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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

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:
1990
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:
1985
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:
1985
Bibliographic source:
NTIS PB86-108172; TER84110
Reference Type:
publication
Title:
Unnamed
Year:
1998
Reference Type:
secondary source
Title:
The developmental toxicity of orally administered theophylline in rats and mice.
Author:
Lindstroem, P.
Year:
1990
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:
1985
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:
1985
Bibliographic source:
NTIS PB86-108172; TER84110; cited in: OECD SIDS for CAS-No. 58-55-9, 2004
Reference Type:
secondary source
Title:
Unnamed
Year:
1998
Reference Type:
secondary source
Title:
Developmental toxicity of theophylline (THEO) in mice and rats.
Author:
George, J.D.
Year:
1986
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

Constituent 1
Chemical structure
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

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