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Developmental toxicity / teratogenicity

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developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP Guideline Study (according to the former OECD 414 - exposure time from gd6-20) performed with melamine

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Physical state: solid (powder), white
- Analytical purity: about 100% (method: potentiographic titration)
- Stability under test conditions: Stability over the study period was proven by reanalyses (method: potentiographic titration and infra-red spectroscopy)
- Storage condition of test material: room temperature
- Purity test date: November 1994

Test animals

Details on test animals or test system and environmental conditions:
- Source: Dr. K. THOMAE GmbH, Biberach an der Riss, FRG
- Age at study initiation:
- Weight at study initiation:
- Housing: Single caging in type DK III stainless steel wire mesh cages supplied by BECKER & CO., Castrop-Rauxel, FRG (floor area about 800 square cm). The cages were arranged on the racks in such a way that uniform experimental conditions (ventilation and light) were ensured.
- Diet (ad libitum): ground Kliba maintenance diet rat/mouse/hamster, 343 meal, supplied by KLINGENTALMÜHLE AG, Kaiseraugst, Switzerland
- Water (ad libitum): drinking water of tap water quality from water bottles.
- Acclimation period:

- Temperature (°C): 20 - 24 ° C.
- Humidity (%): 30 - 70 %, relative
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light.

IN-LIFE DATES: From: 21 November 1994 To: 15 December 1994

Administration / exposure

Route of administration:
oral: feed
unchanged (no vehicle)
Details on exposure:
- Rate of preparation of diet (frequency): no data.
- Mixing appropriate amounts with (Type of food): ground Kliba maintenance diet rat/mouse/hamster, 343 meal, supplied by KLINGENTALMÜHLE AG, Kaiseraugst, Switzerland.
- Storage temperature of food: no data.

Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Analyses of the stability of MELAMINE in the diet up to 32 days at room temperature (and additional 4 days in which the mixture was suspended in water prior to analysis) were carried out before the start of this study. The homogeneity and the correctness of the concentrations of the test substance in the maintenance diet were analytically investigated at the beginning of this study.
Details on mating procedure:
- Mating procedure: cohoused.
- If cohoused:
- M/F ratio per cage: 1:2.
- Length of cohabitation: from 4.00 p.m. to about 7.30 a.m. on the following day.
- Further matings after two unsuccessful attempts: no data.
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy.
- Any other deviations from standard protocol: no data.
Duration of treatment / exposure:
during post coitum Days 6 - 16 (= 11 days)
Frequency of treatment:
Duration of test:
until day 20 post coitum
No. of animals per sex per dose:
Control animals:
yes, concurrent no treatment
Details on study design:
Sex: female
Duration of test: until Day 20 post coitum
- Dose selection rationale: The selection of doses for the present prenatal toxicity study was based on the overall results of 10 feeding studies (Melamine, "BUA-Stoffbericht 105", from June 1992) performed with non pregnant rats . The 40 dosages administered in these studies ranged from 100 to 30,000 ppm (6 .7 up to about 2,500 mg/kg body weight/day), the administration periods were between 14 days and two years .
The most relevant studies for dose selection for the present investigation were as follows :
In a 14-day feeding study Fischer-344 rats received doses of 5,000 ; 10,000 ; 20,000 and 30,000 ppm (417 - 2,500 mg/kg body weight/day) . All male and female rats receiving 15,000 ppm and more had mean body weight depressions when compared to the controls or even lost weight . Hard crystalline solids were found in the urinary bladder of most animals fed 10,000 ppm or more . The kidneys of two high dose males were pale and pitted . Apart from the urinary tract, no compound-related effects were observed in the other organs.
In a 4-week study with the same strain of rats and doses of 2,000 ; 4,000 ; 7,000 ; 13,000 ; 16,000 and 19,000 ppm (133 - 1267 mg/kg body weight/day), significant dose-related depression in body weight gain, elevated water intake and altered food pattern were observed . In addition, a dose-dependent incidence of urinary bladder calculi and urinary bladder hyperplasia occurred .
Taking this into consideration, the following doses were chosen with agreement of AGROLINZ Melamin, Agrarchemikalien GmbH, Linz, Austria, for the present full-scale prenatal toxicity study in Wistar rats with MELAMINE :
1,500 ppm: as the expected no observed adverse effect level
4,500 ppm : as the intermediate dose level
15,000 ppm: as the dose level at which some overt signs of maternal toxicity (e .g . impaired food consumption and body weight gains) were expected and adverse effects on the fetuses could not be ruled out.


Maternal examinations:
- Time schedule: at least once per day (more often when clincial signs of toxicity were elicited)
A check on maortality was made twice a day on working days or once a day on Saturdays and Sundays.

- Time schedule for examinations: d 0, 1,3, 6, 8, 10, 13, 15, 17, 20 post coitum (calculation of body weight change from these results)
Furthermore, the corrected body weight gain was calculated after terminal sacrifice (bw on d 20 p.c. minus weight of the unopened uterus minus body weight on day 6 p.c.)
Only pregnant dams were used for the calculations of body weight and body weight change

- Food consumption for each animal determined and mean daily diet consumption calculated as mg food/kg body weight/day: Yes (group weights were dervied from the intakes by the individual animals)
Only pregnant dams were used for the calculations of mean maternal food consumption.

- Sacrifice on gestation day 20
Assessment by gross pathology. Determination of oiver and kiedey weights.

Calculation of conception rate and pre- and postimplantation losses
Conception rate (in %): (number of pregnant animals/number of fertilized animals)*100
Preimplantation loss (in %): ((number of corpora lutea - number of implanatations)/number of corpora lutea)*100
Postimplantation loss (in%): ((number of implantations - number of live fetuses)/number of implanations)*100
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
- Dead fetuses: Yes

Fetal examinations:
- External examinations: Yes: all per litter
Determination of body weight and sex (by distance between the anus and the base of the genital tubercle and was later confirmed by internal examination) and macroscopical examination; Furthermore, the viability of the fetuses and the condition of the placentae, the umbilical cords, the fetal membranes and fluids were examined . Individual placental weights were recorded .
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter

Evaluation criteria for assessing the fetuses:
Malformations concerning external, soft tissue and skeletal observations ): Permanent structural changes, which may adversely affect survival, development or function and/or occur at a low frequency, were classified as malformations (e .g . exencephaly, atresia ani, hernia umbilicalis).

Variations (concerning external, soft tissue and skeletal observations ): Divergences of the morphogenetic/organogenetic process, which occur regularly also in control groups at a relatively high frequency and which may not adversely affect survival, development or function were regarded as variations (e .g . dilated renal pelvis) .

Retardations (concerning skeletal observations only): Transient delays in skeletal development, which may not adversely affect survival, development or function were considered to be retardations (e .g . sternebra(e) not ossified) . Normally, skeletal retardations occur regularly also in control
groups at a relatively high frequency.

Unclassified observations ((concerning external and soft tissue observations, only ): External or soft tissue observations, which could not be classified as malformations or variations (e .g . blood coagulum around placenta) .
The DUNNETT-Test (Dunnett, 1955/1964) was used for a simultaneous comparison of several dose groups with the control . The hypothesis of equal means was tested . This test was performed two-sided and was used for the statistical evaluation of the following parameters :
Food consumption+, body weight, body weight change, corrected body weight gain (net maternal body weight change), weight of the unopened uterus, weight of liver and kidneys, number of corpora lutea, number of implantations, number of resorptions and number of live fetuses ; proportion of preimplantation loss, postimplantation loss, resorptions and live fetuses in each litter ; litter mean fetal body weight and litter mean placental weight .
FISHER's Exact Test (Siegel, - 1956) was used for a pairwise comparison of each dose group with the control for the hypothesis of equal proportions . This test was performed one-sided and was used for female mortality, females pregnant at terminal sacrifice and the number of litters with fetal findings .
The WILCOXON-Test (Nijenhuis and Wilf, 1978 ; 10 Hettmansperger, 1984) was used for a comparison of each dose group with the control for the hypothesis of equal medians . This test was performed one-sided and was used for the proportion of fetuses with malformations, variations, retardations and/or unclassified observations in each litter . If the results of these tests were significant, labels (* for p < 0 .05, ** for p < 0 .01) were printed in the Summary Tables .

Note : For the parameter food consumption the "mean of means" was calculated and can be found in the relevant Summary Tables . The "mean of means" values allow a rough estimation of the total food consumption during the different time intervals (pretreatment, treatment and posttreatment period) ; they are not exactly precise values, because the size of the intervals taken for calculation differs . For the "mean of means" values no statistical analysis was performed .
- Reproduction data of dams
- Sex distribution of fetuses
- Weight of placentae
- Weight of fetuses
- External malformations of the fetuses
- Soft tissue variations
- Malformations of the fetal skeletons
Historical control data:
Yes, but no access to the data in the report.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
FOOD CONSUMPTION (cf. Remarks on results, Table 1)
High dose group:
The mean food consumption in the high dose group (15,000 ppm) was statistically significantly decreased between days 6 and 16 p .c .
In total, the high dose dams consumed about 26 % less food than the dams of the concurrent control group during this interval .
After cessation of the test substance administration, however, the food consumption of the high dose females exceeded that of the control dams (in total about 10%) .
According to the study report the distinct reductions in food consumption during the period of major organogenesis have to be related to the test substance administration and are in line with the impairments in body weight gain at this dose level.
Mid and low dose:
The food consumption of these dams (1,500 or 4,500 ppm) was similar to the food intake of the concurrent controls during pretreatment, treatment and posttreatment periods ;
According to the study report all observable differences between these groups are without biological relevance .

Amount of test substance consumed by animals between day 6-16 p.c (group mean values):
Low dose: 135.5 mg/kg bw/day; Mid dose: 398.7 mg/kg bw/day; High dose: 1057.3 mg/kg bw/day

BODY WEIGHT (cf. Remarks on results, Table 2 and 3)
High dose group:
The impairments in food consumption at the high dose level during the administration period coincided with statistically significantly lower mean maternal body weights (up to 10%) during most parts of the treatment period and on day 17 p .c . in comparison to the concurrent control group .
(Days 6-10: clear body weight loss; days 10-15: reductions in body weight gain). After cessation of the test substance administration, these animals gained distinctly more weight than the concurrent controls.
In total, the high dose dams gained about 77% less weight than the controls between days 6 - 15 p .c ., but about 22% more weight than the controls between days 15 - 20 p .c .
Mid and low dose group:
There were no statistically significant or biologically relevant differences between the controls and the low and mid dose dams concerning mean body weights . According to the study report the observable differences are without biological relevance.

CORRECTED BODY WEIGHT GAIN (cf. Remarks on results, Table 4)
High dose group:
The dams showed a statistically significantly lower carcass weight and a distinctly lower net weight change (53 % lower than the respective control value) ; thus, at the end of the study and after several days without administration of the test substance clear signs of maternal toxicity are present .
Mid and low dose group:
No statistically significant/biologically relevant differences if compared to the controls .

High dose group:
In 23/25 dams hematuria occured between days 8 and 17 p.c.. According to the study report this is a well known effect of melamine.
In 7/25 animals indrawn flanks were recoreded between days 8 and 16 p.c. 1/25 dams showed piloerection on days 5-25 p.c.
Mid and low dose group:
No abnormal findings were recorded

Not influenced by the administration of the test substance. According to the study report, the differences between the groups and the control group were without biological relevance and did not show any relation to dosing.

The conception rate varied between 92% (control, mid and high dose group) and 96% (low dose group).
No substance related and/or biologically relevant differences between groups in the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions and viable fetuses (the statistically significant increase in the mean number of late resorptions in the high dose groups was cnsidered to be spontaneous in nature, as at this dose level the mean number of live fetuses/dam was hightest.)

Absolute and relative liver and kidney weights were not influenced by the test substance.
There were no substance-related observations at necropsy in any of the dams.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
ca. 400 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The sex distribution of the fetuses in the test groups was comparable with the control fetuses. According to the study report the differences observed in comparison to the control are without any biological relevance.

WEIGHT OF PLACENTAE (cf. Remarks on results, Table 5)
High dose groups:
Weights were statistically significantly decreased (about 7% less than the control).
However, the respective values are fully within the historical control range and the values from the concurrent control group are lower than the values of the mid and the low dose. Therefore this is not considered to represent a substance related effect.
Furthermore, the highest mean number of live fetuses occurred at 15,000 ppm ; this might be a possible explanation for the observed decrease in
placental weights at this dose level .
Mid and low dose:
There were no statistically significant differences in the placental weights between the controls and test groups

Weights were not influenced by the test substance administration and were similar to the control values.

No external variation in any group.
(There were 2 external malformations (1 fetus with anasarca and 2 fetuses with cleft palate) which occured in 3 low dose fetuses. These malformations were considered random because they are not dose-related and can be also found at a low frequency in the historical control data:
Unclassified observations were recorded for 1 control fetus, 7 low dose retuses and 3 hight dose fetuses. These findings were considered to be spontaneous in nature because they appeared without clear dose-response relationship)

The examination of the organs of the fetuses revealed several malformations (cardiomegaly and hyperplasia of liver and/or kidneys) in one low dose litter. These findings were assessed to be spontaneous in nature and not related to substance treatment.
Soft tissue variations (dilated renal plevis and/or hydroureter) were detected in all groups including the controls. Both variations occured without statistically significant and biologically relevant differences between groups and are very common in the rat strain used.
No unclassified observations were recorded.

SKELETAL EXAMINATION (cf. Remarks on results, Table 6)
Malformations of the fetal skeletons:
High dose group: 10/158 fetuses (6.3%); 10/23 litters (43%);
Mid dose group: 6/149 fetuses (4.0%); 5/23 litters (22%);
Low dose group: 8/148 fetuses (5.4%); 7/24 litters (29%);
Control group: 6/153 fetuses (3.9%); 5/23 litters (22%);
Compared to the concurrent control group or the historical control values all malformations except the finding "Sternebrae bipartite, ossification centers dislocated" occured without a clear relation to dosing and/or are within the biological range of varation.
The finding "Sternebrae bipartite, ossification centers dislocated" is outside the historical control range. However, if the overall rate of fetuses/litter with skeletal malformations is taken into account, it can be seen, that no dose-response relationship exists and that the values are fully within the historical control range. Therefore, the increased rate of high dose feutses showing this malformation - as the only statisical significant deviation concerning fetal skeletal malformations- is considered coincidental and not biologically significant.

The skeletal variations elicited were found in all groups without any relation to dosing. The differences observed in comparison to the control retuses were without statistical significance and/or are fully in the historical control range.

In all groups signs of skeletal retardations were without any biological relevance (no relation to dosing, values ar fully in the range of the historical control values)

Effect levels (fetuses)

Dose descriptor:
Effect level:
>= 1 060 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1.: Mean maternal food consumption during gestation


Low dose

Mid dose

High dose


g/animal/day (S.D.)


22.9 (1.47)

22.7 (1.76)

23.2 (1.39)

23.4 (1.85)


24.4 (2.69)

24.6 (2.78)

24.5 (2.00)

16.6 (3.52) (a)


24.5 (2.44)

24.9 (3.06)

25.0 (1.93)

19.6 (3.88) (a)


25.0 (2.42)

24.7 (2.78)

24.2 (2.46)

13.5 (7.08) (a)


24.9 (1.95)

24.9 (3.43)

24.7 (1.99)

15.6 (4.53) (a)


24.7 (2.75)

25.3 (2.54)

24.8 (2.52)

15.5 (4.96) (a)


26.5 (2.31)

25.7 (2.67)

25.8 (2.25)

20.0 (4.97) (a)


26.9 (2.79)

27.0 (2.89)

26.2 (2.62)

21.8 (3.87) (a)


27.4 (2.97)

26.8 (3.21)

26.6 (2.51)

20.9 (4.90) (a)


27.6 (2.47)

27.0 (3.26)

27.6 (2.51)

23.9 (3.16) (a)


28.6 (2.95)

28.5 (3.50)

28.2 (2.68)

25.0 (3.14) (a)


29.1 (2.24)

28.9 (3.10)

30.2 (2.50)

32.8 (4.55) (a)


29.9 (2.56)

29.6 (3.46)

28.7 (2.70)

32.1 (3.32) (b)


29.7 (2.49)

29.3 (3.00)

29.6 (2.62)

33.0 (3.86) (a)


28.0 (2.69)

28.1 (3.63)

28.0 (2.87)

30.8 (3.59) (b)

(a) p = 0.01

(b) p = 0.05

Table2.: Mean maternal body weights during gestation


Low dose

Mid dose

High dose


g/animal/day (S.D.)


247.9 (11.38)

247.2 (12.81)

249.8 (10.48)

248.2 (12.48)


250.1 (10.77)

248.9 (14.47)

252.6 (10.35)

249.8 (14.00)


259.7 (11.48)

258.3 (15.50)

263.0 (12.19)

261.0 (14.13)


271.6 (12.50)

270.6 (17.82)

274.0 (11.95)

274.4 (16.27)


279.0 (13.54)

277.6 (19.00)

281.2 (12.34)

268.7 (12.60)


288.4 (13.98)

285.3 (20.19)

290.2 (12.61)

265.4 (15.62) (a)


304.5 (15.74)

301.8 (21.31)

304.4 (14.84)

274.1 (16.78) (a)


317.2 (16.77)

313.1 (24.10)

316.4 (17.06)

284.9 (18.79) (a)


338.1 (18.89)

333.9 (27.50)

339.4 (21.25)

313.3 (22.01) (a)


383.0 (24.65)


381.5 (29.14)

365.0 (27.78)

(a) p = 0.01

(b) p = 0.05

Table 3: Mean maternal body weight change during gestation


Low dose

Mid dose

High dose


g/animal/day (S.D.)


23.8 (4.30)

23.3 (6.84)

24.2 (6.31)

26.1 (6.18)


45.5 (6.39)

42.6 (8.67)

42.4 (7.88)

10.6 (8.03) (a)


65.8 (11.26)

63.9 (18.92)

65.1 (16.38)

80.1 (14.53) (a)


135.1 (17.75)

129.9 (29.78)

131.7 (25.24)

116.7 (18.89) (b)

(a) p = 0.01

(b) p = 0.05

Table 4: Mean gravid uterine weights and net maternal body weight change


Low dose

Mid dose

High dose

G (S.D.)

Gravid uterus

70.5 (13.17)

67.0 (24.25)

69.5 (22.95)

71.2 (14.23)


312.5 (17.98)

310.1 (25.42)

312.1 (16.00)

293.8 (19.90) (a)

Net weight change from day 6

40.9 (8.10)

39.5 (10.37)

38.0 (7.02)

19.4 (8.00) (a)

(a) p = 0.01

(b) p = 0.05

Table 5: Mean placental weights


Low dose

Mid dose

High dose

G (S.D.)

Off all viable fetuses

0.42 (0.029)

0.45 (0.048)

0.44 (0.075)

0.39 (0.045) (b)

Of male fetuses

0.4 (0.037)

0.46 (0.056)

0.44 (0.077)

0.39 (0.044) (b)

Of female fetuses

0.42 (0.031)

0.43 (0.037)

0.41 (0.030)

0.38 (0.048) (a)

(a) p = 0.01

(b) p = 0.05

Table 6: Fetal and litter incidences and mean percentages of affected fetuses/litter for one skeletal malformation (sternebra(e) bipartite, ossification centres dislocated) and total skeletal malformations


Actual fetal incidence (%)

Historical incidence (mean (min – max) %)

Acutal litter incidence (%)

Historical  litter incidence (mean (min – max) %)

Affected fetuses/litter – actual study (mean %)

Affected fetuses/litter – historical control range (mean (min – max) %)

sternebra(e) bipartite, ossification centres dislocated



0.3 (0.0-1.8)




0.6 (0.0-1.9)













Total fetal skeletal malformation



4.4 (0.6-10.1)


24.6 (4.3-43.5)


4.4 (0.5-8.7)













Applicant's summary and conclusion

Executive summary:

Melamine was tested for its prenatal toxicity in Wistar rats. The test substance was administered as a constant homogeneous addition to the food to 23 – 24 pregnant female Wistar rats/group at concentrations of 1,500 ; 4,500 and 15,000 ppm on day 6 through day 16 post coitum (p.c.). The control group, consisting of 23 dams, was dosed with the food only. Food consumption and body weights of the animals were recorded regularly throughout the study period.The state of health of the animals was checked each day. On day 20 post coitum, all females were sacrificed and assessed by gross pathology (including weight determination of the terminal body weight, the unopened uterus, the liver and the kidneys). The fetuses were removed from the uterus, sexed, weighed and further investigated for any external, soft tissue and/or skeletal findings. The following findings were obtained and assessed as substance-related: 

Test group 3 (15000ppm = about 1060 mg/kgbody weight/day):

-statistically significantly decreased food consumption between days 6 and 16 p.c. (about 26% less than the concurrent control group )

-statistically significantly reduced body weights from day 10 to day 17 p .c .

-statistically significant body weight loss between days 6-10 p.c. and significantly decreased bodyweight gain between days 10 and 15 p.c.

-statistically significantly lower carcass weight and decreased corrected body weight gain (about53 % less than in the concurrent control group )

-hematuria in nearly all and indrawn flanks in 7 out of 25 animals between days 8 and 17 p.c.; piloerection in one female between days 8 and 15 p.c.

Test group 2 (4500ppm = about 400 mg/kg body weight/day):

-no substance-related effects on dams, gestational parameters or fetuses.

Test group 1 (1500ppm= about 136 mg/kg body weight/day) :

-no substance-related effects on dams, gestational parameters or fetuses.


Thus, under the conditions of this study, the administration of MELAMINE to pregnant female Wistar rats during organogenesis elicited signs of maternal toxicity at 15000 ppm, but induced no substance related effects in the dams at 1500 or 4500 ppm. Maternal toxicity was substantiated in this full scale prenatal toxicity study by reduced food consumption, impairments in body weight / body weight gain, decreased corrected body weight gain and clinical symptoms like hematuria, indrawn flanks and piloerection at 15000 ppm (about 1060 mg/kg body weight/day) .

Nearly all signs of maternal toxicity proved to be fully reversible after cessation of the test substance administration. The carcass weight and the corrected body weight gain, however, showed still some impairments at terminal sacrifice .

There were no substance-related findings on the gestational parameters and no signs of developmental toxicity up to and including the highest dose level (15000ppm). Especially no indications of teratogenicity were found.

Based on the results of this full-scale prenatal toxicity study in Wistar rats, the no observed adverse effect level (NOAEL) for the dams is 4500 ppm(about 400 mg/kg body weight/day), but 15000 ppm (about 1060 mg/kg body weight/day) for the fetal organism.

Justification for using the oral route:

The chosen oral route in this study is considered to be appropriate, even if it is not the most likely route of human exposure. Justifications are: There is apparently no metabolism of melamine in the organism and by this no first pass effect. A rapid and near to complete absorption was found after the oral route in rats. The same can be assumed for the inhalation route, whereas a low dermal absorption was estimated for melamine. Effects after oral exposure can stand therefore for effects after inhalation exposure and are on the worst case side of effects after dermal exposure.

It is therefore justified to estimate the possible toxic effects after inhalation or dermal exposure, based on the outcome of the oral experiments.