Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
adopted according to OECD SIDS, peer reviewed data
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Duration of treatment / exposure:
90 d
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 3, 10 or 30 mg/kg bw/day dissolved in corn oil
Basis:

Control animals:
yes
Details on study design:
Post-exposure period: no data
Statistics:
Dunnett's and Bartlett's test,modified Mann-Witney test(Bonferroni inequality), Kolmogorov-Smirnov one-tailed test
Dose descriptor:
LOAEL
Effect level:
ca. 3 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:  increased methemoglobin levels
Critical effects observed:
not specified

one control female died due to physical trauma during dosing.

clinical observation: 30 mg-group, males and females, 10 mg-group, females: general paleness immediately after dosing, no statistically significant differences in body weight gain when compared to control rats, food consumption was sign. higher: females: mid dose, 1 of 13 w, high dose, 5 of 13 w, males: mid dose, 9 of 13 w, high dose, 10 of 13 w hematological changes:  significant increased methemoglobin levels at 3, 10, 30 mg/kg bw: male/female: day 45: 4.2/4.6, 7.8/9.2, 15.0/18.1 %, resp., versus 0.5/0.9 % of controls and day 90: 4.5/4.9, 9.0/9.8, 14.2/18.2 % resp., versus 0.9/1.0 % in controls;
dose-related increase in WBC in males and females (d 45): up to 44.21 % versus 11.67 %(control), (d 90): up to 12.95 %
(control 10.24 %); dose related increase in reticulocyte count in males and females: (d 90): up to 39.8 % versus 0.6
% in controls, and in MCV, MCH values in males and females; significant dose related decrease in erythrocyte count
(d45): up to 5.51 versus 8.49 (control),(d 90): up to 5.58  versus 9.07 in controls, in HGB up to 14.45 % versus 18.78 %
in controls and in HCT, and MCHC values in males and females clinical chemistry: total protein sign. reduced with increasing dosing d45: females 10 and 30 mg/kg bw; d90: males 10 and 30 mg/kg bw 
and SGPT reduced: males 30 mg/kg bw

urinalysis: At week 13 (= d 90) qualitative increases in levels of
urinary urobilinogen were found in all male and female rats receiving TS.
gross and histopathology:
spleen:  (both sexes, all dosages, dose dependent in incidence and severity): abnormal coloration, enlargement 
increased relative and/or absolute spleen weights, excessive hemosiderin, excessive hemopoiesis, congestion,
vacuolization of the congested red pulp liver: male and female, 30 mg: enlargement, hemosiderosis
and excessive hemopoiesis kidneys: both sexes, dose-dependent: discoloration,
enlargement, hemosiderosis in kidney tubules 30 mg-group: enlargement of the hearts in females, in both
sexes: hyperplasia of bone marrow

Endpoint conclusion
Dose descriptor:
LOAEL
3 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
other information
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study
GLP compliance:
yes
Species:
rat
Strain:
other: F344/N
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Duration of treatment / exposure:
13 w
Frequency of treatment:
6 h/d, 5 d/w
Remarks:
Doses / Concentrations:
0, 1.5, 3, 6, 12 or 24 ppm (= ca. 0.0, 9.81, 19.62, 39.24, 78.48 or 156.96 mg/m³ air)
Basis:

No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: no
Statistics:
Parametric multiple comparisons procedures of Williams or Dunnett, nonparametric multiple comparisons methods of Shirley or Dunn, Jonckheere's test or trend-sensitive test, outlier test of Dixon and Massey
Dose descriptor:
LOAEC
Effect level:
ca. 9.81 mg/m³ air
Sex:
male/female
Basis for effect level:
other: haematology (MetHb formation, Heinz bodies)
Critical effects observed:
not specified

no clear clinical signs of toxicity,
no rat died, 3 ppm-gr.: 1 female killed moribund due to
malocclusion,
mean body weight gain similar to those of the respective
controls. 
haematology, male(m) and female(f):
concentration-related increase in methaemoglobinaemia (m:
significant (sign.) from 1.5 ppm at day(d)3 at all time
points with max. of 4.13 g/dl at d3 in 24 ppm-gr; f: sign.
from 1.5 ppm at d3 at all time points with max. of 5.90 g/dl
at d3 in 24 ppm-gr), reticulocyte count (m: sign. d3: 1.5
and 24 ppm, d23 >= 6 ppm, week(w)13 >= 1.5 ppm; f: sign. d3
24 ppm, d23 >= 3 ppm, w13 >= 3 ppm), nucleated erythrocytes
and leucocyte count (predominantly at the highest dose
groups in males and females);
concentration-related decrease in haematocrit, haemoglobin
and RBC at all time points; concentration and time-dependent
alterations of  RBC morphology, severity decreased with
decreasing concentration. RBC indices (MCV, MCH, MCHC) were
increased in males and females exposed to 12 ppm and above
at d23  and exposed to 6 ppm and above at w13. MCV and MCHc
were increased  in females exposed to 1.5 ppm and above at
w13, MCHC in males and females exposed to 24 ppm at d3
clinical chemistry, males and females:
Changes in alanine aminotransferase (decrease), sorbitol
dehydrogenase (increase) and alkaline phospatase activities
(decrease)
bile acid levels increase (m: >=3 ppm, all almost every time
points, f:>=6 ppm d3, d23 >=12 ppm). Increase in serum
activities of sorbitol dehydrogenase in various exposure
groups at different time points
pathology:
increase in abs. and rel. spleen weight (m >=3 ppm, f >=6
ppm), liver weight (m: 24 ppm, f >=6 ppm), kidney (m and f:
24 ppm), decrease in abs. and rel. testes weight (24 ppm); 
incidence of enlarged and darkened spleens in male and
female rats increased with increasing concentrations; 12, 24
ppm: kidneys darkened (female only), mediastinal lymph nodes
enlarged (males and females)
histopathology:
Increasing in severity (average severity is based on the
number of animals with lesions: 1=minimal, 2=mild,
3=moderate, 4=marked) and incidences with increasing
concentration (contr., low to high dose): bone marrow:
haematopoietic cell proliferation (m: = 0/10,
0/3/10/10/10(2.8), f: 0/10, 0/9/10/10/10(3.8)) hadrian
gland: chronic inflammation (m: 2(1), 1/1/3/1/8(2.2), f:
1/10(1.0), 2/4/5/8/10(3.0)), kidney: hyaline droplet
nephropathy (m: 0/10, 8/9/10/10/10(3.0)) and tubule pigment
(m: 0/10, 0/0/0/8/10(1.0), f: 0/10, 0/0/10/10/10(3.0))
liver: haemosiderin (m: 0/10, 0/0/0/9/10(1.0), f: 0/10,
0/7/10/10/10(2.4)), mediastinal lymph nodes: histiocytic
hyperplasia (m: 0/10, 0/0/0/4/9(2.3), f: 0/10,
0/0/0/6/10(2.7)), spleen: congestion (m:0,
10/10/10/10/10(3.0), f: 0/10, 10/10/10/10/10(3.0)),
haemosiderin (m:0/10, 10/10/10/10/10(1.0), f: 3/10(1.0),
10/9/10/10/10(1.0)) haematopoietic cell proliferation m:
0/10,0/10/9/10/10(1.0)), f: 0/10, 0/9/10/9/10(2.0)) capsular
fibrosis (m: 0/10, 0/4/8/10/10(2.1), f: 0/10,
0/2/10/10/10(2.3)), testis atrophy (m: 1/10(4.0),
2/1/0/1/10(1.6))

Endpoint conclusion
Dose descriptor:
LOAEC
9.81 mg/m³

Additional information

Repeated dose toxicity: via oral route - systemic effects (target organ) 9.81: other

Repeated dose toxicity: inhalation - systemic effects (target organ) cardiovascular / hematological: other

Justification for classification or non-classification

The LOAEC for effects on red blood cells (MetHb formation, haemosiderosis) is 9.81 mg/m³, similar effects were seen after oral dosing at 3 mg/kg bw/day. This justifies classification as STOT RE Cat 1. However, the existing legal classification deviates from this finding and is given in Section 2.

Under DSD, T-R48/23/25 is the appropriate classification based on the available data. However, the existing legal classification is deviant from this finding and is given in Section 2.