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EC number: 201-494-2 | CAS number: 83-67-0
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 20 April 1982- 27 September 1984
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
- Remarks:
- Test method according reproductive assessment by continuous breeding (NTP). GLP study. General lack of information on method.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 997
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- other: National Toxicology Program U.S. Reproductive Assessment by Continuous Breeding
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Theobromine
- EC Number:
- 201-494-2
- EC Name:
- Theobromine
- Cas Number:
- 83-67-0
- Molecular formula:
- C7H8N4O2
- IUPAC Name:
- theobromine
- Details on test material:
- - Name of test material (as cited in study report): Theobromine
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- other: CD-1 (ICR)BR outbred albino
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 120 days mininum.
- Frequency of treatment:
- Daily with feed.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 126 mg/kg bw/day (nominal)
- Dose / conc.:
- 335 mg/kg bw/day (nominal)
- Dose / conc.:
- 630 mg/kg bw/day (nominal)
Examinations
- Parental animals: Observations and examinations:
- DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
WATER CONSUMPTION AND COMPOUND INTAKE: Yes
POST-MORTEM EXAMINATIONS: Yes. Organs examined: kidney weight, liver weight
OTHER: Estrous cycle length, absolute testis, epididymis weight, sex accessory gland weight (prostate, seminal vesicle), epidid. sperm parameters (motility, morphology), determination of affected sex (crossover), hormonal analyses (luternizing hormones, follicle stimulating hormones, prolactin, progesteron, estrogen and testosterone. - Sperm parameters (parental animals):
- Parameters examined in all male parental generations: absolute testis, epididymis weight, sex accessory gland weight (prostate, seminal vesicle), epididymis sperm parameters (motility, morphology)
- Litter observations:
- PARAMETERS EXAMINED: The following parameters were examined in F1 and F2 offspring: litters/pair, live pups/litter, pup wt./litter, cumulative days to litter
GROSS EXAMINATION OF DEAD PUPS :no - Postmortem examinations (parental animals):
- SACRIFICEAfter the delivery and analysis of these litters, the first-generation control and high dose animals were killed and necropsied.
- Reproductive indices:
- Reproductive indices were adversely affected by theobromine exposure. The mean number of litters per pair was decreased at the high dose level by 19%.
- Offspring viability indices:
- Live pups per litter dropped by 15% for the low dose, 21% for the medium dose, and 66% for the high dose mice. Additionally, the proportion born alive was reduced by 5 and 35% at the middle and high dose groups, respectively, and pup weight adjusted for litter size was reduced at all dose levels by 4, 13, and 27%, for the low, medium, and high doses.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- 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 examined
- 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:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Reproductive performance:
- no effects observed
Details on results (P0)
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): no alteration
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): no alteration
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): Absolute testis weight decreased by 12% at the high dose. Although epididymal sperm density and motility did not differ between the control and 0.5% theobromine groups, the treated animals had approximately 4-fold more abnormally shaped sperm.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): it clearly reduced female reproductive capability: there was a 74% reduction in the number of live pups delivered of treated females mated to control males, the proportion of those pups born alive was reduced by 50%, and the weight of those pups adjusted for litter size was reduced by 28%.
ORGAN WEIGHTS (PARENTAL ANIMALS): adjusted liver weights increased for both sexes at the high dose by 12% for males and 9% for females.
OTHER FINDINGS (PARENTAL ANIMALS). Hormonal analysis: No differences were seen between the treated and control mice in the levels of luternizing hormones, follicle stimulating hormones, prolactin, progesterone, estrogen, and testosterone.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Reproductive toxicity
- Effect level:
- <= 126 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive function (sperm measures)
- reproductive performance
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- General toxicity
- Effect level:
- < 630 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
Target system / organ toxicity (P0)
open allclose all
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 630 mg/kg bw/day (nominal)
- System:
- male reproductive system
- Organ:
- testes
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 630 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- one control, two middle dose, and one high dose. The variety of postmortem findings and the lack of relationship to dose led to the conclusion that these deaths were not treatment related.
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- 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 specified
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Other effects:
- not examined
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- general toxicity
- Generation:
- F1
- Effect level:
- >= 630 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- Dose descriptor:
- NOAEL
- Remarks:
- toxicity to reproduction
- Generation:
- F1
- Effect level:
- >= 630 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 126 mg/kg bw/day (nominal)
- 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
Any other information on results incl. tables
Tables of results. Summary: NTP Reproductive Assessment by Continuous Breeding Study (theobromine):
Dose concentration |
0.10% |
0.25% |
0.5% |
F0 generation |
|||
General toxicity |
Male, female |
Male, female |
Male, female |
Body weight |
No change, No change |
No change, No change |
No change, No change |
Kidney weight |
No observation |
No observation |
No observation |
Liver weight |
No observation |
No observation |
Statistically significant change (p<0.05), Statistically significant change (p<0.05) |
Mortality |
No change, No change |
No change, No change |
No change, No change |
Feed consumption |
No change, No change |
No change, No change |
No change, No change |
Water consumption |
No observation |
No observation |
No observation |
Clinical signs |
No change, No change |
No change, No change |
No change, No change |
Reproductive toxicity |
|||
Litters/pair |
No change |
No change |
Statistically significant change (p<0.05) |
# Live pups/litter; pup wt./litter |
Statistically significant change (p<0.05), Statistically significant change (p<0.05) |
Statistically significant change (p<0.05), Statistically significant change (p<0.05) |
Statistically significant change (p<0.05), Statistically significant change (p<0.05) |
Cumulative days to litter |
Statistically significant change (p<0.05) |
Statistically significant change (p<0.05) |
Statistically significant change (p<0.05) |
Absolute testis, epididymis weight |
No observation |
No observation |
Statistically significant change (p<0.05), No change |
Sex accessory gland weight (prostate, seminal vesicle) |
No observation |
No observation |
No change, No change |
Epidid. sperm parameters (#, motility, morphology) |
No observation |
No observation |
No change, No change, Statistically significant change (p<0.05) |
Estrous cycle length |
No observation |
No observation |
No observation |
Determination of affected sex (crossover) |
Male |
Female |
Both |
Dose level |
No observation |
0.5% |
No observation |
Dose concentration |
No observation |
No observation |
No observation |
F0 generation |
|||
General toxicity |
Male, female |
Male, female |
Male, female |
Body weight |
No observation |
No observation |
No observation |
Kidney weight |
No observation |
No observation |
No observation |
Liver weight |
No observation |
No observation |
No observation |
Mortality |
No observation |
No observation |
No observation |
Feed consumption |
No observation |
No observation |
No observation |
Water consumption |
No observation |
No observation |
No observation |
Clinical signs |
No observation |
No observation |
No observation |
Reproductive toxicity |
|||
Litters/pair |
No observation |
No observation |
No observation |
# Live pups/litter; pup wt./litter |
No observation |
No observation |
No observation |
Cumulative days to litter |
No observation |
No observation |
No observation |
Absolute testis, epididymis weight |
No observation |
No observation |
No observation |
Sex accessory gland weight (prostate, seminal vesicle) |
No observation |
No observation |
No observation |
Epidid. sperm parameters (#, motility, morphology) |
No observation |
No observation |
No observation |
Estrous cycle length |
No observation |
No observation |
No observation |
Summary information |
|
Affected sex? |
Female |
Study confounders: |
None |
NOAEL reproductive toxicity: |
≤ 0.10% |
NOAEL general toxicity: |
< 0.5% |
F1 more sensitive than F0? |
Unclear |
Postnatal toxicity: |
Unknown |
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for reproductive toxicity was ≤ 0.10% (126 mg/kg bw) and the NOAEL general toxicity was <0.5% (630 mg/kg bw).
- Executive summary:
A Toxicity to Reproduction study was performed with theobromine according to NTP reproductive assessment by continuous breeding method, which is similar to OECD Guideline 416. Data on food and water consumptions, body weights, and clinical signs from the dose-range-finding study were used to set exposure concentrations for the continuous cohabitation phase (126, 335 and 630 mg/kg/day). In the main test, four females died, these deaths were not treatment related. Reproductive indices were adversely affected by theobromine exposure. The mean number of litters per pair was decreased at the high dose level by 19%. Live pups per litter dropped by 15% for the low dose, 21% for the medium dose, and 66% for the high dose mice. Additionally, the proportion born alive was reduced by 5 and 35% at the middle and high dose groups, respectively, and pup weight adjusted for litter size was reduced at all dose levels by 4, 13, and 27%, for the low, medium, and high doses. The mean study day on which each group delivered each litter was increased in all dosed groups. This delay ranged up to 9 days. In the high dose females, significant lengthening was seen even at the first litter. While theobromine consumption did not affect the percent of mice mating or delivering a litter, it clearly reduced female reproductive capability: there was a 74% reduction in the number of live pups delivered of treated females mated to control males, the proportion of those pups born alive was reduced by 50%, and the weight of those pups adjusted for litter size was reduced by 28%. After the delivery and analysis of these litters, the first-generation control and high dose animals were killed and necropsied. While terminal body weights were unchanged, adjusted liver weights increased for both sexes at the high dose by 12% for males and 9% for females. Absolute testis weight decreased by 12% at the high dose. Although epididymal sperm density and motility did not differ between the control and 0.5% theobromine groups, the treated animals had approximately 4-fold more abnormally shaped sperm. At the time of necropsy, blood was taken for hormonal analysis. No differences were seen between the treated and control mice in the parameters checked. In summary, there was evidence that theobromine is a possible a reproductive toxicant (producing fewer live pups per litter and reducing pup weight) at exposure levels that did not affect body weight or mortality, with the female being more sensitive than the male. The NOAEL reproductive toxicity was ≤ 0.10% (126 mg/kg bw) and the NOAEL general toxicity was 0.5 %. (630 mg/kg bw).
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