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Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: without restriction, with GLP, guideline and individual data
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: US OPPTS 870.5450 (Rodent Dominant Lethal Assay, 1989) and OECD guideline 478
Deviations:
no
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
PL90-810 (1,3,5-triglycidyl isocyanurate, Araldite PT 810), ground to an extremely fine powder
Purity: 98% (Batch-no. 177108, technical grade)

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
Animals were kept in stainless-steel wire-mesh cages, at a temperature of 18-23 °C, a relative humidity of 40-70%, and at a 12-hour dark/light cycle. Food and water was available ad libitum.
Animals introduced into the experiment were 56-60 days (males) or 49-55 days (females) after a acclimatisation period of at least 14 days. Body weigths at experimental start were 27-33 gm (males and 21-25 gm (females).
Quality controls were performed on 5 males/5 females upon arrival of the animals (check for viral antigens and histopathology).

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Males only were exposed to TGIC at 2.5, 10, and 50 mg/m3 air (nominal concentrations) for 6 hrs/day, on 5 consecutive days. (whole body exposure)
TGIC dust generation was achieved with a Auger Dust Feeder (Spring Tool Co., Schoolcraft, MI, USA) with 5 chambers of 1330 litre volume each. Airflow in each chamber was approx. 300 l/min (13-14 air changes/hour). Equilibrium of the dust concentration was reached after 20 minutes.
Air concentration of TGIC was measured gravimetrically, particle size distribution was measured 3 times / exposure session. Animal exposure cages were placed into the exposure chambers
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The measured concentration of TGIC during exposure was on average 1.79 +/- 0.18 mg/m3, 10.3 +/- 0.72 mg/m3, and 49.6 +/-1.97 mg/m3 air, thus being in the range of the nominal concentrations.
The average particle size was 2.84 +/-0.04 μm (2.5 mg/m3), 3.49 +/-0.21 μm (10 mg/m3, and 2.56 +/-0.16 μm (50 mg/m3).
Duration of treatment / exposure:
6 hours / day
5 consecutive days
Frequency of treatment:
5 days
Duration of test:
5 days + 8 weeks mating + 15 days in utero dfev.
Doses / concentrations
Remarks:
Doses / Concentrations:
2.5, 10, and 50 mg/m3 air
Basis:
nominal conc.
1.79 +/- 0.18 mg/m3, 10.3 +/- 0.72 mg/m3, and 49.6 +/-1.97 mg/m3 air, analytical
No. of animals per sex per dose:
30 males
480 females , non-treated
Control animals:
yes
Details on study design:
Males only were exposed to TGIC at 2.5, 10, and 50 mg/m3 air (nominal concentrations) for 6 hrs/day, on 5 consecutive days. (whole body exposure)
TGIC dust generation was achieved with a Auger Dust Feeder (Spring Tool Co., Schoolcraft, MI, USA) with 5 chambers of 1330 litre volume each. Airflow in each chamber was approx. 300 l/min (13-14 air changes/hour). Equilibrium of the dust concentration was reached after 20 minutes.
3) Air concentration of TGIC was measured gravimetrically, particle size distribution was measured 3 times / exposure session. Animal exposure cages were placed into the exposure chambers.
7) Groups of 30 male mice were exposed to either air (negative control), TGIC at 2.5, 10, or 50 mg/m3, or injected with 0.3 mg/kg triethylenemelamine (TEM) via the intra-peritoneal route 48 hours prior to mating (positive control).
8) Body weight was measured in males prior to frisat exposure and after last exposure, as well as weekly therafter until sacrifice. In females bw was not measured.
9) Males were sacrificed after the 8th mating period and testes and the entire respiratory tract, as well as liver, kidney and all reproductive organs were fixed for potential analysis; females were sacrificed on gestastion day 15, and uterus and content were analysed for viable and dead fetuses, early and late resorptions, and non-pregnant females for possible early resorptions.
Statistics:
Statistical analysis was performed on all measured parameters using Levin’s ANOVA test, t-tests, Mann-Whitney U test, Fisher’s exact test, with ptobabilit yvalues of 0.05 (two-tailed).

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
ca. 10 mg/m³ air (nominal)
Sex:
male
Basis for effect level:
other: for toxixity, no dominant-lethal effects observed
Dose descriptor:
NOEC
Effect level:
ca. 2.5 mg/m³ air (nominal)
Sex:
male
Basis for effect level:
other: fertility

Observed effects

The measured concentration of TGIC during exposure was on average 1.79 +/- 0.18 mg/m3, 10.3 +/- 0.72 mg/m3, and 49.6 +/-1.97 mg/m3 air, thus being in the range of the nominal concentrations.
The average particle size was 2.84 +/-0.04 μm (2.5 mg/m3), 3.49 +/-0.21 μm (10 mg/m3, and 2.56 +/-0.16 μm (50 mg/m3).
Clinical signs were observed mainly at 50 mg/m3 air and were restricted to ocular discharge and opacity of the eyes, as well as mortality 10% at 50 mg/m3 (days 5-6), and 1/30 at each of 2.5 mg/m3 and 10 mg/m3 (on days 45/48).
Transient body weight reduction were observed mainly at 50 mg/m3 between days 4-19, but at terminal sacrifice, group means were comparable. No exposure-related gross findings were observed at necropsy.
TEM caused significantly reduced total and viable implants, increased dead implants and increased early resorption during the first 3 mating periods of each one week, indicating that TEM affected spermiogenesis, but not meiosis or mitosis.
TGIC had no significant effect on fetal parameters over the entire 8 mating periods, but caused reduced male and female mating rates during the first three mating periods, and reduced female mating rat during mating period 6. At 10 mg/m3 reduced number of of mated and fertilised females was observed during mating period 3, only.
Effects observed at 50 mg/m3 on exposed males were on maturing spermatids, but not on the spermatocyte stages. The toxic effects observed during mating period 6 asre related to type B spermatogonia.
No dominant-lethal effects have been observed upon TGIC exposure

Any other information on results incl. tables

No Dominant-Lethal Effects was observed, but reduced fertility of males exposed to 50 mg/m3 air TGIC was recorded. 50 mg/m3 air exceeded the MTD, as 3/30 males died during the first mating period.

Applicant's summary and conclusion

Conclusions:
No dominant-lethal effect was associated with TGIC-inhalation in mice, but reduced fertility was observed during the first three mating periods (= 3 weeks following exposure). NOAEL for toxicity is 10 mg/m3 air, NOEL for fertility is 2.5 mg/m3
TGIC had no significant effect on fetal parameters over the entire 8 mating periods, but caused reduced male and female mating rates during the first three mating periods, and reduced female mating rat during mating period 6. At 10 mg/m3 reduced number of of mated and fertilised females was observed during mating period 3, only.
Executive summary:

No dominant-lethal effect was associated with TGIC-inhalation in mice, but reduced fertility was observed during the first three mating periods (= 3 weeks following exposure). NOAEL for toxicity is 10 mg/m3 air, NOEL for fertility is 2.5 mg/m3

TGIC had no significant effect on fetal parameters over the entire 8 mating periods, but caused reduced male and female mating rates during the first three mating periods, and reduced female mating rat during mating period 6. At 10 mg/m3 reduced number of of mated and fertilised females was observed during mating period 3, only.