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EC number: 200-385-7 | CAS number: 58-55-9
- 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
Developmental toxicity / teratogenicity
Administrative data
- 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 procedure according to national standards.
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- The developmental toxicity of orally administered theophylline in rats and mice.
- Author:
- Lindstroem, P.
- Year:
- 1 990
- Bibliographic source:
- Fund. Appl. Toxicol. 14, 167-178
- Reference Type:
- publication
- Title:
- Teratologic Evaluation of Theophylline (CAS No. 58-55-9) administered to CD (R) Rats on Gestational Days 6 through 15, Final Study Report
- Author:
- George, J.D.
- Year:
- 1 985
- Bibliographic source:
- NTP-85-194, PB86-108172
- Reference Type:
- publication
- Title:
- Teratologic Evaluation of Theophylline (CAS No.58-55-9): Administered to CD (R) Rats on Gestational Days 6 Through 15, Final Report.
- Author:
- NTP
- Year:
- 1 985
- Bibliographic source:
- NTIS PB86-108172; TER84110
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 998
- Reference Type:
- secondary source
- Title:
- The developmental toxicity of orally administered theophylline in rats and mice.
- Author:
- Lindstroem, P.
- Year:
- 1 990
- Bibliographic source:
- Fund. Appl. Toxicol. 14, 167-178; cited in: OECD SIDS for CAS-No. 58-55-9, 2004
- Reference Type:
- secondary source
- Title:
- Teratologic Evaluation of Theophylline (CAS No. 58-55-9) administered to CD (R) Rats on Gestational Days 6 through 15, Final Study Report
- Author:
- George, J.D.
- Year:
- 1 985
- Bibliographic source:
- NTP-85-194, PB86-108172; cited in: OECD SIDS for CAS-No. 58-55-9, 2004.
- Reference Type:
- secondary source
- Title:
- Teratologic Evaluation of Theophylline (CAS No.58-55-9): Administered to CD (R) Rats on Gestational Days 6 Through 15, Final Report.
- Author:
- NTP
- Year:
- 1 985
- Bibliographic source:
- NTIS PB86-108172; TER84110; cited in: OECD SIDS for CAS-No. 58-55-9, 2004
- Reference Type:
- secondary source
- Title:
- Unnamed
- Year:
- 1 998
- Reference Type:
- secondary source
- Title:
- Developmental toxicity of theophylline (THEO) in mice and rats.
- Author:
- George, J.D.
- Year:
- 1 986
- Bibliographic source:
- Teratology 33, 70C-71C, cited in: NTP Tech. Rep. No. 473 (1998), PB99-113342
Materials and methods
- Principles of method if other than guideline:
- Standard method of the National Toxicology Program (NTP) without recovery period.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Theophylline
- EC Number:
- 200-385-7
- EC Name:
- Theophylline
- Cas Number:
- 58-55-9
- Molecular formula:
- C7H8N4O2
- IUPAC Name:
- 1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
- Details on test material:
- - Name of test material (as cited in study report): theophylline;
- Analytical purity: >99%
- Lot/batch No.: 484
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc, Kingston, NY;
- Weight at study initiation: 207 - 275 g on gestation day 0 (day of vaginal sperm);
- Housing: Sperm-positive females were housed two to four per cage.
- Diet (e.g. ad libitum): Purina Certified Rodent Chow, St. Louis, MO;
- Water (e.g. ad libitum): deionized/foltered water, ad libitum;
- Acclimation period: 7 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.3 - 22.8 °F;
- Humidity (%): 43 - 81 %;
- Photoperiod (hrs dark / hrs light): 12h/12h.
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Mixing appropriate amounts with (Type of food): groung rodent chow (Purina Certified Rodent Chow (5002) Ralston Purina Co., St. Louis, MO. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Aliquots were analyzed by UV spectroscopy prior to administration to verify the concentration and following the dosing peroid to confirm stability.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 : 1;
- Length of cohabitation: overnight;
- Proof of pregnancy: sperm in vaginal smear, referred to as day 0 of pregnancy. - Duration of treatment / exposure:
- days 6 to 15 of gestation
- Frequency of treatment:
- continuously in the diet
- Duration of test:
- On gestation day 20, the animals were sacrificed.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
ca. 124, 218, 259 mg/kg bw/d (0.15, 0.30, 0.40% in the diet)
Basis:
nominal in diet
- No. of animals per sex per dose:
- 27 - 29 females per dose in total; 20 - 21 pregnant females per dose;
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: Doses were selected based on preliminary studies using timed-mated rats (George et al., 1985). Dosed feed was used for the rat study because 0.40% Theophylline in the drinking water (in the pilot study) resulted in a slight precipitate and was unpalatable to the animals. Consequently, the animals were not exposed to theophylline over a large enough range of doses to allow an effective evaluation of toxicity . The high dose was expected to produce maternal and/or fetal toxicity without causing maternal death or significant reduction in food or water consumption. The middle dose was expected to cause minimal but still detectable maternal and/or fetal toxicity. The low dose was expected to cause no detectable maternal and/or fetal toxicity.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data;
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no data;
BODY WEIGHT: Yes
- Time schedule for examinations: Weighing was performed on gestation day 0, 6 through 15, 18, and 20.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption was determined by weighing the feed jars on gestation days 0, 3, 6, 9, 12, 15, 18, and 20.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: liver weight, gravid uterine weight, and uterine contents (i .e., number of implantation sites, resorptions, dead fetuses, live fetuses) were evaluated and weights recorded. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes;
Examinations included:
- Gravid uterus weight: Yes;
- Number of implantations: Yes;
- Number of resorptions: Yes.
The uteri of dams with no apparent implants were evaluated with a solution of l0% ammonium sulfide in order to visualize implantation sites that may have undergone very early resorption (Salewski, 1964). - Fetal examinations:
- Live fetuses were dissected from the uterus, weighed, sexed, and examined for gross morphological abnormalities. All live fetuses were examined for visceral malformations using a fresh tissue dissection method (Staples, 1974, Teratology 9, A37; Stuckhardt and Poppe, 1984, Teratog. Carcinog. Mutagen. 4, 181-188).
Half of the fetuses were decapitated prior to dissection and the heads were fixed in Bouin's solution for free-hand sectioning and examination (Wilson, 1965, In Teratology: Principles and Techniques (J . G . Wilson and J . Warkany, Eds .), pp. 251-277. Univ, of Chicago Press, Chicago).
All fetal carcasses were prepared with Alcian blue/Alizarin Red S stain and examined for skeletal malformations (Marr et al., 1988) .
- External examinations: Yes;
- Soft tissue examinations: Yes;
- Skeletal examinations: Yes;
- Head examinations: Yes. - Statistics:
- Statistical analysis. Analysis of data was carried out by the general linear model procedures as described by Morrissey et al. (1987). Dose-response relationships for selected measures were evaluated with a test for linear trend. Analysis of variance (ANOVA) was used to determine whether significant dose effects or dose X replicate interactions had occurred. When ANOVA revealed significant differences among groups, Williams' and/or Dunnett's multiple comparison test (Williams, 1971, 1972; Dunnett, 1955, 1964) were used to compare THEO-exposed groups to vehicle control groups (a level = 0.05). Nominal scale measures were analyzed by the χ2-Test (test for independence for differences among treatment groups and a test for linear trend on proportions. When χ2 revealed significant (p < 0 .05) differences among groups, then a one-tailed Fisher's exact test was used for pairwise comparisons between each Theophylline treated group and the vehicle control group.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
There was no maternal mortality. The primary clinical signs in all treatment groups included piloerection, transitory weight loss, and rough coat, which were observed more frequently in the two higher treatment groups in comparison to the control groups throughout most of the treatment period.
Maternal body weight gain during gestation (day 0 through day 20), and treatment (day 6 through day 15), as well as corrected maternal weight gain (maternal weight gain during gestation corrected for gravid uterine weight) decreased in the high dose group (19.5; 53.3; 22.4 %) in a dose dependent manner and exhibited significant differences among treatment groups with the high dose group significantly (p < 0.05) being below controls. Additionally, gravid uterine weight and absolute maternal liver weight showed a decreasing trend with an increasing theophilline concentration in the feed; there were, however, no differences between controls and any single treatment group. Relative maternal liver weight (i .e., percentage body weight) was unaffected by treatment.
During treatment and during the entire gestation period maternal food consumption (g/kg/day) decreased in a dose related manner and was significantly below controls in both the 0.3 % and 0.4 % dose groups during treatment, and in the 0.4 % dose group for the entire gestation period. Maternal water consumption during treatment (g/day or g/kg/day) increased in a dose related manner up to 15% during gestation and up to 26% during treatment, with all theophilline treated groups significantly above controls.
In summary, theophylline administered continuously in the feed to timed pregnant CD rats from gestation day 6 through 15 at levels of 0 %, 0.15 %, 0.3 % or 0.4 % produced at the high dose level a decrease in maternal body weight and maternal body weight gain and decreased maternal food consumption.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 124 mg/kg bw/day
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
There were no differences among treatment groups in the number of corpora lutea or implantation sites per dam, or in the percent preimplantation loss. Theophylline treatment had no effect on the percent of dead fetuses per litter, or on the percent of litters with one or more resorptions, dead fetuses, nonliving implants (i.e. resorptions and dead fetuses), or adversely affected implants (i.e. resorptions, dead fetuses and malformed live fetuses), or on the percent of resorptions, dead fetuses, nonliving implants, or adversely affected implants per litter.
Theophylline treatment resulted in a significant decrease in live fetuses per litter in the high dose group (12) compared to the control (13.8). Average fetal body weight per litter (male, female, and combined) decreased in a dose- related manner, an effect significant for the mid (9%) and high dose (up to 15%) group.
Theophylline administered continuously from gestation day 6 to 15 had no effect on the percent of live fetuses malformed per litter or the percent of live male or female fetuses malformed per litter.
Malformed fetuses per litter occurred with an incidence of 1.38%, 0.92%, 0.33%, and 1.57% for the vehicle control, low, medium, and high dose groups, respectively.
The incidence of litters with one or more malformed live fetuses (1.4%, 0.9%, 0.3%, and 1.6% in the control, low, mid, and high dose group, respectively) as well as with one or more external, skeletal, or visceral malformations was unaffected by treatment.
In summary, theophylline administered continuously in the feed to timed pregnant CD rats from gestation day 6 through 15 at levels of 0 %, 0.15 %, 0.3 % or 0.4 % had no effect on the percent of resorptions, nonlive implants, adversely affected implants or malfomations per litter. However, theophylline exposure resulted in significant dose-related fetotoxicity as evidenced by decreased average fetal body weight per litter at dose levels of 0.3 and 0 .4% and reduced number of live fetuses per litter at the high dose.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 124 mg/kg bw/day
- Basis for effect level:
- other: fetotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 259 mg/kg bw/day
- Basis for effect level:
- other: teratogenicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
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