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EC number: 214-122-9 | CAS number: 1087-21-4
- 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
Link to relevant study records
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 24 April to 07 May 2003
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- ANALOGUE APPROACH JUSTIFICATION
Please refer to attached document. - Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- not specified
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Sprague-Dawley Crl:CD (SD) IGS BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Commercial laboratory animal supplier.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: (P) Males: 308 - 366g; Females: 196 - 234g;
- Fasting period before study: No
- Housing: Polypropylene cages with stell grid floors and tops, suspended over paper-lined polypropylene trays.
- Diet: Rodent pellets ad libitum
- Water: ad libitum
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2°C
- Humidity (%): 55 ± 15%
- Air changes (per hr): 15
- Photoperiod: 12 hrs dark / 12 hrs light - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): once
VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: No data
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required):
- Purity: - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation:
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 / day 1 no data of pregnancy - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The standard and sample solutions were analysed by HPLC using the following conditions;
HPLC; Agilent technologies 1050 or 1100, incorporating autosampler and workstation
Column; Prodigy ODS (250 x 4.6 mm id)
Mobile phase; acetonitrile:water (75:25 v/v)
Flow-rate; 1.0 ml/min
UV detector wavelength; 223 nm
Injection volume; 25 µl
Retention time; ~5.6 min - Duration of treatment / exposure:
- 14 days pre coitus
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 16.7 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily in the week and once daily during weekends and public holidays.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily, immediately before dosing, immediately after dosing and one hour after dosing for clinical signs of toxicity.
BODY WEIGHT: Yes
- Time schedule for examinations: During maturation and mating weighed weekly. Following mating weighed weekly until termination. Parental females showing evidence of mating weighed on days 0, 7, 14 and 20 post coitum. Parental generation females with a live litter were weighed on days 1 and 4 post partum.
- Oestrous cyclicity (parental animals):
- No data
- Sperm parameters (parental animals):
- No data
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
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 and internal abnormalities; - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals killed on day 5 post partum
- Maternal animals: All surviving animals killed on day 5 post partum
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
All main organs were prepared for microscopic examination and weighed - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 5 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.
HISTOPATHOLOGY / ORGAN WEIGTHS
All main tissues were prepared for microscopic examination and weighed, respectively. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- All animals showed increased salivation immediately post dose at 150 mg/kg/day
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- At 150 mg/kg/day there were 3 mortalities
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 150 mg/kg/day there was a slight reduction in bodyweight gain.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- gross pathology
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 150 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- > 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects seen clinically or histopathologically.
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- The F1 generation displayed no treatment-related effects on growth or development. No macroscopic abnormalities were seen at terminal necropsy.
The P0 parent showed dose-related effects to their livers; periportal hepatocyte necrosis, enlargement and basophilia, bile duct proliferation and periportal fibrosis.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Based on two oral studies in rats no treatment-related effects were recorded on fertility, offspring viability, growth or development . The oraldoses across the two studies ranged from 16.7 to 250 mg/kg/day. In one study (Knox and Brooks) the dose of 150 mg/kg/day induced severe effects in females probably due to dystocia. However, this was not repeated at the same dose in the other study (Saillenfait et al) and only recorded for two females exposed at 200 mg/kg/day. Maternal weight gain and food consumption were significantly reduced at and above 200 mg/kg/day.
There was no significant increase in the incidence of resorptions, or malformations, at any dose in either of the two studies. In the
Saillenfait et al study fetal body weight was significantly reduced at and above 200 mg/kg/day but significant effects on skeletal development were only recorded at 250 mg/kg/day. Thus, DAP caused fetal toxicity at doses which also produced maternal effects (> 150 mg DAP/kg/day), but which did not affect fertility or induce significant embryo-lethality or teratogenicity.
The Safepharm study showed that the F1 generation displayed no treatment-related effects on growth or development. No macroscopic abnormalities were seen at terminal necropsy. The P0 parent showed dose-related effects to their livers; periportal hepatocyte necrosis, enlargement and basophilia, bile duct proliferation and periportal fibrosis.
Short description of key information:
The key information is based on the results of a guideline study
performed under GLP in 2003 and a study published in 2008 (see the
section of Developmental Toxicity). The study method used concerns a
reproduction/developmental toxicity screening test [OECD TG 421] with
parental exposure prior to mating until 1 to 4 days post partum.
Endpoints related parameters examined include histopathological changes
in the reproductive organs of parental animals as well as offspring
viability, growth and development.
Effects on developmental toxicity
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2008
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Justification for type of information:
- ANALOGUE APPROACH JUSTIFICATION
Please refer to attached document. - Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Commercial laboratory animal supplier
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing: clear polycarbonate cages with stainless steel wire lids and corn cob granules for bedding.
- Diet; food pellets ad libitum
- Water; ad libitum
- Acclimation period: 1-2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2°C
- Humidity (%): 50 ± 5%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12h light-dark photocycle
IN-LIFE DATES: From: To: - Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food: ambient
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation:
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: - Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Based on study in 2004 giving LD50 of 891 mg/kg in males and 656 mg/kg in females
- Rationale for animal assignment (if not random):
- Other: - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Maternal bodyweights, first weight after GD=0 was GD = 6. After that every 3 days until GD = 21.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: uterus, uterine contents, ovaries, fetuses,
OTHER: - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: - Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes:
- Head examinations: No data - Statistics:
- Whenever possible, the data were presented as mean +/- SD. The number of corpora lutea, implantaion sites and live foetuses, and various body weights were analysed by one-way analysis of variance, followed by Dunnett's test if differences were found. The frequency of post-implantation loss, dead foetuses, resorptions and alterations among litterswas evaluated by using Kruskal-Wallis test followed by the Mann-Whitney test where appropriate. Rates of pregnancy and of litters with dead foetuses or resorptions and incidences of foetal alterations per dose were analysed by using Fishers's test. Where applicable, least-squares analysis was caried out. The reported level of statitsical significance was p < 0.05. The litter was used as the basis for the analysis of foetal variables.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Macroscopic changes in the liver. This mainly consisted of a pale and mottled organ.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- one dam from the 250 mg/kg dose group was found dead on GD 21. No obvious cause for death was established.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduced body weight gain.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Foetal skeletal variations and delayed ossification in fore and hinf limbs and caudal vertebra centra.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- Macroscopic changes were noted in most of the dams at 150 mg/kg dose and higher.
- Key result
- Dose descriptor:
- dose level:
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- necropsy findings
- Remarks on result:
- other: Liver pale and mottled.
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other:
- Description (incidence and severity):
- Liver pale and mottled.
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, treatment-related
- Visceral malformations:
- effects observed, treatment-related
- Key result
- Dose descriptor:
- dose level:
- Effect level:
- 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Reduced foetal body weight.
- Remarks on result:
- other: Dose related
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: skull
- skeletal: forelimb
- skeletal: sternum
- skeletal: rib
- skeletal: vertebra
- skeletal: hindlimb
- Description (incidence and severity):
- Significantly delayed ossification at 250 mg/kg/day as evidenced by the reduced numbers of osified phalanged in fore and hind limbs, metatarsals in hindlimbs and caudal vertebral centra.
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 200 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- not specified
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- At 150 mg/kg/day, maternal response to treatment was indicated by macroscopic changes in the liver.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 50 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Klimisch 1
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
The studies were carried out on DAP, a closely related structural analogue to DAIP. The classification system for reproductive toxicity is subdivided in adverse effects on sexual function and fertility and adverse effects on development of the offspring. The key information provided here indicates that sexual function and fertility are not affected by oral DAP and therefore DAIP, exposure at doses that induce parental and foetal toxicity. Although, there are indications that the gestation period might be delayed at lower dose levels, these proved not to be consistent or reproducible. Further, these were recorded at a dose that also induced histopathological changes in the liver. Developmental toxicity concerned mainly fetal body weight and only minimal differences in skeletal variations and malformations. Also these were only recorded at dose levels, which also affected maternal body weight
Classification was not considered, because only minor effects were recorded in skeletal examinations, and foetal weights were affected at dose levels that also affected maternal body weights.
Additional information
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.