Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1983 - 1984
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Very little experimental detail is available. The information is spread over at least three publications. Whole body exposure to a dusty material (secondary exposure from grooming).

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Melaminecyanurate, melamine and cyanuric acid: toxicological characteristics
Author:
Babayan EA and Aleksandrian AV
Year:
1985
Bibliographic source:
Zhurnal Eksperimental Nov Kunicheskoi Meditsiny 25 (4), 345-349
Reference Type:
publication
Title:
Effects of melaminecyanurate on the chromosome apparatus of experimental animals
Author:
Babayan EA, Bagramyan SB, Pogosyan AS and Aleksandryan AV
Year:
1986
Bibliographic source:
Biological Journal of Armenia 39, 381 - 384
Reference Type:
review article or handbook
Title:
Setting permissable levels for melamine cyanurate in the air of the workplace
Author:
Aleksandryan AV
Year:
1984
Bibliographic source:
Aktual. Vopr. Gig. Tr. Profpatol. Prom.-Sti. Sel^sk Khoz. Editor: M. Ya p. 125 - 128

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Four month aerosol inhalation study with rats
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Identified as melamine cyanurate without further details.

Test animals

Species:
rat
Strain:
other: "white rats"
Sex:
not specified
Details on test animals and environmental conditions:
body weight 180 - 230 g

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
Animals were kept in cages of 750 L. A modified sprayer by Shirakov was used to generate the aerosol. The concentrations were determined via a chemical method (no details mentioned).
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
4 months (aborted after 3 month for highest concentration, also interim sacrifices)
Frequency of treatment:
Daily for 4h
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1.15 +/- 0.19 mg/m3
Basis:
no data
Remarks:
Doses / Concentrations:
2.68 +/- 0.21 mg/m3 air
Basis:
no data
Remarks:
Doses / Concentrations:
27.64 +/- 1.34 mg/m3 air
Basis:
no data
No. of animals per sex per dose:
30
Control animals:
yes
Details on study design:
The study was run in two sets.
In the first set, a single concentration of 27.64 mg/m3 air was planned for testing of 120 days. Exposure was stopped after 90 days because of unexpected high mortality. In some of the animals, bone marrow was prepared for cytogenetic investigations. The results are given in the genotoxicity section.
In the second set, 2.68 mg/m3 air were tested for up to 120 days. A treatment-free recovery period is also included, but the duration is not mentioned. Again, part of the animals were used for cytogenetic investigations.
Further procedures are vague. The publication of 1986 mentions effects related to reproductive toxicity, such as an increased embryo mortality, reducted placenta an embryo weight for animals treated with this concentration for 2.5 months.

In the third set, 1.15 mg/m3 was tested for up to 120 days.

Animals were killed after 1, 30, 60, 90 and 120 days after the beginning of the experiment.
Investigated parameters for which average values are reported are: Body weight, oxygen consumption, creatinine in urine, creatinine in blood, protein in urine, chloride in urine, alaninetransaminase, butyrocholinesterase, ceruloplasmin, glucose, thiol-groups, alkaline phosphatase, acidic phosphatase. In addition a "summary threshold value" is assesses, without further specification.
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes, each month

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION: No data



OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: each month
- Anaesthetic used for blood collection: No data
- Animals fasted: No data



CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: every month
- Animals fasted: No data



URINALYSIS: Yes
- Time schedule for collection of urine: every month
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data



NEUROBEHAVIOURAL EXAMINATION: No data


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No data
Statistics:
yes, but type of test not mentioned.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
High dose-group: 27.6 mg/m3:
Severe signs of intoxication and mortality occured after 45 days.
Animals that survived until sacrifice showed reduced body weight and oxygen consumption and an overall indication of severe kidney damage as indicated by effusion of blood in brain accompanied with infiltration. In lungs, vessels were swollen, borderline to stasis. Alveoles showed edema and thickened walls. Bronchial epithelia showed desquamation. Pericellular and perivascular edema was also observed in kidneys. The Schlingen apparaturs appeared inflammed. The tubular epithelium showed protein dystrophy.

Indication of kidney and liver damage was apparent from blood and urine parameters measured at the earliest time point of one month. Creatinine concentration was decreased in urine, but increased in blood. The protein and chloride content in urine increased. Alaninetransaminase concentration was doubled and the content of thiol-groups was increased.

After the second and third month, kidney damage had worsened as indicated by the same parameters as above. Chloride concentration in urine decreased, plasma ceruloplasmine decreased and alkalic and acidic phosphatise doubled.

After 2.5 months, testes weight was reduced, the number of dead spermatocytes increased, sperm motility decreased, overall embryonic mortality increased, the number of implantation sites, placenta weight and embryonic weight decreased. Actual values on the reproductive parameters were not reported.

Cytogenetic damage as indicated by the number of chromosome aberrations in bone marrow cells was evident at the first observation time point (4.7% versus 1.25 in controls) and increased to 6.3 and 8.0% after 60 and 90 days, respectively.


Mid dose-group: 2.68 mg/m3
No clinical signs of intoxication were observed. Blood and urine parameters were less strongly, but similarly effected as described for the high dose group. Some of them normalised during the treatment period. Adverse effects on cytogeneticity, gonadotoxicity or embryotoxicity were not observed. At the end of a non-specified recovery period, all parameters had returned to normal.

Low dose-group: 1.15 mg/m3
No adverse effects were recorded.

Effect levels

Dose descriptor:
NOEC
Effect level:
1.15 mg/m³ air (analytical)
Sex:
not specified
Basis for effect level:
other: Higher concentrations caused kidney toxicity as indicated by clinical parameters for blood and urine. The highest concentration of 27 mg/m3 air caused mortality due to renal failure with the associated secondary effects in other organs.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Inhalation of melamine cyanurate causes severe kidney damage. The NOEL is not reliable since the rat was exposed with the whole body and a significant amount is taken up by grooming. This adds to the overall body burden. Also, systemic uptake after ingestion is favoured by pH-induced hydrolysis in the stomach.
Executive summary:

Inhalation of melamine cyanurate causes severe kidney damage. All other findings observed in this investigation are considered to be secondary effects. The data is consistent with the literature data reporting that melamine and cyanurate form precipitates of melamine cyanurate in the kidney thereby causing renal failure.

The authors of the publication conclude that a safe workplace threshold level is 0.5 mg/m3 air.