added and the mixture was thoroughly mixed for over an hour. The contents were then transferred to a graduated cylinder and the remaining vehicle was added. The formulations were then transferred
back into the HOPE container. The following preparations reflect the total amounts used to make each final dosing formulation. - Doses:
- Five groups consisting of five animals per sex per group were allocated to the study. Four groups consisting of three animals per sex per group were dosed at 0. 50. 250 and 1000 mg/kg on Day I. Since neither lethality nor other relevant clinical signs were observed. the remaining two animals per sex of Groups 1 thru 4 were not dosed and all animals allocated to Group 5 (5/sex) were dosed at 2000 mg/kg.
- No. of animals per sex per dose:
- Five groups consisting of five animals per sex per group were allocated to the study. Four groups consisting of three animals per sex per group were dosed at 0. 50. 250 and 1000 mg/kg on Day I. Since neither lethality nor other relevant clinical signs were observed. the remaining two animals per sex of Groups 1 thru 4 were not dosed and all animals allocated to Group 5 (5/sex) were dosed at 2000 mg/kg.
- Control animals:
- yes
- Details on study design:
- Pretest period: A minimum of at least 5 days was allowed between animal receipt and the start of dosing to acclimate animals to the laboratory environment and to observe them for the development of infectious disease.
Study period: Fifteen days
The test article dosing preparations were administered once to each rat orally. Each animal received 20 mL/kg via a syringe (5 cc) and a 16 g gavage needle. The dosing formulations were shaken then stirred via a magnetic stir plate and stir bar prior to dosing and continued during dosing. Unused portions of dosing formulations were discarded at the end of each dosing day. - Key result
- Sex:
- male/female
- Effect level:
- 2 000 mg/kg bw
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Mortality:
- There was no mortality
- Clinical signs:
- other: No clinical signs were observed in any animals receiving the vehicle formulation or the test article at 50, 250, 1000 and 2000 mg/kg during the study with the exception of soft feces in one animal at the 6 hour observation at the 2000 mg/kg dose level.
- Gross pathology:
- There were no gross necropsy findings in any of the animals receiving the vehicle formulation
or the test article at 50, 250, 1000 or 2000 mg/kg. - Interpretation of results:
- GHS criteria not met
- Conclusions:
- Single oral administration of AHU377 at 50, 250, 1000 and 2000 mg/kg to rats revealed no clinical signs with an absence of mortality. Under the conditions of this study, a no-effect level was identified at 2000 mg/kg.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Acute toxicity: via inhalation route
Link to relevant study records
- Endpoint:
- acute toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Feb - Sep 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 403 (Acute Inhalation Toxicity)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.2 (Acute Toxicity (Inhalation))
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.1300 (Acute inhalation toxicity)
- Qualifier:
- according to guideline
- Guideline:
- other: JMAFF Guidelines (2000)
- GLP compliance:
- yes
- Test type:
- acute toxic class method
- Species:
- rat
- Strain:
- other: Crl:WI(Han) (outbred, SPF-Quality)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- 5 males and 5 females (females were nulliparous and nonpregnant)
Animals used within the study were of approximately the same age and body weight variation did not exceed +/- 20% of the sex mean.
Identification Individual unique number by tattoo on hind leg.
Health inspection At least prior to exposure. It was ensured that the animals were healthy and without any abnormality that might affect the study integrity.
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome
of the study.
Accommodation
Group housing of five animals per sex per cage in labelled Makrolon cages (type IV; height 18 cm) containing sterilised sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm.
Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest,
Germany) except during exposure to the test substance.
Water
Free access to tap water except during exposure to the test substance.
Animal husbandry on the day of exposure
The animals were moved to the inhalation area to in order to perform the exposure. During the exposure, there was no access to food and water. After exposure, the animals were returned to their cages which were placed in a fume cupboard for a short time period to allow test
substance remnants to evaporate. A sheet of filter paper was used to cover the bedding material to prevent suffocation in case of bad health condition and in order to recover and to aid the clinical observations. The sheet was removed and before the end of the exposure day, the
surviving animals were returned to the animal room.
Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study. - Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- nose only
- Vehicle:
- air
- Mass median aerodynamic diameter (MMAD):
- >= 3.5 - <= 3.7 µm
- Geometric standard deviation (GSD):
- >= 1.9 - <= 2.4
- Remark on MMAD/GSD:
- The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (gsd) were determined twice during the exposure period. The MMAD was 3.5 µm (gsd 1.9) and 3.7 µm (gsd 2.4)
- Details on inhalation exposure:
- Administering the test substance to a stream of pressurized air using a combination of a spiral feeder and micronizing jet mill generated an aerosol. The aerosol was passed through a series of three cyclones, allowing larger particles to settle, before it entered the exposure chamber. The mean airflow 11 L/min.
From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
The nominal concentration was calculated by dividing the amount of test substance used by the volume of pressurized air (average air flow times exposure time) entering the exposure chamber used for exposure of the animals. Due to the small volume of the exposure chamber the
equilibrium time was negligible. The volume of air was calculated from the average air flow (measured by means of thermal mass flow meters and was recorded regularly, preferably in 30 minute intervals) and the exposure time.
The actual concentration was determined eighteen times during the exposure period. Samples were drawn from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. Samples were drawn through a glass fiber filter
(type APFC04700, Millipore, Billerica, MA, USA). The collected amount of the test substance in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter (type G 1.6, Actaris Meterfabriek B.V., Dordrecht, The Netherlands).
Subsequently the time-weighted mean concentration with the standard deviation was calculated. - Analytical verification of test atmosphere concentrations:
- yes
- Duration of exposure:
- 4 h
- Concentrations:
- 4 hours to a target
concentration of the test substance of 5 mg/L - No. of animals per sex per dose:
- 5 males and 5 females
- Control animals:
- no
- Details on study design:
- Target concentrations were based on the cut off concentration values specified in the UN and
EC classification guidelines. Five animals of each sex were exposed for 4 hours to a target
concentration of the test substance of 5 mg/L.
Prior to exposure the animals were restrained in polycarbonate restraining tubes; these tubes
were connected to the exposure chamber. Twenty-three minutes after the last animal was
placed the generation of the test atmosphere was started. The exposure time was 4 hours. - Key result
- Sex:
- male/female
- Dose descriptor:
- LC50
- Effect level:
- > 5 mg/L air (analytical)
- Based on:
- test mat.
- Exp. duration:
- 4 h
- Mortality:
- Three males were found dead. Two males were found dead 18 minutes after the start of the
exposure and the third male was found dead 4 minutes after completion of the exposure. No
further mortality occurred. - Clinical signs:
- other: During exposure, laboured and shallow respiration was seen for all animals observed (not presented in the table). After exposure, lethargy, hunched posture, laboured respiration, piloerection, ptosis was seen for the animals. The surviving animals had rec
- Body weight:
- Body weight gain in one surviving male and all females was within the range expected for rats of
this strain and age used in this type of study. One male showed body weight loss up to Day 8
and regained body weight during the second week post-exposure. - Gross pathology:
- Macroscopic post mortem examination of the three males that were found dead during the study
revealed an enlarged heart in one animal, foamy contents of the trachea in another animal and
granulated gray-white contents of the trachea in all three animals. No abnormalities were noted
for the surviving animals. - Interpretation of results:
- GHS criteria not met
- Conclusions:
- The inhalatory LC50, 4h value of Calcium bis (4-{[ (1S, 3R)-1-(biphenyl-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate) in Wistar rats was established to exceed 5 mg/L.
Based on these results and according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS), United Nations, New York and Geneva (2011) (including all amendments), Calcium bis (4-{[ (1S, 3R)-1-(biphenyl-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate) should be classified in Category 5 for acute toxicity by the inhalation route.
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments), Calcium bis (4-{[ (1S, 3R)-1-(biphenyl-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate) does not have to be classified and has no obligatory labelling requirement for inhalation toxicity.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LC0
- Value:
- 5 000 mg/m³ air
Acute toxicity: via dermal route
Link to relevant study records
- Endpoint:
- acute toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Oct 2014 - Apr 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 402 (Acute Dermal Toxicity)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.3 (Acute Toxicity (Dermal))
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.1200 (Acute Dermal Toxicity)
- Qualifier:
- according to guideline
- Guideline:
- other: JMAFF Guidelines (2000)
- GLP compliance:
- yes
- Test type:
- fixed dose procedure
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Rat, Wistar strain, Crl:WI (Han) (outbred, SPF-Quality).
Conditions
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.
Accommodation
Individually housed in labeled Makrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
Acclimatization period was at least 5 days before start of treatment under laboratory conditions.
During the acclimatization period the animals were group housed in Makrolon cages (MIV type, height 18 cm).
Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
Water
Free access to tap water.
Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study. - Type of coverage:
- not specified
- Vehicle:
- water
- Details on dermal exposure:
- One day before exposure (Day -1) an area of approximately 5x7 cm on the back of each animal was clipped.
The formulation was applied on an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for
females. The formulation was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D)*,
successively covered with aluminum foil and Coban elastic bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only. - Duration of exposure:
- Single dosage, on Day 1
- Doses:
- 2000 mg/kg (10 mL/kg) body weight
- No. of animals per sex per dose:
- 5 males and 5 females
- Control animals:
- no
- Details on study design:
- Calcium bis (4-{[ (1S, 3R)-1-(biphenyl-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate) was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice
(Day 15).
The study was carried out based on the guidelines described in:
OECD No.402 (1987) "Acute Dermal Toxicity"
Commission Regulation (EC) No 440/2008, B3: "Acute Toxicity (Dermal)"
EPA, OPPTS 870.1200 (1998), "Acute Dermal Toxicity"
JMAFF Guidelines (2000), including the most recent revisions. - Key result
- Sex:
- male/female
- Effect level:
- > 2 000 mg/kg bw
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Mortality:
- No mortality occurred.
- Clinical signs:
- other: No clinical signs were noted for the animals. White staining was seen on the treated skin-area of all animals on Days 2 and/or 3. Additionally, scales were noted for one animal between Days 4 and 7.
- Gross pathology:
- No abnormalities were found at macroscopic post mortem examination of the animals.
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The dermal LD50 value of Calcium bis (4-{[ (1S, 3R)-1-(biphenyl-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate) in Wistar rats was established to exceed 2000 mg/kg body weight.
Based on these results, Calcium bis (4-{[ (1S, 3R)-1-(biphenyl-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate) does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments).
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- LD0
- Value:
- 2 000 mg/kg bw
Additional information
Justification for classification or non-classification
Single dose oral toxicity studies in mice and rats revealed NOELs of 2000 mg/kg in both species. In single dose intraperitoneal studies in mice and rats, a NOEL of 300 mg/kg was reported in mice but a NOEL was not identified in rats. The dermal LD50 value of AHU 377 in Wistar rats was established to exceed 2000 mg/kg body weight. The inhalatory LC50, 4h value of AHU 377 in Wistar rats was established to exceed 5 mg/L.
Based on these results and according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments), AHU 377 does not have to be classified and has no obligatory labelling requirement for acute toxicity by the oral, dermal or inhalation routes.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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.