Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methacrylate

Endpoint summary

Description of key information

IBOMA

OECD 421, GLP, rat, oral: NOAEL systemic toxicity 25 mg/kg bw/day (based on liver and kidney findings)

Metabolite data

MMA (metabolite donor for MAA)

2 yrs, rat, drinking water: NOAEL 2000 ppm (no adverse effects found)

NTP, 2 yrs, rat, inhalation: NOAEC systemic toxicity 500 ppm; LOAEC local toxicity 250 ppm

MAA

OECD 413, GLP, 90 d, rat, inhalation: NOAEC systemic & local toxicity 100 ppm

IBOAc (metabolite donor for IBO)

OECD 408, 90 d, rat, oral gavage: NOAEL systemic 15 mg/kg bw/day (based on liver and kidney findings)

In conclusion, the overall database does not justify a classification of isobornyl methacrylate as dangerous to human health with respect to specific target organ toxicity at repeated exposure.

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:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Read across to the alcohol metabolite:

According to RAAF 2019, the analogue read-across approach, Scenario 1: “read-across based on (bio)transformation to common compound(s)” has been identified as appropriate in order to fulfill the data gap.

Thus, the information requirement (according to REACH Regulation Annex IX) is covered with read across to the methacrylic metabolites.

For detailed information and justification please refer to the attached Read across Justification Document: “Read across assessment according to ECHA’s Read Across Assessment Framework (RAAF)”.

Reason / purpose for cross-reference:

read-across source

Frequency of treatment:

daily

Dose descriptor:

NOAEL

Effect level:

90 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: males appear to be more sensitive

Critical effects observed:

yes

Lowest effective dose / conc.:

270 mg/kg bw/day (nominal)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

no

Conclusions:

In a subchronic oral gavage study with rats the NOAEL of Isobornyl acetate was found to be 15 mg/kg/d based on nephrotoxic effects at doses of 270 and 90 mg/kg/d.

For IBOMA, IBOAc serves as metabolite donor substance of the isobornyl moiety of IBOMA (see Read Across Document). From this study the adverse effect levels and potential target organs of IBOAc can be concluded. For read across purposes according to ECHA's RAAF (2017), this study is applicable with a high level of confidence.

Executive summary:

Isobornyl acetate dissolved in corn oil was administered daily to rats by stomach tube in doses of 0 (control), 15, 90 or 270 mg/kg body weight/day for 13 wk. There were no differences between treated and control animals in the rate of body-weight gain, the food intake or the results of haematological investigations. In male rats given 270 mg/kg/day there was a decrease in renal concentrating ability, an increase in water intake, exfoliation of renal tubular cells, increased kidney weight and vacuolation of the renal tubular cells. Signs of nephrotoxicity were also seen with daily doses of 90 mg/kg. Vacuolation of the epithelium of the intrahepatic bile-duct and an increase in liver weights were found at 270 mg/kg. The caeca were also enlarged at this dosage level.

The NOAEL was found to be 90 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

17 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Organ:

bile duct

liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Short-term repeated dose toxicity of IBOMA has been investigated in OECD 421 combined reproductive/ developmental toxicity study. Subchronic studies with IBOMA are available for rats and dogs, however due to the low detail level of these pre-guideline feeding studies they function only as supportive studies in this assessment.

IBOMA is rapidly hydrolized by non-specific carboxylesterases to MMA and IBO (see chapter “Toxicokinetics”) so that the systemic toxicity of the parent ester can be assessed with information from the metabolites and their donor substances (i.e. MMA for MAA and IBOAc for IBO). Here, the systemic repeated dose toxicity of the primary metabolite MAA is assessed byan oral (drinking water) study and an inhalation study of chronic duration from MMA as metabolite donor substance for MAA.From MAA as such, a 90 day inhalation study was selected to assess systemic and local toxicity. The repeated dose toxicity of the primary metabolite IBO is assessed by a subchronic study with IBOAc.

 

IBOMA

In a reproduction/developmental toxicity screening study according to OECD 421 and GLP requirements, Sprague-Dawley rats (10 male and 10 females per dose group) received IBOMA by daily oral (gavage) administration for 15 days before mating, through mating, gestation and the beginning of the lactation period (until day 5 post-partum, p.p.). The dose-levels were 25, 100 and 500 mg/kg/day. Another group of 10 males and 10 females received the vehicle, corn oil, alone, under the same experimental conditions and acted as a control group. The dosing volume was 5 mL/kg.

Based on the experimental conditions of the reproductive/developmental toxicity screening study the NOAEL for parental toxcitity was 25 mg/kg bw/day (based on liver and kidney findings) and the reproductive NOAEL was 500 mg/kg bw/day.

The minimal hepatocellular degeneration in 1/10 males and the minimal bilary proliferation/ hypertrophy in 3/10 animals observed in the 100 mg/kg dose group are not considered as clear signs of toxicity. The increase in acidophilic globules in the 100 and 500 mg/kg male dose groups is considered to be related to micro-2µ-globulin which is rat specific and therefore not relevant to human hazard assessment.

 

MMA (metabolite donor substance of MAA)

In an early 2-year chronic drinking water study with 25 male and 25 female rats administered 6, 60 and 2000 ppm MMA no adverse effects were observed other than elevated kidney weights without corresponding findings in histopathology in female rats at 2000 ppm (Borzelleca et al., 1964). The NOAEC was reported as 2000 ppm in female and male rats (corresponding to 164 and 124 mg/kg bw/d, respectively).

The US National Toxicology Program conducted a series of repeat-exposure inhalation toxicity studies of increasing duration 14 weeks and 104 weeks in male and female rats and mice. (Battelle Pacific Northwest Lab., 1980 and NTP; 1986). In the two-year study reduced mean body weights in female rats was observed at 500 ppm (2080 mg/m3) after week 73 but this was likely a consequence of the local nasal lesion and effects on smell and behaviour/appetite rather than any other systemic organ toxicity. The NOAEC for this effect was 250 ppm (1040 mg/m3) in females. After a 14-week inhalation, mice had cellular necrosis in liver and renal cortices > ca. 8.2 mg/L (2,000 ppm) and rats showed splenic follicular atrophy and bone marrow atrophy at ca. 20.8 mg/L (5,000 ppm; Battelle 1980). Malacia and gliosis of the brain in the 14 week range finder to the NTP study (Battelle, 1980) is considered being the relevant systemic effect, which was seen in 5/9 female rats exposed at 2000 ppm and 1/8 females at 1000 ppm. Therefore, the absence of this effect at 500 ppm (2028 mg/m³) in the corresponding 2-year study (NTP) is considered representing the NOAEC for chronic systemic effects of MMA.

 

MAA (methacrylic metabolite)

In an OECD 413, 90-day vapour inhalation study in Sprague Dawley rats with MAA revealed general toxicity at 350 ppm (1253 mg/m3) in male animals (BASF 2008). Local, marginal irritation of the respiratory epithelium in the nasal cavity was observed in two female animals. No changes in sexual organs or sperm mobility and sperm head counts were noted. The NOAEC was 100 ppm (358 mg/m3) for local irritation effects in male and females The NOAEC for systemic effects based upon reduced body weight gain in the presence of reduced feed intake but no other systemic effects was also 100 ppm (358 mg/m3) in male and females.

 

IBOAc (metabolite donor substance of IBO)

In a 13-week study similar to OECD TG 408,“IBOAc dissolved in corn oil was administered daily to rats by stomach tube in doses of 0 (control), 15, 90 or 270 mg/kg body weight/day for 13 wk. There were no differences between treated and control animals in the rate of body-weight gain, the food intake or the results of haematological investigations. In male rats given 270 mg/kg/day there was a decrease in renal concentrating ability, an increase in water intake, exfoliation of renal tubular cells, increased kidney weight and vacuolation of the renal tubular cells. Signs of nephrotoxicity (increased cell excretion) were also seen with daily doses of 90 mg/kg. Vacuolation of the epithelium of the intrahepatic bile-duct and an increase in liver weights were found at 270 mg/kg. The caeca were also enlarged at this dosage level. The NOAEL found was 15 mg/kg/day” (Gaunt Consuelo et al. 1970). The NOAEL of 15 mg/kg was converted to 17 mg/kg bw based on the molecular ratio of IBoAC and IBoMA. 

 

 

In conclusion, the overall database does not justify a classification of isobornyl methacrylate as dangerous to human health with respect to specific target organ toxicity at repeated exposure.

 

Read across assessment according to ECHA’s Read Across Assessment Framework (RAAF)

Repeated dose toxicity of IBOMA has been investigated in a reliable OECD 421 combined reproductive/ developmental toxicity study. Further subchronic studies with IBOMA are available, however due to their low detail level they function only as supportive studies in this assessment.Potential data gaps are covered using the read across approach mentioned in chapter1considering the ECHA guidance on Read Across (RAAF, ECHA 2017a). For this endpoint, the common metabolic pathway of the read across substances (rapid hydrolysis of IBOMA by ester cleavage, leading to the primary metabolites MAA and IBO) is considered as most relevant aspect of the read across approach. Consequently, the relatively short half-life demonstrated on IBOMA as parent ester leads to the conclusion that systemic effects after repeated exposure are mainly driven by the products of ester hydrolysis, namely MAA and IBO. Local effects after inhalation are determined by local release of MAA. MMAand IBOAc are known to hydrolyse also rapidly so that these substances serve as donor substances for the primary metabolites MAA and IBO.

Qualitatively, this aspect can be categorized as “(Bio) transformation to common compound(s)” (RAAF scenario #1). The read across approach is done with a high level of confidence.

Justification for classification or non-classification

According to the criteria as of directive 1272/2008/EC, no classification is warranted.