Hydroxy(2-methylprop-2-enoato-O)zinc

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: The study was performed according to the Annex VB.29, 67/548/EEC with some minor restrictions (the list of serum chemistry parameters was limited, i.e. there were no parameters of protein metabolism. Adrenals were not weighed)

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

Methacrylic acid

Author:

EU

Year:

2002

Bibliographic source:

Risk assessment report, 1st priority list, Volume 25

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1984

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methacrylic acid

EC Number:

201-204-4

EC Name:

Methacrylic acid

Cas Number:

79-41-4

IUPAC Name:

methacrylic acid

Details on test material:

methacrylic acid (purity > 99%)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Sprague-Dawley rats, Fischer-344 rats and B6C3F1-mice

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

6 hours/day and 5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
20, 100, and 300 ppm (equivalent to 0.0714, 0.357, and 1.071 mg/L)
Basis:
nominal conc.

No. of animals per sex per dose:

10

Control animals:

yes, sham-exposed

Details on study design:

Each dose and control group consisted of 10 males and 10 females. Additionally, 10 animals per sex/group were exposed for 4 days and killed on day 5

Positive control:

None

Results and discussion

Results of examinations

Details on results:

No exposure-related death was recorded. After 90 days of exposure high-dose animals had reduced body weight gains (-10%) and food consumption (-9%) (male F-344 rats) or reduced body weight gains (both sexes of B6C3F1-mice -11% in males, (-12% in females). Reduced leukocyte counts and an increased activity of alkaline phosphatase were observed in female high-dose mice. An increased level of BUN was seen in high-dose males of F-344 rats. In both rat strains reduced absolute liver weights were found in high-dose males, as well as in both sexes of high-dose B6C3F1-mice. The liver/body weight ratio was comparable to that of the controls, only after adjustment to the brain weight a significant decrease of relative liver weight
was obvious. In mice, the liver/body weight ratio was lower in high-dose mice of both sexes (significant only in males), the liver/brain weight ratio was significantly higher in high-dose males and significantly lower in high-dose female mice.
Microscopically, all treatment groups of both rat strains and mice of the high-dose group showed a rhinitis of the anterior regions of the turbinates. The incidences in rats showed no clear dose relationship. The high-dose rats had a more severe inflammation than the other groups. A low-grade rhinitis almost without additional lesions was also evident in some of the control rats (not seen in mice). At high-dose level the incidence of rhinitis was increased compared to control rats; in some of the treated rats rhinitis was accompanied by ulceration, epithelial hyperplasia and vesiculation, goblet cell hyperplasia, and exudation of the respiratory epithelium. Ulceration of the anterior part of the nose was also observed in some high-dose male and female mice. A degeneration of olfactory epithelium of the mid part of the nasal cavity was observed in mice at mid- and high-dose level, but not in the rat nose. The lesion consisted of intracellular accumulation of an orange-pink material in the cytoplasm of ciliated cells (eosinophilic globules) which appeared to be the sustencular cells lining the middle portions of the septum and dorso-medioal aspects of the dorsal scroll of the nasal turbinates in histological sections at level B and C. In severe cases this material filled the cell, displaced the nucleus or in most severely affected areas epithelial cells dropped out. In all treated Sprague-Dawley groups increased lymphocytic infiltrations in the larynx were found in both sexes, in males a higher incidence of focal aggregates of lymphocytes in the lung periphery was seen (both findings showed no clear dose relation). Outside the upper respiratory tract, lymphocytic hyperplasia of mandibular lymph nodes were more frequent in high-dose animals of both rat strains compared to controls. The kidneys of male high-dose mice showed cytomegaly of tubular epithelium. Other findings showed no relationship
to treatment. After interim sacrifice on day 5 satellite animals of each strain showed acute inflammation and, in mice, necrosis of the anterior respiratory epithelium of the turbinates similar to the findings reported after 90 days. Food consumption (-16% in males, - 14% in females), body weight gain (-30% in males, -38% in females) and lower final mean body weights (-5% in males and -6% in females, non significant) were reduced in high-dose F344 rats. At this time, high-dose mice also presented lower final mean body weights (-8% in males, -7% in females) and high-dose males of
the SD strain showed a reduction of food consumption of 13%.

Effect levels

1

Dose descriptor:

NOAEC

Remarks:

for rats

Effect level:

300 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

NOAEC

Remarks:

for mice

Effect level:

100 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: lower body weight gains at the high dose (300 ppm) were not associated to a reduction of food consumption

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Conclusively, the high dose of 300 ppm (1.071 mg/l) represented the NOAEC for systemic effects in rats. In mice, lower body weight gains at the high dose (300 ppm) were not associated to a reduction of food consumption, so that 100 ppm (0.357 mg/l) was the NOAEC for systemic effects. The decrease of absolute liver weights was not considered to represent a clear adverse effect because of the lack of corresponding findings (clinical pathology and histopathology). For explanation, reduction of the absolute weights may be related to lower final body weight as liver/body weight ratio was normal in rats and not conclusive in mice. Similarly, the higher incidence of lymphocytic hyperplasia in the mandibular lymph nodes of male rats was not considered to be a clear adverse effect. More likely this effect can be interpreted to be related to the inflammatory changes of the upper and lower respiratory tract and to the assumption that minimum traces of methacrylic acid were swallowed.

Executive summary:

In a valid 90-day inhalation study, Sprague-Dawley rats, Fischer-344 rats and B6C3F1-mice were exposed (whole body exposure) to 20, 100, and 300 ppm (equivalent to 0.0714, 0.357, and 1.071 mg/l) of methacrylic acid (purity > 99%) on 6 hours/day and 5 days/week. Each dose and control group consisted of 10 males and 10 females. Additionally, 10 animals per sex/group were exposed for 4 days and killed on day 5.

Conclusively, the high dose of 300 ppm (1.071 mg/l) represented the NOAEC for systemic effects in rats. In mice, lower body weight gains at the high dose (300 ppm) were not associated to a reduction of food consumption, so that 100 ppm (0.357 mg/l) was the NOAEC for systemic effects. The decrease of absolute liver weights was not considered to represent a clear adverse effect because of the lack of corresponding findings (clinical pathology and histopathology). For explanation, reduction of the absolute weights may be related to lower final body weight as liver/body weight ratio was normal in rats and not conclusive in mice. Similarly, the higher incidence of lymphocytic hyperplasia in the mandibular lymph nodes of male rats was not considered to be a clear adverse effect. More likely this effect can be interpreted to be related to the inflammatory changes of the upper and lower respiratory tract and to the assumption that minimum traces of methacrylic acid were swallowed.